Pakistan Journal of Neurological Sciences (PJNS)

Volume 10 | Issue 3 Article 10

12-2015 Is oral lornoxicam effective in the treatment of acute migraine attacks? : a randomized-controlled study Murat Cabalar Cabalar Dr.SadiKonuk Training and Research Hospital, stanbul.

Selcuk Dincer istanbul University Medicine Faculty, Istanbul

Suleyman Ozyalcin , istanbul University Medicine Faculty, Istanbul

Follow this and additional works at: http://ecommons.aku.edu/pjns Part of the Neurology Commons

Recommended Citation Cabalar, Murat Cabalar; Dincer, Selcuk; and Ozyalcin, Suleyman (2015) "Is oral lornoxicam effective in the treatment of acute migraine attacks? : a randomized-controlled study," Pakistan Journal of Neurological Sciences (PJNS): Vol. 10 : Iss. 3 , Article 10. Available at: http://ecommons.aku.edu/pjns/vol10/iss3/10 observed. But these studies were of small sample size imbalance, prolonged prothrombin time were treated and shorter follow ups.11 Another meta-analysis done accordingly. Performa was completed for each patient on three studies showed that LOLA therapy causes to record demographics, vitals, complete blood counts, decrease in serum ammonia levels, and also clinical liver function tests, prothrombin time, total proteins, improvement.12 Moreover most of the available data electrolytes, serum ammonia, random blood glucose assessed role of LOLA in minimal encephalopathy, not and renal status. In addition, ultra-sound of the whole the over encephalopathy. In the review of local data, abdomen was also done, to assess the size of liver, there are only two authentic large trials available.13,14 spleen and portal vein. Trial-Treatment group received a Therefore due to absence of large studies, controversial daily intravenous infusion of 20 g (4 ampoules) existing data and paucity of local data, we conducted a L-Ornithine L-Aspartate (Inj HepaMerz, Brooks pharma) study to observe effect of LOLA on clinical improvement diluted in 250 ml of 5% dextrose water administered in most stages of hepatic encephalopathy. slowly over 4 hours for three consecutive days. The Placebo group received a daily administration of 250 ml MATERIAL & METHOD normal saline over 4 hours for three consecutive days. It was ensured that the infusions were given at the After approval of Ethical review committee of Jinnah same specified time to both groups of patients. About 5 Medical and Dental College, a randomized, placebo- ml of blood of each patient was drawn on Day 1 and control trial was performed in medical department of Day 3 under aseptic techniques, stored in rubber Jinnah medical and dental college Hospital Korangi corked glass tubes for checking ammonia levels. The Karachi from July 2013 to June 2014. The trial was Tubes were frozen at 4 degrees centigrade temperature. designed and reported according to CONSORT The ammonia determination was performed according guidelines.15 An informed consent was taken before to the enzymatic determination of ammonia with entry in the trial. Data was collected by Interns and glutamine dehydrogenase in a rapid and interference – residents of the ward, who were trained by the authors free photomertric determination of NH4+ in native for this study through workshops and meetings. blood plasma. The testing was performed at a reliable Patients > 18 years of age, admitted in medical ward, laboratory of Karachi. Sample on Day 1, was collected diagnosed with Chronic liver disease (CLD) due to any as soon as a patient presented, before any treatment cause, having grade II to grade IV Hepatic was started. The second sample was drawn on Day 3 Encephalopathy were included in the study after i.e. after the patient received three days of the informed consent. CLD was diagnosed by common Trial-Treatment or Placebo. Clinical improvement in complications like ascites, gastro-oesophagal varices, hepatic encephalopathy was noted by West Haven’s INTRODUCTION conditions associated with excess ammonia with sonographic findings of shrunken liver, splenomegaly, criteria, on day 1 before LOLA infusion and on day III (constipation, protein overload, internal bleeding or portal vein size > 1 cm, deranged clotting profile and after infusion. Data was collected on the prescribed Cirrhosis or end stage liver disease is destruction of sepsis).5 It also explains the reason why some patients and inverse albumin /globulin ratio. Hepatic performa and analyzed using Statistical Package for normal liver parenchyma, replaced by regenerating have marginal elevation of arterial ammonia, despite encephalopathy was diagnosed on the basis of Social Services (SPSS) V 17. Numerical data was nodules and scar tissue, due to various reasons hepatic encephalopathy.6 Therefore reduction in confusion, drowsiness, restlessness, disorientation and recorded as mean and standard deviation, nominal data common causes includes HBV, HCV, and alcoholic liver ammonia levels in the body is important treatment asterixis without any altered explanation of these was recorded as frequency and percentage. Patients on disease. Hepatic Encephalopathy is present in about strategy.7 The L-ornithine L-Aspartate(LOLA) are salts of symptoms. Clinical grading of hepatic encephalopathy treatment with Ornithine - Aspartate infusion and on 50-70% of all patients with cirrhosis.(1) Hepatic naturally occurring aminoacids ornithine and aspartate. was done by West Haven’s criteria.16 Patient having placebo were compared by paired t-test. A p-value of < Encephalopathy is a complex neuropsychiatric syndrome They stimulate urea cycle and glutamine synthesis, sepsis, hepatorenal syndrome, acute/ chronic kidney 0.05 was considered statistically significant. associated with acute or chronic hepato- cellular failure which are major mechanisms of ammonia detoxification.8 disease were excluded from the study because they and porto-systemic shunting of blood. It is one of the Over last 25 years, various studies were carried out might affect ammonia levels. Hypoglycemia and RESULT major complications of cirrhosis. Various neurotoxins regarding efficacy of LOLA in improvement of hepatic respiratory failure was excluded by measuring random have been known to involve in pathogenesis of hepatic encephalopathy, showed controversial results. Blanco blood sugar and arterial blood gases. The estimated Out of 102, two patients were discharged or referred encephalopathy. High levels of ammonia, glutamate, et al compared the standard treatment, with LOLA and sample size was 102 patients, considering 500 annual before collection of data. The remaining patients endogenous benzodiazepines, Gamma Amino butyric concluded that LOLA was effective not only in reducing admissions in our ward. The patients meeting inclusion completed study. Half of the patients (50), received Acid (GABA) have been strongly associated with acute hyperammonemia and the severity of this disease, but criteria were randomly allocated into two groups with 50 L-Ornithine L-Aspartate (LOLA) and half received Placebo hepatic encephalopathy. 2 Among these, raised level of also in improving the patient's perceived quality of life.9 patients in each group. The Trial-Treatment group (50). In LOLA group 20(40%) were female and 30(60%) ammonia is thought to play a major role in pathogenesis Sharma et al conducted a study in 2014and concluded received L-Ornithine L-Aspartate; the Placebo group were male. In placebo group were 22(44%) female and of hepatic encephalopathy. 3,4 In hepatic encephalopat- that LOLA, probiotics and rifxamine were all superior to received normal saline. Both groups continued to 28(56%) male. Mean age was 49.66+ 12.25 SD in trial hy the rate of ammonia metabolism decreases and its placebo, although this study was conducted on patients receive all other standard supportive treatment group and 46.06 +9.83 SD in placebo group. Out of 100 permeability to blood brain barrier increases, resulting with minimal hepatic encephalopathy.10 A meta-analysis including lactulose and metronidazole. The patients people 43 % had HCV, 22 % had HBV, 4 % were non B-C in elevated ammonia levels in brain with variable done in 2009 reviewed four studies and concluded that with precipitating factors such as infection, and 8 % had both B and C virus. (Table: I) On Day I mean changes in blood. This mechanism is also supported by although use of LOLA was associated with decreasing constipation, hypokalemia, dehydration, electrolyte ammonia was 105.2 micromol/l in trial group. (Normal the fact that cirrhotic patients are sensitive to serum ammonia levels, no clinical improvement was

RANDOMIZED CONTROLLED TRIAL range: 6-47 micromol/l). In placebo group mean to identify two clinical trials. In 2011 Abid et al conducted Health Dr. Sadi Konuk Research and Training Hospital improvement; 1= a little, 2= some, 3= a lot, 4= Evaluation of patients’ pain relief scores treatment of acute migraine, but epigastric pain was ACKNOWLEDGEMENTS ammonia level was 112.28 micromole /dl on Day a study in Agha Khan university Hospital on 110 patients IS ORAL LORNOXICAM EFFECTIVE IN THE TREATMENT OF between January 2010 and December 2012. Inclusion complete, and worsening; -1= a litte, -2= some, -3= The pain relief was assessed individually after found significantly higher in the naproxen sodium I.(Table:II) On Day III mean ammonia level in the trial concluded that LOLA was safe and associated with rapid criteria was: a lot, -4= complete) after the administration of drug at administration of the first dose at 15th, 30th, 60th, group. (11) Ravishankar and colleagues evaluated the We certify that there is no conflict of interest with any financial organization regarding the subject discussed in the 14 ACUTE MIGRAINE ATTACKS? : A RANDOMIZED-CONTROLLED group was 74.16 micromol/L. In placebo group mean clinical improvement and shorter hospital stay. Ahmed et 15 th, 30 th, 60 th, 90 th minutes and at 2 nd, 3 th, 90th minutes and the 2nd, 3th, 6th, 12th, 24th hours efficacy of sublingual piroxicam in patients suffering manuscript. We greatly appreciate recommendations and contributions of Professor, M.D. Rian Disci, Associate ammonia level was 110.52 micromol/L .On comparison of al conducted a study in in Shaikh Zyed hospital Lahore on STUDY - age between 18 and 65 years, 6 th, 12 th, 24 th hours. Evaluation of patient in both groups. There was not found any difference from migraine without aura. In their study, either Proffesor, M.D. Habip Gedik, and M.D. Arsida Bajrami about the manuscript. serum ammonia levels before(day 1) and after (day 3) 80 patients in 2008 concluded that ornithine infusion - being diagnosed with migraine without aura satisfaction was assessed at the end of the 24-h period between pain intensity scores which were surveyed after piroxicam 40 mg or placebo was administered (8) L-ornithine L aspartate therapy ,the difference was was associated with rapid clinical recovery and decrease 1 2 3 4 according to the International Headache (1= satisfied, 2= unsatisfied). LNX and placebo treatments, statistically (Table 4). 13 Murat Cabalar , Selcuk Dincer , Vildan Yayla , Suleyman Ozyalcin randomly and double-blind to 60 patients who were statistically significant in trial group(p value 0.0013) while serum ammonia. Considering the results of our trial and 1 Neurology Physician, Department of Neurology, Ministry of Health Bakirkoy Dr. SadiKonuk Training and Research Hospital, stanbul. Society criteria (the year 2004), suffering from two to 16 migraine attacks per month it was non significant in placebo group.(p value 0.124) other national and international studies and meta 2 Algology Physician, Department of Algology, istanbul University Medicine Faculty, Istanbul - having experience of first headache attack A Statistical Analysis Evaluation of patients’ satisfaction scores without aura at age 18-50 years. (12) The severity of the (Table : II) To assess clinical improvement with LOLA, we analysis, we can recommend use of LOLA as addition to before 50 years of age, Age was expressed as mean ±standard deviation. Patients’ satisfaction scores were insignificant between pain was evaluated using the visual analogue scale used clinical grading of hepatic encephalopathy. In trial other standard therapies of hepatic encephalopathy since Correspondence to: Murat Cabalar, NorolojiKlinigi, S. B. BakırkoySadiKonukEgitimVeArastırmaHastanesi Istanbul - Turkiye. Phone: 0090 5333640283, E-Mail: [email protected] - having moderate to severe migraine attacks Changes in headache severity were assessed by LNX and placebo treatments, statistically (Table 5). Date of Submission: January 14, 2015, Date of Revision: May 29, 2015, Date of Acceptance: June 10, 2015 (VAS). This study described the decrease in pain group, On Day I 10(20%) were in grade II, 17(34%) were ornithine therapy is safe, with mild side effects like with frequency less than 4 times per month. Mann-Whitney U test in the pre-treatment period and in grade III and 23(46%) were in grade IV hepatic nausea and vomiting and is easily available, can be given after the treatment at 15th, 30th, 60th, 90th minutes Evaluation of drug associated side-effects intensity at 15 min and even 24 hours after sublingual encephalopathy, while on day III 4(8%) were in grade both orally and parenterally and does not adds significant ABSTRACT This study was approved by ethics committee that was and 2nd, 3th, 6th, 12th, 24th hours. Characteristics of No adverse reactions were with both placebo treatment piroxicam administration. This decrease was (12) zero, 18(36%) were in I, 20(40% ) were in grade II, cost to treatment of hepatic encephalopathy. Future established in the School of Medicine, Istanbul patient and placebo groups and satisfaction with the and LNX treatment. statistically significant compared to placebo 8(16%) in grade III and zero were in grade IV hepatic studies should be directed towards comparison of Objective: The aim of this study was to assess the efficacy of lornoxicam (LNX) in the treatment of acute migraine University. Randomization table has been used for treatment between placebo and treatment group was Ravishankar and his colleagues administered placebo encephalopathy. (Table:III) In placebo group on day I efficacy L ornithine therapy with others drugs used for attacks. Material and Methods: This prospective, randomized, double-blind, placebo-controlled trial was conducted randomization of the patients. Diagnosis of migraine of assessed by Chi-square test. Statistical significance Table 2: Distribution of the number of migraine attacks and the drug in different patient groups, whereas drug 12(24%) % were in grade II, 19(38%) were in grade III, standard treatment of hepatic encephalopathy like administering either LNX or placebo to patients who were diagnosed with migraine without aura according to the the included patients was done by a neurology was determined at p <0.05. in which LNX and placebo treatments were given and placebo were administered to the same group of 19(38%) were in grade IV hepatic encephalopathy, while lactitol, rifixamine, Zinc supplements and branch chain International Headache Society (the year 2004) criteria between 2010 and 2012 Results: Of 44 patients with 120 physician. Patients’ migraine attacks were recorded to patients in our study. The small population size and migraine attacks, 38 were female and rest were males. Mean age was 37.75 ± 9.28 years. Patients recorded using on day III no patient % was in grade zero,10(20%) were in amino acids. assess the effectiveness of LNX. After being informed Table 1: Demographic characteristics of the study administration of both the drug and placebo into a LNX in 87 migraine attacks and placebo in 33 migraine attacks, respectively. Pain intensity scores of the patients were grade I, 12 (24%) were in grade II, 18(36%) were in about the study, all volunteers were asked to sign the participants. group of patients are likely to be related to this found similar between LNX and placebo groups, statistically. Conclusion: Although oral LNX was found to have efficacy grade III and 10(20%) were in grade IV hepatic "informed consent form". Patients’ physical insignificance. Although mean age and the number of encephalopathy. On Day I clinical difference in grading of CONCLUSION similar to placebo statistically in the treatment of acute migraine attacks, further studies are needed to evaluate examinations, pulse rates and blood pressure of appropriately the efficacy of LNX for treatment of acute migraine attacks. migraine attacks in our study were similar to hepatic encephalopathy between two groups was patients as well as medical history regarding usage of Ravinshankar’s study, sublingual form is likely to cause statistically non significant. (p-values > 0.05) while on LOLA is effective in decreasing serum ammonia as well drug or non-drug medications and simultaneous to different results compared to oral form as well. Since Day III, significant clinical improvement was observed p as causes clinical improvement in patients with hepatic Key Words: Lornoxicam, migraine, acute attack, treatment efficacy systemic diseases were recorded during all visits. the administration of piroxicam sublingually reaches an value < 0.05.(Table: III) encephalopathy. It can be recommended that LOLA Patients who were pregnant, nursing and planning to be effective blood plasma concentration without being may be used in the patients with hepatic pregnant during the study, not informed about INTRODUCTION Although the central effects of NSAIDs are not exactly exposed to the first-pass elimination in the liver. The encephalopathy especially when not responsive to treatment sufficiently, used different treatment for known, three mechanisms are mainly emphasized. side - effect did not develop in our study. In a study DISCUSSION standard treatment regimen. Migraine is a common cause of headache. Prevalence These are the inhibition of central nervous system migraine attacks, and who quitted the follow-up were DISCUSSION comparing of LNX with intravenous morphine in the of migraine is reported to be 11% in the adult prostaglandin synthesis by NSAIDs, the increasing of excluded from the study. Patients received two different treatment of post operative pain, LNX was found to In developing countries like Pakistan cirrhosis liver is more Table I: Distribution of patients according to population in the studies from western countries. (1) The CNS catecholamine and serotonin cycle, and the blisters containing either placebo or the study drug (8 LNX has been evaluated for the first time in terms of its 17 provide similar analgesic effect with a lower incidence prevalent compared to developed countries. In fact both characteristics study, which was conducted by Turkish headache inhibition of serotonin release during pain stimulus. (6) mg LNX) for two migraine attacks during first and efficacy and side-effects, due to the fact that there has (10) hepatitis B virus (HBV) and hepatitis C virus (HCV) epidemiology study group reported the incidence of Lornoxicam (LNX) (6-chloro-4-hydroxy 2-methyl second visits. The 3rd visit was arranged at the end of RESULTS been no study about it in the treatment of acute of adverse events. Adverse effects, such as nausea, 18,19 infections have become endemic in our community. migraine to be 16.4% between 15-65 years old. (2) It is N-pyridyl 2H-thienol (2, 3 e) 1, 2-thiazine the fourth week or within five days after second attack migraine attacks. In context with that although NSAIDs vomiting, gastritis, heartburn, and diarrhea were Hepatic Encephalopathy is a common neuro-psychiatric seen three times more in women than men, and it often 2-karbaksamid 1, 1-dioxide), is a NSAID drug in and the 4th visit was arranged at the end of the eighth During the study period, 6 of 50 patients were excluded were presented to be effective in the treatment of acute reported to develop less with a sublingual form of LNX complication in CLD. High levels of ammonia in the body occurs between the ages of 25 to 55 years. (3, 4) non-selective, oxicam group according to former week or within five days after third attack. They were from the study due to excluding criteria. Of 44 patients migraine attacks, serum level concentration of LNX than naproxen sodium in the study of Aabakken et al. (9) is a major cause of hepatic encephalopathy, that’s why Migraine treatments are generally based on two major classification. LNX has potent anti-inflammatory and allowed to use maximum two tablets in a day. If whose 120 migraine attacks were evaluated, 38 were should be measured after oral use to evaluate the In a study performed on healthy volunteers, it has been most of the treatments are targeted against the groups, including non-pharmacological and pharmacol- analgesic effects similar to other oxicams but unlike headache persisted despite the use of the two tablets females. Mean age 37.75 ± 9.28 years. efficacy appropriately. (5) Since oral usage of LNX cannot verified that less gastro-duodenal injury developed with detoxification of ammonia. L Ornithine L aspartate (LOLA) ogical methods. Pharmacological treatment is divided them it has a shorter half life (3-5 hours). Both oral and given for the study, they were permitted to use Characteristics of patients have been shown in Table 1. reach therapeutic blood concentration rapidly and LNX (16 mg / day) compared to naproxen sodium stimulates the urea cycle and ammonia utilization that’s into two groups; prophylactic and acute attack parenteral preparations are used. LNX has a better eletriptan 40 mg as a subsidiary medicine at least an There was no comorbidity in both patient and placebo sufficiently despite its short and rapid time of action, (1000 mg / day). (9) The limitations of our study are why thought to be useful in acute hepatic encephalopathy. treatment.(5) Acute migraine attacks should be managed tolerability profile compared with other oxicam drugs hour after the second tablet. Patients were inquired groups. During the study period, LNX was used in the because of first-pass elimination. Also a parenteral form small population size, administration of both drug and In our study, it was observed that the LOLA has beneficial (7) rapidly and effectively. Therapy is considered to be because of shorter half life. Clinical trials suggest LNX which blister they had taken if they had headache 87 attacks, placebo was used in the 33 attacks. The of LNX may be evaluated or compared with oral form to placebo in some cases, usage of only oral form of LNX. effects not only in clinical improvement of encephalopathy successful when there is decrease in the frequency and as an effective drug in the treatment of post-operative attack and whether they had taken one more tablet number of headache attacks in which placebo and LNX reveal its effectiveness and whether the administration Intravenous form of LNX should be evaluated in terms of but also obvious decrease in serum ammonia levels after (5) from blisters when headache persisted for three hours. were used is given in Table 2. route is important or not. Despite studies showing the severity of attacks. Acute attack treatment should be and joint pains. The aim of this study was to assess the efficacy and side-effects compared with oral forms of infusion of LOLA. These results were comparable to other Migraine attacks of patients which were not recorded effectiveness of oral administration of LNX’ are tailored to the patients systemic disease and symptoms efficacy of LNX in treatment of headaches due to acute LNX with a randomized-controlled study for treatment of studies. Bai et al concluded after meta-analysis of 8 during follow up were not evaluated. Pain intensity Evaluation of patients’ pain intensity scores associated with pains other than migraine it is as well as the severity, duration and frequency of the migraine attacks. acute migraine attacks. As a result, although oral LNX randomized clinical trials including 646 patients that, attacks. In mild and moderate attacks, non-specific score was rated from 0 to 3 points (0= none, 1= mild, The severity of the headache was assessed individually important to ensure early, rapid and effective plasma was found to have efficacy similar to placebo LOLA was beneficial in both overt and minimal hepatic therapy non-steroidal anti-inflammatory drugs (NSAIDs) MATERIAL AND METHODS 2= moderate, 3= severe) in the survey. Headache after administration of the first dose at the beginning, concentration in pains related to migraine. (9, 10) NSAIDs statistically in the treatment of acute migraine attacks, encephalopathy, causes both clinical and biochemical alone or in combination with either caffeine or codeine severity was evaluated with a questionnaire performed 15th, 30th, 60th, 90th minutes and the 2nd, 3th, 6th, in the oxicam groups were reported to be effective for 20 further studies are needed, including two different detoxification of ammonia. Another meta analysis done may be used. Moderate and severe attacks which This is a prospective, randomized, double-blind, before taking the drug at 0.min and at 15th, 30th, 12th, 24th hours in both groups. There was not found acute migraine attacks. In a study conducted by CY et in 2011 supported the use of LOLA for neuro-psychiatric cannot be prevented with nonspecific migraine drugs placebo-controlled study conducted by department of 60th, 90th minutes and at 2nd, 3th, 6th, 12th, 24th difference between pain intensity scores which were al the effectiveness of celecoxib and naproxen sodium groups, two forms and different dosages of LNX to 21 improvement as well as decreasing levels of ammonia. are managed with specific drugs such as triptans or clinical of algology, school of medicine Istanbul hours after the administration of drug. Pain relief was surveyed after LNX and placebo treatments, statistically in the treatment of acute migraine was investigated. evaluate appropriately the efficacy of LNX for treatment Although regional data is sparse however, it is necessary ergot derivatives.(5) University and department of neurology, Ministry of assessed with a rating system of 5 points (0= none, (Table 3). Both drugs were found to be equally effective in the of acute migraine attacks.

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES 42 VOL. 10 (3) JUL - SEPT 2015 observed. But these studies were of small sample size imbalance, prolonged prothrombin time were treated and shorter follow ups.11 Another meta-analysis done accordingly. Performa was completed for each patient on three studies showed that LOLA therapy causes to record demographics, vitals, complete blood counts, decrease in serum ammonia levels, and also clinical liver function tests, prothrombin time, total proteins, improvement.12 Moreover most of the available data electrolytes, serum ammonia, random blood glucose assessed role of LOLA in minimal encephalopathy, not and renal status. In addition, ultra-sound of the whole the over encephalopathy. In the review of local data, abdomen was also done, to assess the size of liver, there are only two authentic large trials available.13,14 spleen and portal vein. Trial-Treatment group received a Therefore due to absence of large studies, controversial daily intravenous infusion of 20 g (4 ampoules) existing data and paucity of local data, we conducted a L-Ornithine L-Aspartate (Inj HepaMerz, Brooks pharma) study to observe effect of LOLA on clinical improvement diluted in 250 ml of 5% dextrose water administered in most stages of hepatic encephalopathy. slowly over 4 hours for three consecutive days. The Placebo group received a daily administration of 250 ml MATERIAL & METHOD normal saline over 4 hours for three consecutive days. It was ensured that the infusions were given at the After approval of Ethical review committee of Jinnah same specified time to both groups of patients. About 5 Medical and Dental College, a randomized, placebo- ml of blood of each patient was drawn on Day 1 and control trial was performed in medical department of Day 3 under aseptic techniques, stored in rubber Jinnah medical and dental college Hospital Korangi corked glass tubes for checking ammonia levels. The Karachi from July 2013 to June 2014. The trial was Tubes were frozen at 4 degrees centigrade temperature. designed and reported according to CONSORT The ammonia determination was performed according guidelines.15 An informed consent was taken before to the enzymatic determination of ammonia with entry in the trial. Data was collected by Interns and glutamine dehydrogenase in a rapid and interference – residents of the ward, who were trained by the authors free photomertric determination of NH4+ in native for this study through workshops and meetings. blood plasma. The testing was performed at a reliable Patients > 18 years of age, admitted in medical ward, laboratory of Karachi. Sample on Day 1, was collected diagnosed with Chronic liver disease (CLD) due to any as soon as a patient presented, before any treatment cause, having grade II to grade IV Hepatic was started. The second sample was drawn on Day 3 Encephalopathy were included in the study after i.e. after the patient received three days of the informed consent. CLD was diagnosed by common Trial-Treatment or Placebo. Clinical improvement in complications like ascites, gastro-oesophagal varices, hepatic encephalopathy was noted by West Haven’s INTRODUCTION conditions associated with excess ammonia with sonographic findings of shrunken liver, splenomegaly, criteria, on day 1 before LOLA infusion and on day III (constipation, protein overload, internal bleeding or portal vein size > 1 cm, deranged clotting profile and after infusion. Data was collected on the prescribed Cirrhosis or end stage liver disease is destruction of sepsis).5 It also explains the reason why some patients and inverse albumin /globulin ratio. Hepatic performa and analyzed using Statistical Package for normal liver parenchyma, replaced by regenerating have marginal elevation of arterial ammonia, despite encephalopathy was diagnosed on the basis of Social Services (SPSS) V 17. Numerical data was nodules and scar tissue, due to various reasons hepatic encephalopathy.6 Therefore reduction in confusion, drowsiness, restlessness, disorientation and recorded as mean and standard deviation, nominal data common causes includes HBV, HCV, and alcoholic liver ammonia levels in the body is important treatment asterixis without any altered explanation of these was recorded as frequency and percentage. Patients on disease. Hepatic Encephalopathy is present in about strategy.7 The L-ornithine L-Aspartate(LOLA) are salts of symptoms. Clinical grading of hepatic encephalopathy treatment with Ornithine - Aspartate infusion and on 50-70% of all patients with cirrhosis.(1) Hepatic naturally occurring aminoacids ornithine and aspartate. was done by West Haven’s criteria.16 Patient having placebo were compared by paired t-test. A p-value of < Encephalopathy is a complex neuropsychiatric syndrome They stimulate urea cycle and glutamine synthesis, sepsis, hepatorenal syndrome, acute/ chronic kidney 0.05 was considered statistically significant. associated with acute or chronic hepato- cellular failure which are major mechanisms of ammonia detoxification.8 disease were excluded from the study because they and porto-systemic shunting of blood. It is one of the Over last 25 years, various studies were carried out might affect ammonia levels. Hypoglycemia and RESULT major complications of cirrhosis. Various neurotoxins regarding efficacy of LOLA in improvement of hepatic respiratory failure was excluded by measuring random have been known to involve in pathogenesis of hepatic encephalopathy, showed controversial results. Blanco blood sugar and arterial blood gases. The estimated Out of 102, two patients were discharged or referred encephalopathy. High levels of ammonia, glutamate, et al compared the standard treatment, with LOLA and sample size was 102 patients, considering 500 annual before collection of data. The remaining patients endogenous benzodiazepines, Gamma Amino butyric concluded that LOLA was effective not only in reducing admissions in our ward. The patients meeting inclusion completed study. Half of the patients (50), received Acid (GABA) have been strongly associated with acute hyperammonemia and the severity of this disease, but criteria were randomly allocated into two groups with 50 L-Ornithine L-Aspartate (LOLA) and half received Placebo hepatic encephalopathy. 2 Among these, raised level of also in improving the patient's perceived quality of life.9 patients in each group. The Trial-Treatment group (50). In LOLA group 20(40%) were female and 30(60%) ammonia is thought to play a major role in pathogenesis Sharma et al conducted a study in 2014and concluded received L-Ornithine L-Aspartate; the Placebo group were male. In placebo group were 22(44%) female and of hepatic encephalopathy. 3,4 In hepatic encephalopat- that LOLA, probiotics and rifxamine were all superior to received normal saline. Both groups continued to 28(56%) male. Mean age was 49.66+ 12.25 SD in trial hy the rate of ammonia metabolism decreases and its placebo, although this study was conducted on patients receive all other standard supportive treatment group and 46.06 +9.83 SD in placebo group. Out of 100 permeability to blood brain barrier increases, resulting with minimal hepatic encephalopathy.10 A meta-analysis including lactulose and metronidazole. The patients people 43 % had HCV, 22 % had HBV, 4 % were non B-C in elevated ammonia levels in brain with variable done in 2009 reviewed four studies and concluded that with precipitating factors such as infection, and 8 % had both B and C virus. (Table: I) On Day I mean changes in blood. This mechanism is also supported by although use of LOLA was associated with decreasing constipation, hypokalemia, dehydration, electrolyte ammonia was 105.2 micromol/l in trial group. (Normal the fact that cirrhotic patients are sensitive to serum ammonia levels, no clinical improvement was

range: 6-47 micromol/l). In placebo group mean to identify two clinical trials. In 2011 Abid et al conducted Health Dr. Sadi Konuk Research and Training Hospital improvement; 1= a little, 2= some, 3= a lot, 4= Evaluation of patients’ pain relief scores treatment of acute migraine, but epigastric pain was ACKNOWLEDGEMENTS ammonia level was 112.28 micromole /dl on Day a study in Agha Khan university Hospital on 110 patients between January 2010 and December 2012. Inclusion complete, and worsening; -1= a litte, -2= some, -3= The pain relief was assessed individually after found significantly higher in the naproxen sodium I.(Table:II) On Day III mean ammonia level in the trial concluded that LOLA was safe and associated with rapid criteria was: a lot, -4= complete) after the administration of drug at administration of the first dose at 15th, 30th, 60th, group. (11) Ravishankar and colleagues evaluated the We certify that there is no conflict of interest with any financial organization regarding the subject discussed in the 14 group was 74.16 micromol/L. In placebo group mean clinical improvement and shorter hospital stay. Ahmed et 15 th, 30 th, 60 th, 90 th minutes and at 2 nd, 3 th, 90th minutes and the 2nd, 3th, 6th, 12th, 24th hours efficacy of sublingual piroxicam in patients suffering manuscript. We greatly appreciate recommendations and contributions of Professor, M.D. Rian Disci, Associate ammonia level was 110.52 micromol/L .On comparison of al conducted a study in in Shaikh Zyed hospital Lahore on - age between 18 and 65 years, 6 th, 12 th, 24 th hours. Evaluation of patient in both groups. There was not found any difference from migraine without aura. In their study, either Proffesor, M.D. Habip Gedik, and M.D. Arsida Bajrami about the manuscript. serum ammonia levels before(day 1) and after (day 3) 80 patients in 2008 concluded that ornithine infusion - being diagnosed with migraine without aura satisfaction was assessed at the end of the 24-h period between pain intensity scores which were surveyed after piroxicam 40 mg or placebo was administered L-ornithine L aspartate therapy ,the difference was was associated with rapid clinical recovery and decrease (8) according to the International Headache (1= satisfied, 2= unsatisfied). LNX and placebo treatments, statistically (Table 4). randomly and double-blind to 60 patients who were statistically significant in trial group(p value 0.0013) while serum ammonia.13 Considering the results of our trial and Society criteria (the year 2004), suffering from two to 16 migraine attacks per month it was non significant in placebo group.(p value 0.124) other national and international studies and meta - having experience of first headache attack A Statistical Analysis Evaluation of patients’ satisfaction scores without aura at age 18-50 years. (12) The severity of the (Table : II) To assess clinical improvement with LOLA, we analysis, we can recommend use of LOLA as addition to before 50 years of age, Age was expressed as mean ±standard deviation. Patients’ satisfaction scores were insignificant between pain was evaluated using the visual analogue scale used clinical grading of hepatic encephalopathy. In trial other standard therapies of hepatic encephalopathy since - having moderate to severe migraine attacks Changes in headache severity were assessed by LNX and placebo treatments, statistically (Table 5). (VAS). This study described the decrease in pain group, On Day I 10(20%) were in grade II, 17(34%) were ornithine therapy is safe, with mild side effects like with frequency less than 4 times per month. Mann-Whitney U test in the pre-treatment period and in grade III and 23(46%) were in grade IV hepatic nausea and vomiting and is easily available, can be given after the treatment at 15th, 30th, 60th, 90th minutes Evaluation of drug associated side-effects intensity at 15 min and even 24 hours after sublingual encephalopathy, while on day III 4(8%) were in grade both orally and parenterally and does not adds significant This study was approved by ethics committee that was and 2nd, 3th, 6th, 12th, 24th hours. Characteristics of No adverse reactions were with both placebo treatment piroxicam administration. This decrease was (12) zero, 18(36%) were in I, 20(40% ) were in grade II, cost to treatment of hepatic encephalopathy. Future established in the School of Medicine, Istanbul patient and placebo groups and satisfaction with the and LNX treatment. statistically significant compared to placebo 8(16%) in grade III and zero were in grade IV hepatic studies should be directed towards comparison of University. Randomization table has been used for treatment between placebo and treatment group was Ravishankar and his colleagues administered placebo encephalopathy. (Table:III) In placebo group on day I efficacy L ornithine therapy with others drugs used for randomization of the patients. Diagnosis of migraine of assessed by Chi-square test. Statistical significance Table 2: Distribution of the number of migraine attacks and the drug in different patient groups, whereas drug 12(24%) % were in grade II, 19(38%) were in grade III, standard treatment of hepatic encephalopathy like the included patients was done by a neurology was determined at p <0.05. in which LNX and placebo treatments were given and placebo were administered to the same group of 19(38%) were in grade IV hepatic encephalopathy, while lactitol, rifixamine, Zinc supplements and branch chain physician. Patients’ migraine attacks were recorded to patients in our study. The small population size and on day III no patient % was in grade zero,10(20%) were in amino acids. assess the effectiveness of LNX. After being informed Table 1: Demographic characteristics of the study administration of both the drug and placebo into a grade I, 12 (24%) were in grade II, 18(36%) were in about the study, all volunteers were asked to sign the participants. group of patients are likely to be related to this grade III and 10(20%) were in grade IV hepatic "informed consent form". Patients’ physical insignificance. Although mean age and the number of encephalopathy. On Day I clinical difference in grading of CONCLUSION examinations, pulse rates and blood pressure of Placebo (n=14) LNX (n=30) P migraine attacks in our study were similar to hepatic encephalopathy between two groups was patients as well as medical history regarding usage of Female/Male 11/3 27/3 0.364 Ravinshankar’s study, sublingual form is likely to cause statistically non significant. (p-values > 0.05) while on LOLA is effective in decreasing serum ammonia as well Age (years; 37.9 ± 10.1 37.5 ± 8.4 0.902 drug or non-drug medications and simultaneous to different results compared to oral form as well. Since Day III, significant clinical improvement was observed p as causes clinical improvement in patients with hepatic mean ± SD) systemic diseases were recorded during all visits. the administration of piroxicam sublingually reaches an value < 0.05.(Table: III) encephalopathy. It can be recommended that LOLA Patients who were pregnant, nursing and planning to be Illiterate 2 1 effective blood plasma concentration without being may be used in the patients with hepatic pregnant during the study, not informed about Elementary 10 16 INTRODUCTION Although the central effects of NSAIDs are not exactly exposed to the first-pass elimination in the liver. The encephalopathy especially when not responsive to treatment sufficiently, used different treatment for School known, three mechanisms are mainly emphasized. side - effect did not develop in our study. In a study DISCUSSION standard treatment regimen. Migraine is a common cause of headache. Prevalence These are the inhibition of central nervous system migraine attacks, and who quitted the follow-up were High School - 4 DISCUSSION comparing of LNX with intravenous morphine in the of migraine is reported to be 11% in the adult prostaglandin synthesis by NSAIDs, the increasing of excluded from the study. Patients received two different University 2 9 treatment of post operative pain, LNX was found to In developing countries like Pakistan cirrhosis liver is more Table I: Distribution of patients according to population in the studies from western countries. (1) The CNS catecholamine and serotonin cycle, and the blisters containing either placebo or the study drug (8 0.902 LNX has been evaluated for the first time in terms of its 17 provide similar analgesic effect with a lower incidence prevalent compared to developed countries. In fact both characteristics study, which was conducted by Turkish headache inhibition of serotonin release during pain stimulus. (6) mg LNX) for two migraine attacks during first and efficacy and side-effects, due to the fact that there has (10) hepatitis B virus (HBV) and hepatitis C virus (HCV) epidemiology study group reported the incidence of Lornoxicam (LNX) (6-chloro-4-hydroxy 2-methyl second visits. The 3rd visit was arranged at the end of RESULTS been no study about it in the treatment of acute of adverse events. Adverse effects, such as nausea, 18,19 infections have become endemic in our community. migraine to be 16.4% between 15-65 years old. (2) It is N-pyridyl 2H-thienol (2, 3 e) 1, 2-thiazine the fourth week or within five days after second attack migraine attacks. In context with that although NSAIDs vomiting, gastritis, heartburn, and diarrhea were Hepatic Encephalopathy is a common neuro-psychiatric seen three times more in women than men, and it often 2-karbaksamid 1, 1-dioxide), is a NSAID drug in and the 4th visit was arranged at the end of the eighth During the study period, 6 of 50 patients were excluded were presented to be effective in the treatment of acute reported to develop less with a sublingual form of LNX complication in CLD. High levels of ammonia in the body occurs between the ages of 25 to 55 years. (3, 4) non-selective, oxicam group according to former week or within five days after third attack. They were from the study due to excluding criteria. Of 44 patients migraine attacks, serum level concentration of LNX than naproxen sodium in the study of Aabakken et al. (9) is a major cause of hepatic encephalopathy, that’s why Migraine treatments are generally based on two major classification. LNX has potent anti-inflammatory and allowed to use maximum two tablets in a day. If whose 120 migraine attacks were evaluated, 38 were should be measured after oral use to evaluate the In a study performed on healthy volunteers, it has been most of the treatments are targeted against the groups, including non-pharmacological and pharmacol- analgesic effects similar to other oxicams but unlike headache persisted despite the use of the two tablets females. Mean age 37.75 ± 9.28 years. efficacy appropriately. (5) Since oral usage of LNX cannot verified that less gastro-duodenal injury developed with detoxification of ammonia. L Ornithine L aspartate (LOLA) ogical methods. Pharmacological treatment is divided them it has a shorter half life (3-5 hours). Both oral and given for the study, they were permitted to use Characteristics of patients have been shown in Table 1. reach therapeutic blood concentration rapidly and LNX (16 mg / day) compared to naproxen sodium stimulates the urea cycle and ammonia utilization that’s into two groups; prophylactic and acute attack parenteral preparations are used. LNX has a better eletriptan 40 mg as a subsidiary medicine at least an There was no comorbidity in both patient and placebo sufficiently despite its short and rapid time of action, (1000 mg / day). (9) The limitations of our study are why thought to be useful in acute hepatic encephalopathy. treatment.(5) Acute migraine attacks should be managed tolerability profile compared with other oxicam drugs hour after the second tablet. Patients were inquired groups. During the study period, LNX was used in the because of first-pass elimination. Also a parenteral form small population size, administration of both drug and In our study, it was observed that the LOLA has beneficial (7) rapidly and effectively. Therapy is considered to be because of shorter half life. Clinical trials suggest LNX which blister they had taken if they had headache 87 attacks, placebo was used in the 33 attacks. The of LNX may be evaluated or compared with oral form to placebo in some cases, usage of only oral form of LNX. effects not only in clinical improvement of encephalopathy successful when there is decrease in the frequency and as an effective drug in the treatment of post-operative attack and whether they had taken one more tablet number of headache attacks in which placebo and LNX reveal its effectiveness and whether the administration Intravenous form of LNX should be evaluated in terms of but also obvious decrease in serum ammonia levels after (5) from blisters when headache persisted for three hours. were used is given in Table 2. route is important or not. Despite studies showing the severity of attacks. Acute attack treatment should be and joint pains. The aim of this study was to assess the efficacy and side-effects compared with oral forms of infusion of LOLA. These results were comparable to other Migraine attacks of patients which were not recorded effectiveness of oral administration of LNX’ are tailored to the patients systemic disease and symptoms efficacy of LNX in treatment of headaches due to acute LNX with a randomized-controlled study for treatment of studies. Bai et al concluded after meta-analysis of 8 during follow up were not evaluated. Pain intensity Evaluation of patients’ pain intensity scores associated with pains other than migraine it is as well as the severity, duration and frequency of the migraine attacks. acute migraine attacks. As a result, although oral LNX randomized clinical trials including 646 patients that, attacks. In mild and moderate attacks, non-specific score was rated from 0 to 3 points (0= none, 1= mild, The severity of the headache was assessed individually important to ensure early, rapid and effective plasma was found to have efficacy similar to placebo LOLA was beneficial in both overt and minimal hepatic therapy non-steroidal anti-inflammatory drugs (NSAIDs) MATERIAL AND METHODS 2= moderate, 3= severe) in the survey. Headache after administration of the first dose at the beginning, concentration in pains related to migraine. (9, 10) NSAIDs statistically in the treatment of acute migraine attacks, encephalopathy, causes both clinical and biochemical alone or in combination with either caffeine or codeine severity was evaluated with a questionnaire performed 15th, 30th, 60th, 90th minutes and the 2nd, 3th, 6th, in the oxicam groups were reported to be effective for 20 further studies are needed, including two different detoxification of ammonia. Another meta analysis done may be used. Moderate and severe attacks which This is a prospective, randomized, double-blind, before taking the drug at 0.min and at 15th, 30th, 12th, 24th hours in both groups. There was not found acute migraine attacks. In a study conducted by CY et in 2011 supported the use of LOLA for neuro-psychiatric cannot be prevented with nonspecific migraine drugs placebo-controlled study conducted by department of 60th, 90th minutes and at 2nd, 3th, 6th, 12th, 24th difference between pain intensity scores which were al the effectiveness of celecoxib and naproxen sodium groups, two forms and different dosages of LNX to 21 improvement as well as decreasing levels of ammonia. are managed with specific drugs such as triptans or clinical of algology, school of medicine Istanbul hours after the administration of drug. Pain relief was surveyed after LNX and placebo treatments, statistically in the treatment of acute migraine was investigated. evaluate appropriately the efficacy of LNX for treatment Although regional data is sparse however, it is necessary ergot derivatives.(5) University and department of neurology, Ministry of assessed with a rating system of 5 points (0= none, (Table 3). Both drugs were found to be equally effective in the of acute migraine attacks.

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES 43 VOL. 10 (3) JUL - SEPT 2015 observed. But these studies were of small sample size imbalance, prolonged prothrombin time were treated and shorter follow ups.11 Another meta-analysis done accordingly. Performa was completed for each patient on three studies showed that LOLA therapy causes to record demographics, vitals, complete blood counts, decrease in serum ammonia levels, and also clinical liver function tests, prothrombin time, total proteins, improvement.12 Moreover most of the available data electrolytes, serum ammonia, random blood glucose assessed role of LOLA in minimal encephalopathy, not and renal status. In addition, ultra-sound of the whole the over encephalopathy. In the review of local data, abdomen was also done, to assess the size of liver, there are only two authentic large trials available.13,14 spleen and portal vein. Trial-Treatment group received a Therefore due to absence of large studies, controversial daily intravenous infusion of 20 g (4 ampoules) existing data and paucity of local data, we conducted a L-Ornithine L-Aspartate (Inj HepaMerz, Brooks pharma) study to observe effect of LOLA on clinical improvement diluted in 250 ml of 5% dextrose water administered in most stages of hepatic encephalopathy. slowly over 4 hours for three consecutive days. The Placebo group received a daily administration of 250 ml MATERIAL & METHOD normal saline over 4 hours for three consecutive days. It was ensured that the infusions were given at the After approval of Ethical review committee of Jinnah same specified time to both groups of patients. About 5 Medical and Dental College, a randomized, placebo- ml of blood of each patient was drawn on Day 1 and control trial was performed in medical department of Day 3 under aseptic techniques, stored in rubber Jinnah medical and dental college Hospital Korangi corked glass tubes for checking ammonia levels. The Karachi from July 2013 to June 2014. The trial was Tubes were frozen at 4 degrees centigrade temperature. designed and reported according to CONSORT The ammonia determination was performed according guidelines.15 An informed consent was taken before to the enzymatic determination of ammonia with entry in the trial. Data was collected by Interns and glutamine dehydrogenase in a rapid and interference – residents of the ward, who were trained by the authors free photomertric determination of NH4+ in native for this study through workshops and meetings. blood plasma. The testing was performed at a reliable Patients > 18 years of age, admitted in medical ward, laboratory of Karachi. Sample on Day 1, was collected diagnosed with Chronic liver disease (CLD) due to any as soon as a patient presented, before any treatment cause, having grade II to grade IV Hepatic was started. The second sample was drawn on Day 3 Encephalopathy were included in the study after i.e. after the patient received three days of the informed consent. CLD was diagnosed by common Trial-Treatment or Placebo. Clinical improvement in complications like ascites, gastro-oesophagal varices, hepatic encephalopathy was noted by West Haven’s INTRODUCTION conditions associated with excess ammonia with sonographic findings of shrunken liver, splenomegaly, criteria, on day 1 before LOLA infusion and on day III (constipation, protein overload, internal bleeding or portal vein size > 1 cm, deranged clotting profile and after infusion. Data was collected on the prescribed Cirrhosis or end stage liver disease is destruction of sepsis).5 It also explains the reason why some patients and inverse albumin /globulin ratio. Hepatic performa and analyzed using Statistical Package for normal liver parenchyma, replaced by regenerating have marginal elevation of arterial ammonia, despite encephalopathy was diagnosed on the basis of Social Services (SPSS) V 17. Numerical data was nodules and scar tissue, due to various reasons hepatic encephalopathy.6 Therefore reduction in confusion, drowsiness, restlessness, disorientation and recorded as mean and standard deviation, nominal data common causes includes HBV, HCV, and alcoholic liver ammonia levels in the body is important treatment asterixis without any altered explanation of these was recorded as frequency and percentage. Patients on disease. Hepatic Encephalopathy is present in about strategy.7 The L-ornithine L-Aspartate(LOLA) are salts of symptoms. Clinical grading of hepatic encephalopathy treatment with Ornithine - Aspartate infusion and on 50-70% of all patients with cirrhosis.(1) Hepatic naturally occurring aminoacids ornithine and aspartate. was done by West Haven’s criteria.16 Patient having placebo were compared by paired t-test. A p-value of < Encephalopathy is a complex neuropsychiatric syndrome They stimulate urea cycle and glutamine synthesis, sepsis, hepatorenal syndrome, acute/ chronic kidney 0.05 was considered statistically significant. associated with acute or chronic hepato- cellular failure which are major mechanisms of ammonia detoxification.8 disease were excluded from the study because they and porto-systemic shunting of blood. It is one of the Over last 25 years, various studies were carried out might affect ammonia levels. Hypoglycemia and RESULT major complications of cirrhosis. Various neurotoxins regarding efficacy of LOLA in improvement of hepatic respiratory failure was excluded by measuring random have been known to involve in pathogenesis of hepatic encephalopathy, showed controversial results. Blanco blood sugar and arterial blood gases. The estimated Out of 102, two patients were discharged or referred encephalopathy. High levels of ammonia, glutamate, et al compared the standard treatment, with LOLA and sample size was 102 patients, considering 500 annual before collection of data. The remaining patients endogenous benzodiazepines, Gamma Amino butyric concluded that LOLA was effective not only in reducing admissions in our ward. The patients meeting inclusion completed study. Half of the patients (50), received Acid (GABA) have been strongly associated with acute hyperammonemia and the severity of this disease, but criteria were randomly allocated into two groups with 50 L-Ornithine L-Aspartate (LOLA) and half received Placebo hepatic encephalopathy. 2 Among these, raised level of also in improving the patient's perceived quality of life.9 patients in each group. The Trial-Treatment group (50). In LOLA group 20(40%) were female and 30(60%) ammonia is thought to play a major role in pathogenesis Sharma et al conducted a study in 2014and concluded received L-Ornithine L-Aspartate; the Placebo group were male. In placebo group were 22(44%) female and of hepatic encephalopathy. 3,4 In hepatic encephalopat- that LOLA, probiotics and rifxamine were all superior to received normal saline. Both groups continued to 28(56%) male. Mean age was 49.66+ 12.25 SD in trial hy the rate of ammonia metabolism decreases and its placebo, although this study was conducted on patients receive all other standard supportive treatment group and 46.06 +9.83 SD in placebo group. Out of 100 permeability to blood brain barrier increases, resulting with minimal hepatic encephalopathy.10 A meta-analysis including lactulose and metronidazole. The patients people 43 % had HCV, 22 % had HBV, 4 % were non B-C in elevated ammonia levels in brain with variable done in 2009 reviewed four studies and concluded that with precipitating factors such as infection, and 8 % had both B and C virus. (Table: I) On Day I mean changes in blood. This mechanism is also supported by although use of LOLA was associated with decreasing constipation, hypokalemia, dehydration, electrolyte ammonia was 105.2 micromol/l in trial group. (Normal the fact that cirrhotic patients are sensitive to serum ammonia levels, no clinical improvement was

range: 6-47 micromol/l). In placebo group mean to identify two clinical trials. In 2011 Abid et al conducted Health Dr. Sadi Konuk Research and Training Hospital improvement; 1= a little, 2= some, 3= a lot, 4= Evaluation of patients’ pain relief scores treatment of acute migraine, but epigastric pain was ACKNOWLEDGEMENTS ammonia level was 112.28 micromole /dl on Day a study in Agha Khan university Hospital on 110 patients between January 2010 and December 2012. Inclusion complete, and worsening; -1= a litte, -2= some, -3= The pain relief was assessed individually after found significantly higher in the naproxen sodium I.(Table:II) On Day III mean ammonia level in the trial concluded that LOLA was safe and associated with rapid criteria was: a lot, -4= complete) after the administration of drug at administration of the first dose at 15th, 30th, 60th, group. (11) Ravishankar and colleagues evaluated the We certify that there is no conflict of interest with any financial organization regarding the subject discussed in the 14 group was 74.16 micromol/L. In placebo group mean clinical improvement and shorter hospital stay. Ahmed et 15 th, 30 th, 60 th, 90 th minutes and at 2 nd, 3 th, 90th minutes and the 2nd, 3th, 6th, 12th, 24th hours efficacy of sublingual piroxicam in patients suffering manuscript. We greatly appreciate recommendations and contributions of Professor, M.D. Rian Disci, Associate ammonia level was 110.52 micromol/L .On comparison of al conducted a study in in Shaikh Zyed hospital Lahore on - age between 18 and 65 years, 6 th, 12 th, 24 th hours. Evaluation of patient in both groups. There was not found any difference from migraine without aura. In their study, either Proffesor, M.D. Habip Gedik, and M.D. Arsida Bajrami about the manuscript. serum ammonia levels before(day 1) and after (day 3) 80 patients in 2008 concluded that ornithine infusion - being diagnosed with migraine without aura satisfaction was assessed at the end of the 24-h period between pain intensity scores which were surveyed after piroxicam 40 mg or placebo was administered L-ornithine L aspartate therapy ,the difference was was associated with rapid clinical recovery and decrease (8) according to the International Headache (1= satisfied, 2= unsatisfied). LNX and placebo treatments, statistically (Table 4). randomly and double-blind to 60 patients who were statistically significant in trial group(p value 0.0013) while serum ammonia.13 Considering the results of our trial and Society criteria (the year 2004), suffering from two to 16 migraine attacks per month it was non significant in placebo group.(p value 0.124) other national and international studies and meta - having experience of first headache attack A Statistical Analysis Evaluation of patients’ satisfaction scores without aura at age 18-50 years. (12) The severity of the (Table : II) To assess clinical improvement with LOLA, we analysis, we can recommend use of LOLA as addition to before 50 years of age, Age was expressed as mean ±standard deviation. Patients’ satisfaction scores were insignificant between pain was evaluated using the visual analogue scale used clinical grading of hepatic encephalopathy. In trial other standard therapies of hepatic encephalopathy since - having moderate to severe migraine attacks Changes in headache severity were assessed by LNX and placebo treatments, statistically (Table 5). (VAS). This study described the decrease in pain group, On Day I 10(20%) were in grade II, 17(34%) were ornithine therapy is safe, with mild side effects like with frequency less than 4 times per month. Mann-Whitney U test in the pre-treatment period and in grade III and 23(46%) were in grade IV hepatic nausea and vomiting and is easily available, can be given after the treatment at 15th, 30th, 60th, 90th minutes Evaluation of drug associated side-effects intensity at 15 min and even 24 hours after sublingual encephalopathy, while on day III 4(8%) were in grade both orally and parenterally and does not adds significant This study was approved by ethics committee that was and 2nd, 3th, 6th, 12th, 24th hours. Characteristics of No adverse reactions were with both placebo treatment piroxicam administration. This decrease was (12) zero, 18(36%) were in I, 20(40% ) were in grade II, cost to treatment of hepatic encephalopathy. Future established in the School of Medicine, Istanbul patient and placebo groups and satisfaction with the and LNX treatment. statistically significant compared to placebo 8(16%) in grade III and zero were in grade IV hepatic studies should be directed towards comparison of University. Randomization table has been used for treatment between placebo and treatment group was Ravishankar and his colleagues administered placebo encephalopathy. (Table:III) In placebo group on day I efficacy L ornithine therapy with others drugs used for randomization of the patients. Diagnosis of migraine of assessed by Chi-square test. Statistical significance Table 2: Distribution of the number of migraine attacks and the drug in different patient groups, whereas drug 12(24%) % were in grade II, 19(38%) were in grade III, standard treatment of hepatic encephalopathy like the included patients was done by a neurology was determined at p <0.05. in which LNX and placebo treatments were given and placebo were administered to the same group of 19(38%) were in grade IV hepatic encephalopathy, while lactitol, rifixamine, Zinc supplements and branch chain physician. Patients’ migraine attacks were recorded to patients in our study. The small population size and on day III no patient % was in grade zero,10(20%) were in amino acids. assess the effectiveness of LNX. After being informed Table 1: Demographic characteristics of the study Placebo LNX p administration of both the drug and placebo into a grade I, 12 (24%) were in grade II, 18(36%) were in about the study, all volunteers were asked to sign the participants. The number n % n % group of patients are likely to be related to this grade III and 10(20%) were in grade IV hepatic "informed consent form". Patients’ physical of migraine insignificance. Although mean age and the number of encephalopathy. On Day I clinical difference in grading of CONCLUSION examinations, pulse rates and blood pressure of attacks migraine attacks in our study were similar to hepatic encephalopathy between two groups was patients as well as medical history regarding usage of 1 13 39.4 29 33.3 Ravinshankar’s study, sublingual form is likely to cause statistically non significant. (p-values > 0.05) while on LOLA is effective in decreasing serum ammonia as well drug or non-drug medications and simultaneous 2 8 24.2 20 23 to different results compared to oral form as well. Since Day III, significant clinical improvement was observed p as causes clinical improvement in patients with hepatic systemic diseases were recorded during all visits. 3 5 15.2 26 29.9 the administration of piroxicam sublingually reaches an value < 0.05.(Table: III) encephalopathy. It can be recommended that LOLA Patients who were pregnant, nursing and planning to be 4 7 21.2 12 13.8 effective blood plasma concentration without being may be used in the patients with hepatic pregnant during the study, not informed about Total 33 100 87 100 0.360 INTRODUCTION Although the central effects of NSAIDs are not exactly exposed to the first-pass elimination in the liver. The encephalopathy especially when not responsive to treatment sufficiently, used different treatment for known, three mechanisms are mainly emphasized. side - effect did not develop in our study. In a study DISCUSSION standard treatment regimen. Migraine is a common cause of headache. Prevalence These are the inhibition of central nervous system migraine attacks, and who quitted the follow-up were DISCUSSION comparing of LNX with intravenous morphine in the of migraine is reported to be 11% in the adult prostaglandin synthesis by NSAIDs, the increasing of excluded from the study. Patients received two different treatment of post operative pain, LNX was found to In developing countries like Pakistan cirrhosis liver is more Table I: Distribution of patients according to population in the studies from western countries. (1) The CNS catecholamine and serotonin cycle, and the blisters containing either placebo or the study drug (8 LNX has been evaluated for the first time in terms of its 17 provide similar analgesic effect with a lower incidence prevalent compared to developed countries. In fact both characteristics study, which was conducted by Turkish headache inhibition of serotonin release during pain stimulus. (6) mg LNX) for two migraine attacks during first and efficacy and side-effects, due to the fact that there has (10) hepatitis B virus (HBV) and hepatitis C virus (HCV) epidemiology study group reported the incidence of Lornoxicam (LNX) (6-chloro-4-hydroxy 2-methyl second visits. The 3rd visit was arranged at the end of RESULTS been no study about it in the treatment of acute of adverse events. Adverse effects, such as nausea, 18,19 infections have become endemic in our community. migraine to be 16.4% between 15-65 years old. (2) It is N-pyridyl 2H-thienol (2, 3 e) 1, 2-thiazine the fourth week or within five days after second attack migraine attacks. In context with that although NSAIDs vomiting, gastritis, heartburn, and diarrhea were Hepatic Encephalopathy is a common neuro-psychiatric seen three times more in women than men, and it often 2-karbaksamid 1, 1-dioxide), is a NSAID drug in and the 4th visit was arranged at the end of the eighth During the study period, 6 of 50 patients were excluded were presented to be effective in the treatment of acute reported to develop less with a sublingual form of LNX complication in CLD. High levels of ammonia in the body occurs between the ages of 25 to 55 years. (3, 4) non-selective, oxicam group according to former week or within five days after third attack. They were from the study due to excluding criteria. Of 44 patients migraine attacks, serum level concentration of LNX than naproxen sodium in the study of Aabakken et al. (9) is a major cause of hepatic encephalopathy, that’s why Migraine treatments are generally based on two major classification. LNX has potent anti-inflammatory and allowed to use maximum two tablets in a day. If whose 120 migraine attacks were evaluated, 38 were should be measured after oral use to evaluate the In a study performed on healthy volunteers, it has been most of the treatments are targeted against the groups, including non-pharmacological and pharmacol- analgesic effects similar to other oxicams but unlike headache persisted despite the use of the two tablets females. Mean age 37.75 ± 9.28 years. efficacy appropriately. (5) Since oral usage of LNX cannot verified that less gastro-duodenal injury developed with detoxification of ammonia. L Ornithine L aspartate (LOLA) ogical methods. Pharmacological treatment is divided them it has a shorter half life (3-5 hours). Both oral and given for the study, they were permitted to use Characteristics of patients have been shown in Table 1. reach therapeutic blood concentration rapidly and LNX (16 mg / day) compared to naproxen sodium stimulates the urea cycle and ammonia utilization that’s into two groups; prophylactic and acute attack parenteral preparations are used. LNX has a better eletriptan 40 mg as a subsidiary medicine at least an There was no comorbidity in both patient and placebo sufficiently despite its short and rapid time of action, (1000 mg / day). (9) The limitations of our study are why thought to be useful in acute hepatic encephalopathy. treatment.(5) Acute migraine attacks should be managed tolerability profile compared with other oxicam drugs hour after the second tablet. Patients were inquired groups. During the study period, LNX was used in the because of first-pass elimination. Also a parenteral form small population size, administration of both drug and In our study, it was observed that the LOLA has beneficial (7) rapidly and effectively. Therapy is considered to be because of shorter half life. Clinical trials suggest LNX which blister they had taken if they had headache 87 attacks, placebo was used in the 33 attacks. The of LNX may be evaluated or compared with oral form to placebo in some cases, usage of only oral form of LNX. effects not only in clinical improvement of encephalopathy successful when there is decrease in the frequency and as an effective drug in the treatment of post-operative attack and whether they had taken one more tablet number of headache attacks in which placebo and LNX reveal its effectiveness and whether the administration Intravenous form of LNX should be evaluated in terms of but also obvious decrease in serum ammonia levels after (5) from blisters when headache persisted for three hours. were used is given in Table 2. route is important or not. Despite studies showing the severity of attacks. Acute attack treatment should be and joint pains. The aim of this study was to assess the efficacy and side-effects compared with oral forms of infusion of LOLA. These results were comparable to other Migraine attacks of patients which were not recorded effectiveness of oral administration of LNX’ are tailored to the patients systemic disease and symptoms efficacy of LNX in treatment of headaches due to acute LNX with a randomized-controlled study for treatment of studies. Bai et al concluded after meta-analysis of 8 during follow up were not evaluated. Pain intensity Evaluation of patients’ pain intensity scores associated with pains other than migraine it is as well as the severity, duration and frequency of the migraine attacks. acute migraine attacks. As a result, although oral LNX randomized clinical trials including 646 patients that, attacks. In mild and moderate attacks, non-specific score was rated from 0 to 3 points (0= none, 1= mild, The severity of the headache was assessed individually important to ensure early, rapid and effective plasma was found to have efficacy similar to placebo LOLA was beneficial in both overt and minimal hepatic therapy non-steroidal anti-inflammatory drugs (NSAIDs) MATERIAL AND METHODS 2= moderate, 3= severe) in the survey. Headache after administration of the first dose at the beginning, concentration in pains related to migraine. (9, 10) NSAIDs statistically in the treatment of acute migraine attacks, encephalopathy, causes both clinical and biochemical alone or in combination with either caffeine or codeine severity was evaluated with a questionnaire performed 15th, 30th, 60th, 90th minutes and the 2nd, 3th, 6th, in the oxicam groups were reported to be effective for 20 further studies are needed, including two different detoxification of ammonia. Another meta analysis done may be used. Moderate and severe attacks which This is a prospective, randomized, double-blind, before taking the drug at 0.min and at 15th, 30th, 12th, 24th hours in both groups. There was not found acute migraine attacks. In a study conducted by CY et in 2011 supported the use of LOLA for neuro-psychiatric cannot be prevented with nonspecific migraine drugs placebo-controlled study conducted by department of 60th, 90th minutes and at 2nd, 3th, 6th, 12th, 24th difference between pain intensity scores which were al the effectiveness of celecoxib and naproxen sodium groups, two forms and different dosages of LNX to 21 improvement as well as decreasing levels of ammonia. are managed with specific drugs such as triptans or clinical of algology, school of medicine Istanbul hours after the administration of drug. Pain relief was surveyed after LNX and placebo treatments, statistically in the treatment of acute migraine was investigated. evaluate appropriately the efficacy of LNX for treatment Although regional data is sparse however, it is necessary ergot derivatives.(5) University and department of neurology, Ministry of assessed with a rating system of 5 points (0= none, (Table 3). Both drugs were found to be equally effective in the of acute migraine attacks.

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES 44 VOL. 10 (3) JUL - SEPT 2015 observed. But these studies were of small sample size imbalance, prolonged prothrombin time were treated and shorter follow ups.11 Another meta-analysis done accordingly. Performa was completed for each patient on three studies showed that LOLA therapy causes to record demographics, vitals, complete blood counts, decrease in serum ammonia levels, and also clinical liver function tests, prothrombin time, total proteins, improvement.12 Moreover most of the available data electrolytes, serum ammonia, random blood glucose assessed role of LOLA in minimal encephalopathy, not and renal status. In addition, ultra-sound of the whole the over encephalopathy. In the review of local data, abdomen was also done, to assess the size of liver, there are only two authentic large trials available.13,14 spleen and portal vein. Trial-Treatment group received a Therefore due to absence of large studies, controversial daily intravenous infusion of 20 g (4 ampoules) existing data and paucity of local data, we conducted a L-Ornithine L-Aspartate (Inj HepaMerz, Brooks pharma) study to observe effect of LOLA on clinical improvement diluted in 250 ml of 5% dextrose water administered in most stages of hepatic encephalopathy. slowly over 4 hours for three consecutive days. The Placebo group received a daily administration of 250 ml MATERIAL & METHOD normal saline over 4 hours for three consecutive days. It was ensured that the infusions were given at the After approval of Ethical review committee of Jinnah same specified time to both groups of patients. About 5 Medical and Dental College, a randomized, placebo- ml of blood of each patient was drawn on Day 1 and control trial was performed in medical department of Day 3 under aseptic techniques, stored in rubber Jinnah medical and dental college Hospital Korangi corked glass tubes for checking ammonia levels. The Karachi from July 2013 to June 2014. The trial was Tubes were frozen at 4 degrees centigrade temperature. designed and reported according to CONSORT The ammonia determination was performed according guidelines.15 An informed consent was taken before to the enzymatic determination of ammonia with entry in the trial. Data was collected by Interns and glutamine dehydrogenase in a rapid and interference – residents of the ward, who were trained by the authors free photomertric determination of NH4+ in native for this study through workshops and meetings. blood plasma. The testing was performed at a reliable Patients > 18 years of age, admitted in medical ward, laboratory of Karachi. Sample on Day 1, was collected diagnosed with Chronic liver disease (CLD) due to any as soon as a patient presented, before any treatment cause, having grade II to grade IV Hepatic was started. The second sample was drawn on Day 3 Encephalopathy were included in the study after i.e. after the patient received three days of the informed consent. CLD was diagnosed by common Trial-Treatment or Placebo. Clinical improvement in complications like ascites, gastro-oesophagal varices, hepatic encephalopathy was noted by West Haven’s INTRODUCTION conditions associated with excess ammonia with sonographic findings of shrunken liver, splenomegaly, criteria, on day 1 before LOLA infusion and on day III (constipation, protein overload, internal bleeding or portal vein size > 1 cm, deranged clotting profile and after infusion. Data was collected on the prescribed Cirrhosis or end stage liver disease is destruction of sepsis).5 It also explains the reason why some patients and inverse albumin /globulin ratio. Hepatic performa and analyzed using Statistical Package for normal liver parenchyma, replaced by regenerating have marginal elevation of arterial ammonia, despite encephalopathy was diagnosed on the basis of Social Services (SPSS) V 17. Numerical data was nodules and scar tissue, due to various reasons hepatic encephalopathy.6 Therefore reduction in confusion, drowsiness, restlessness, disorientation and recorded as mean and standard deviation, nominal data common causes includes HBV, HCV, and alcoholic liver ammonia levels in the body is important treatment asterixis without any altered explanation of these was recorded as frequency and percentage. Patients on disease. Hepatic Encephalopathy is present in about strategy.7 The L-ornithine L-Aspartate(LOLA) are salts of symptoms. Clinical grading of hepatic encephalopathy treatment with Ornithine - Aspartate infusion and on 50-70% of all patients with cirrhosis.(1) Hepatic naturally occurring aminoacids ornithine and aspartate. was done by West Haven’s criteria.16 Patient having placebo were compared by paired t-test. A p-value of < Encephalopathy is a complex neuropsychiatric syndrome They stimulate urea cycle and glutamine synthesis, sepsis, hepatorenal syndrome, acute/ chronic kidney 0.05 was considered statistically significant. associated with acute or chronic hepato- cellular failure which are major mechanisms of ammonia detoxification.8 disease were excluded from the study because they and porto-systemic shunting of blood. It is one of the Over last 25 years, various studies were carried out might affect ammonia levels. Hypoglycemia and RESULT major complications of cirrhosis. Various neurotoxins regarding efficacy of LOLA in improvement of hepatic respiratory failure was excluded by measuring random have been known to involve in pathogenesis of hepatic encephalopathy, showed controversial results. Blanco blood sugar and arterial blood gases. The estimated Out of 102, two patients were discharged or referred encephalopathy. High levels of ammonia, glutamate, et al compared the standard treatment, with LOLA and sample size was 102 patients, considering 500 annual before collection of data. The remaining patients endogenous benzodiazepines, Gamma Amino butyric concluded that LOLA was effective not only in reducing admissions in our ward. The patients meeting inclusion completed study. Half of the patients (50), received Acid (GABA) have been strongly associated with acute hyperammonemia and the severity of this disease, but criteria were randomly allocated into two groups with 50 L-Ornithine L-Aspartate (LOLA) and half received Placebo hepatic encephalopathy. 2 Among these, raised level of also in improving the patient's perceived quality of life.9 patients in each group. The Trial-Treatment group (50). In LOLA group 20(40%) were female and 30(60%) ammonia is thought to play a major role in pathogenesis Sharma et al conducted a study in 2014and concluded received L-Ornithine L-Aspartate; the Placebo group were male. In placebo group were 22(44%) female and of hepatic encephalopathy. 3,4 In hepatic encephalopat- that LOLA, probiotics and rifxamine were all superior to received normal saline. Both groups continued to 28(56%) male. Mean age was 49.66+ 12.25 SD in trial hy the rate of ammonia metabolism decreases and its placebo, although this study was conducted on patients receive all other standard supportive treatment group and 46.06 +9.83 SD in placebo group. Out of 100 permeability to blood brain barrier increases, resulting with minimal hepatic encephalopathy.10 A meta-analysis including lactulose and metronidazole. The patients people 43 % had HCV, 22 % had HBV, 4 % were non B-C in elevated ammonia levels in brain with variable done in 2009 reviewed four studies and concluded that with precipitating factors such as infection, and 8 % had both B and C virus. (Table: I) On Day I mean changes in blood. This mechanism is also supported by although use of LOLA was associated with decreasing constipation, hypokalemia, dehydration, electrolyte ammonia was 105.2 micromol/l in trial group. (Normal the fact that cirrhotic patients are sensitive to serum ammonia levels, no clinical improvement was

range: 6-47 micromol/l). In placebo group mean to identify two clinical trials. In 2011 Abid et al conducted Health Dr. Sadi Konuk Research and Training Hospital improvement; 1= a little, 2= some, 3= a lot, 4= Evaluation of patients’ pain relief scores treatment of acute migraine, but epigastric pain was ACKNOWLEDGEMENTS ammonia level was 112.28 micromole /dl on Day a study in Agha Khan university Hospital on 110 patients between January 2010 and December 2012. Inclusion complete, and worsening; -1= a litte, -2= some, -3= The pain relief was assessed individually after found significantly higher in the naproxen sodium I.(Table:II) On Day III mean ammonia level in the trial concluded that LOLA was safe and associated with rapid criteria was: a lot, -4= complete) after the administration of drug at administration of the first dose at 15th, 30th, 60th, group. (11) Ravishankar and colleagues evaluated the We certify that there is no conflict of interest with any financial organization regarding the subject discussed in the 14 group was 74.16 micromol/L. In placebo group mean clinical improvement and shorter hospital stay. Ahmed et 15 th, 30 th, 60 th, 90 th minutes and at 2 nd, 3 th, 90th minutes and the 2nd, 3th, 6th, 12th, 24th hours efficacy of sublingual piroxicam in patients suffering manuscript. We greatly appreciate recommendations and contributions of Professor, M.D. Rian Disci, Associate ammonia level was 110.52 micromol/L .On comparison of al conducted a study in in Shaikh Zyed hospital Lahore on - age between 18 and 65 years, 6 th, 12 th, 24 th hours. Evaluation of patient in both groups. There was not found any difference from migraine without aura. In their study, either Proffesor, M.D. Habip Gedik, and M.D. Arsida Bajrami about the manuscript. serum ammonia levels before(day 1) and after (day 3) 80 patients in 2008 concluded that ornithine infusion - being diagnosed with migraine without aura satisfaction was assessed at the end of the 24-h period between pain intensity scores which were surveyed after piroxicam 40 mg or placebo was administered L-ornithine L aspartate therapy ,the difference was was associated with rapid clinical recovery and decrease (8) Table 3: Evaluation of patients’ pain intensity scores after LNX and placebo treatments according to the International Headache (1= satisfied, 2= unsatisfied). LNX and placebo treatments, statistically (Table 4). randomly and double-blind to 60 patients who were statistically significant in trial group(p value 0.0013) while serum ammonia.13 Considering the results of our trial and Society criteria (the year 2004), suffering from two to 16 migraine attacks per month it was non significant in placebo group.(p value 0.124) other national and international studies and meta - having experience of first headache attack A Statistical Analysis Evaluation of patients’ satisfaction scores without aura at age 18-50 years. (12) The severity of the Post-treatment (Table : II) To assess clinical improvement with LOLA, we analysis, we can recommend use of LOLA as addition to before 50 years of age, Age was expressed as mean ±standard deviation. Patients’ satisfaction scores were insignificant between pain was evaluated using the visual analogue scale used clinical grading of hepatic encephalopathy. In trial other standard therapies of hepatic encephalopathy since - having moderate to severe migraine attacks Changes in headache severity were assessed by LNX and placebo treatments, statistically (Table 5). Pain Beginning 15-min 30-min 60-min 90-min 2-h 3-h 6-h 12- h 24-h (VAS). This study described the decrease in pain group, On Day I 10(20%) were in grade II, 17(34%) were ornithine therapy is safe, with mild side effects like with frequency less than 4 times per month. Mann-Whitney U test in the pre-treatment period and intensity n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) in grade III and 23(46%) were in grade IV hepatic nausea and vomiting and is easily available, can be given after the treatment at 15th, 30th, 60th, 90th minutes Evaluation of drug associated side-effects intensity at 15 min and even 24 hours after sublingual score Placebo 0 - - 1(3.1) 2(6.3) 3(10.7) 2(6.7) 2(8.3) 3(37.5) 2(33.3) 3(50) encephalopathy, while on day III 4(8%) were in grade both orally and parenterally and does not adds significant This study was approved by ethics committee that was and 2nd, 3th, 6th, 12th, 24th hours. Characteristics of No adverse reactions were with both placebo treatment piroxicam administration. This decrease was (12) Group 1 4(12.1) 5(15.6) 7(21.9) 9(28.1) 7(25) 5(16.7) 8(33.3) 3(37.5) 3(50) 3(50) zero, 18(36%) were in I, 20(40% ) were in grade II, cost to treatment of hepatic encephalopathy. Future statistically significant compared to placebo established in the School of Medicine, Istanbul patient and placebo groups and satisfaction with the and LNX treatment. 2 16(48.5) 17(53.1) 16(50) 13(40.6) 11(39.3) 12(40) 8(33.3) 1(12.5) 1(16.7) - Ravishankar and his colleagues administered placebo 8(16%) in grade III and zero were in grade IV hepatic studies should be directed towards comparison of University. Randomization table has been used for treatment between placebo and treatment group was 3 13(39.4) 10(31.3) 8(25) 8(25) 7(25) 11(36.6) 6(25.1) 1(12.5) - - encephalopathy. (Table:III) In placebo group on day I efficacy L ornithine therapy with others drugs used for randomization of the patients. Diagnosis of migraine of assessed by Chi-square test. Statistical significance Table 2: Distribution of the number of migraine attacks and the drug in different patient groups, whereas drug LNX 0 - - 2(2.4) 8(10.1) 4(6) 7(9.3) 13(22.1) 14(42.4) 15(53.6) 13(52) 12(24%) % were in grade II, 19(38%) were in grade III, standard treatment of hepatic encephalopathy like the included patients was done by a neurology was determined at p <0.05. in which LNX and placebo treatments were given and placebo were administered to the same group of Group 1 13(14.9) 12(14.5) 17(20.5) 19(24.1) 21(31.8) 20(26.7) 14(23.7) 6(18.2) 8(28.6) 6(24) 19(38%) were in grade IV hepatic encephalopathy, while lactitol, rifixamine, Zinc supplements and branch chain physician. Patients’ migraine attacks were recorded to patients in our study. The small population size and 2 44(50.6) 38(45.8) 32(38.5) 29(36.7) 23(34.9) 26(34.7) 18(30.5) 9(27.3) 2(7.1) 2(8) on day III no patient % was in grade zero,10(20%) were in amino acids. assess the effectiveness of LNX. After being informed Table 1: Demographic characteristics of the study administration of both the drug and placebo into a 3 30(34.5) 33(39.7) 32(38.6) 23(29.1) 18(27.3) 22(29.3) 14(23.7) 4(12.1) 3(10.7) 4(16) grade I, 12 (24%) were in grade II, 18(36%) were in about the study, all volunteers were asked to sign the participants. group of patients are likely to be related to this grade III and 10(20%) were in grade IV hepatic "informed consent form". Patients’ physical insignificance. Although mean age and the number of Table 4: The pain relief scores of the cases after LNX and placebo treatments encephalopathy. On Day I clinical difference in grading of CONCLUSION examinations, pulse rates and blood pressure of migraine attacks in our study were similar to hepatic encephalopathy between two groups was patients as well as medical history regarding usage of Ravinshankar’s study, sublingual form is likely to cause statistically non significant. (p-values > 0.05) while on LOLA is effective in decreasing serum ammonia as well Post-treatment drug or non-drug medications and simultaneous to different results compared to oral form as well. Since Day III, significant clinical improvement was observed p as causes clinical improvement in patients with hepatic systemic diseases were recorded during all visits. the administration of piroxicam sublingually reaches an Pain relief 15 min 30 min 60 min 90 min 2 h 3 h 6 h 12 h 24 h value < 0.05.(Table: III) encephalopathy. It can be recommended that LOLA Patients who were pregnant, nursing and planning to be effective blood plasma concentration without being score n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) may be used in the patients with hepatic pregnant during the study, not informed about Placebo 4 ------INTRODUCTION Although the central effects of NSAIDs are not exactly exposed to the first-pass elimination in the liver. The encephalopathy especially when not responsive to treatment sufficiently, used different treatment for Treatment 3 - 1(3.1) - - - - 1(12.5) - 1(16.7) known, three mechanisms are mainly emphasized. side - effect did not develop in our study. In a study DISCUSSION standard treatment regimen. Migraine is a common cause of headache. Prevalence These are the inhibition of central nervous system migraine attacks, and who quitted the follow-up were DISCUSSION 2 1(3.1) 2(6.3) 4(12.5) 5(17.9) 3(10) 6(25) 1(12.5) 3(50) 2(33.3) comparing of LNX with intravenous morphine in the 1 4(12.5) 5(15.6) 8(25) 8(28.5) 9(30) 5(20.8) 5(62.5) 2(33.3) 3(50) of migraine is reported to be 11% in the adult prostaglandin synthesis by NSAIDs, the increasing of excluded from the study. Patients received two different treatment of post operative pain, LNX was found to 0 25(78.1) 22(68.7) 17(53.1) 12(42.9) 12(40) 10(41.7) - 1(16.7) - In developing countries like Pakistan cirrhosis liver is more Table I: Distribution of patients according to population in the studies from western countries. (1) The CNS catecholamine and serotonin cycle, and the blisters containing either placebo or the study drug (8 LNX has been evaluated for the first time in terms of its 17 -1 2(6.3) 2(6.3) 3(9.4) 3(10.7) 5(16.7) 3(12.5) 1(12.5) - - prevalent compared to developed countries. In fact both characteristics (6) mg LNX) for two migraine attacks during first and efficacy and side-effects, due to the fact that there has provide similar analgesic effect with a lower incidence study, which was conducted by Turkish headache inhibition of serotonin release during pain stimulus. -2 - - - - 1(3.3) - - - - hepatitis B virus (HBV) and hepatitis C virus (HCV) of adverse events. (10) Adverse effects, such as nausea, epidemiology study group reported the incidence of Lornoxicam (LNX) (6-chloro-4-hydroxy 2-methyl second visits. The 3rd visit was arranged at the end of RESULTS been no study about it in the treatment of acute -3 ------18,19 infections have become endemic in our community. migraine to be 16.4% between 15-65 years old. (2) It is N-pyridyl 2H-thienol (2, 3 e) 1, 2-thiazine the fourth week or within five days after second attack migraine attacks. In context with that although NSAIDs vomiting, gastritis, heartburn, and diarrhea were -4 ------Hepatic Encephalopathy is a common neuro-psychiatric seen three times more in women than men, and it often 2-karbaksamid 1, 1-dioxide), is a NSAID drug in and the 4th visit was arranged at the end of the eighth During the study period, 6 of 50 patients were excluded were presented to be effective in the treatment of acute reported to develop less with a sublingual form of LNX LNX 4 ------complication in CLD. High levels of ammonia in the body occurs between the ages of 25 to 55 years. (3, 4) non-selective, oxicam group according to former week or within five days after third attack. They were from the study due to excluding criteria. Of 44 patients migraine attacks, serum level concentration of LNX than naproxen sodium in the study of Aabakken et al. (9) Treatment 3 - - 2(2.5) 2(3) 2(2.7) 5(8.5) 6(18.2) 6(21.4) 6(24) is a major cause of hepatic encephalopathy, that’s why Migraine treatments are generally based on two major classification. LNX has potent anti-inflammatory and allowed to use maximum two tablets in a day. If whose 120 migraine attacks were evaluated, 38 were should be measured after oral use to evaluate the In a study performed on healthy volunteers, it has been 2 1(1.2) 4(4.8) 6(7.6) 5(7.6) 9(12) 11(18.6) 9(27.3) 11(39.3) 9(36) most of the treatments are targeted against the groups, including non-pharmacological and pharmacol- analgesic effects similar to other oxicams but unlike headache persisted despite the use of the two tablets females. Mean age 37.75 ± 9.28 years. efficacy appropriately. (5) Since oral usage of LNX cannot verified that less gastro-duodenal injury developed with 1 5(6) 11(13.3) 23(29.1) 21(31.8) 18(24) 12(20.3) 6(18.2) 6(21.4) 4(16) 0 66(79.5) 54(65) 36(45.6) 27(40.9) 33(44) 20(33.9) 9(27.3) 3(10.7) 4(16) detoxification of ammonia. L Ornithine L aspartate (LOLA) ogical methods. Pharmacological treatment is divided them it has a shorter half life (3-5 hours). Both oral and given for the study, they were permitted to use Characteristics of patients have been shown in Table 1. reach therapeutic blood concentration rapidly and LNX (16 mg / day) compared to naproxen sodium -1 11(13.3) 13(15.7) 11(13.9) 10(15.2) 11(14.6) 10(17) 1(3) - - stimulates the urea cycle and ammonia utilization that’s eletriptan 40 mg as a subsidiary medicine at least an There was no comorbidity in both patient and placebo sufficiently despite its short and rapid time of action, (9) into two groups; prophylactic and acute attack parenteral preparations are used. LNX has a better (1000 mg / day). The limitations of our study are -2 - 1(1.2) 1(1.3) 1(1.5) 2(2.7) 1(1.7) 2(6) 2(7.2) 2(8) why thought to be useful in acute hepatic encephalopathy. (5) hour after the second tablet. Patients were inquired groups. During the study period, LNX was used in the because of first-pass elimination. Also a parenteral form treatment. Acute migraine attacks should be managed tolerability profile compared with other oxicam drugs small population size, administration of both drug and -3 ------In our study, it was observed that the LOLA has beneficial (7) rapidly and effectively. Therapy is considered to be because of shorter half life. Clinical trials suggest LNX which blister they had taken if they had headache 87 attacks, placebo was used in the 33 attacks. The of LNX may be evaluated or compared with oral form to placebo in some cases, usage of only oral form of LNX. -4 ------effects not only in clinical improvement of encephalopathy successful when there is decrease in the frequency and as an effective drug in the treatment of post-operative attack and whether they had taken one more tablet number of headache attacks in which placebo and LNX reveal its effectiveness and whether the administration Intravenous form of LNX should be evaluated in terms of p value 0.106 0.135 0.793 0.466 0.811 0.967 0.961 0.522 1 but also obvious decrease in serum ammonia levels after (5) from blisters when headache persisted for three hours. were used is given in Table 2. route is important or not. Despite studies showing the severity of attacks. Acute attack treatment should be and joint pains. The aim of this study was to assess the efficacy and side-effects compared with oral forms of infusion of LOLA. These results were comparable to other Migraine attacks of patients which were not recorded effectiveness of oral administration of LNX’ are tailored to the patients systemic disease and symptoms efficacy of LNX in treatment of headaches due to acute LNX with a randomized-controlled study for treatment of studies. Bai et al concluded after meta-analysis of 8 during follow up were not evaluated. Pain intensity Evaluation of patients’ pain intensity scores associated with pains other than migraine it is Table 5: Patients’ satisfaction scores as well as the severity, duration and frequency of the migraine attacks. acute migraine attacks. As a result, although oral LNX randomized clinical trials including 646 patients that, attacks. In mild and moderate attacks, non-specific score was rated from 0 to 3 points (0= none, 1= mild, The severity of the headache was assessed individually important to ensure early, rapid and effective plasma was found to have efficacy similar to placebo LOLA was beneficial in both overt and minimal hepatic therapy non-steroidal anti-inflammatory drugs (NSAIDs) MATERIAL AND METHODS 2= moderate, 3= severe) in the survey. Headache after administration of the first dose at the beginning, concentration in pains related to migraine. (9, 10) NSAIDs Placebo LNX p statistically in the treatment of acute migraine attacks, n % n % encephalopathy, causes both clinical and biochemical alone or in combination with either caffeine or codeine severity was evaluated with a questionnaire performed 15th, 30th, 60th, 90th minutes and the 2nd, 3th, 6th, in the oxicam groups were reported to be effective for detoxification of ammonia.20 Another meta analysis done before taking the drug at 0.min and at 15th, 30th, 12th, 24th hours in both groups. There was not found acute migraine attacks. In a study conducted by CY et further studies are needed, including two different Satisfied 18 54.5 48 55.2 may be used. Moderate and severe attacks which This is a prospective, randomized, double-blind, Unsatisfied 15 45.5 39 44.8 in 2011 supported the use of LOLA for neuro-psychiatric cannot be prevented with nonspecific migraine drugs placebo-controlled study conducted by department of 60th, 90th minutes and at 2nd, 3th, 6th, 12th, 24th difference between pain intensity scores which were al the effectiveness of celecoxib and naproxen sodium groups, two forms and different dosages of LNX to 21 Total 33 100 87 100 0.690 improvement as well as decreasing levels of ammonia. are managed with specific drugs such as triptans or clinical of algology, school of medicine Istanbul hours after the administration of drug. Pain relief was surveyed after LNX and placebo treatments, statistically in the treatment of acute migraine was investigated. evaluate appropriately the efficacy of LNX for treatment Although regional data is sparse however, it is necessary ergot derivatives.(5) University and department of neurology, Ministry of assessed with a rating system of 5 points (0= none, (Table 3). Both drugs were found to be equally effective in the of acute migraine attacks.

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES 45 VOL. 10 (3) JUL - SEPT 2015 observed. But these studies were of small sample size imbalance, prolonged prothrombin time were treated and shorter follow ups.11 Another meta-analysis done accordingly. Performa was completed for each patient on three studies showed that LOLA therapy causes to record demographics, vitals, complete blood counts, decrease in serum ammonia levels, and also clinical liver function tests, prothrombin time, total proteins, improvement.12 Moreover most of the available data electrolytes, serum ammonia, random blood glucose assessed role of LOLA in minimal encephalopathy, not and renal status. In addition, ultra-sound of the whole the over encephalopathy. In the review of local data, abdomen was also done, to assess the size of liver, there are only two authentic large trials available.13,14 spleen and portal vein. Trial-Treatment group received a Therefore due to absence of large studies, controversial daily intravenous infusion of 20 g (4 ampoules) existing data and paucity of local data, we conducted a L-Ornithine L-Aspartate (Inj HepaMerz, Brooks pharma) study to observe effect of LOLA on clinical improvement diluted in 250 ml of 5% dextrose water administered in most stages of hepatic encephalopathy. slowly over 4 hours for three consecutive days. The Placebo group received a daily administration of 250 ml MATERIAL & METHOD normal saline over 4 hours for three consecutive days. It was ensured that the infusions were given at the After approval of Ethical review committee of Jinnah same specified time to both groups of patients. About 5 Medical and Dental College, a randomized, placebo- ml of blood of each patient was drawn on Day 1 and control trial was performed in medical department of Day 3 under aseptic techniques, stored in rubber Jinnah medical and dental college Hospital Korangi corked glass tubes for checking ammonia levels. The Karachi from July 2013 to June 2014. The trial was Tubes were frozen at 4 degrees centigrade temperature. designed and reported according to CONSORT The ammonia determination was performed according guidelines.15 An informed consent was taken before to the enzymatic determination of ammonia with entry in the trial. Data was collected by Interns and glutamine dehydrogenase in a rapid and interference – residents of the ward, who were trained by the authors free photomertric determination of NH4+ in native for this study through workshops and meetings. blood plasma. The testing was performed at a reliable Patients > 18 years of age, admitted in medical ward, laboratory of Karachi. Sample on Day 1, was collected diagnosed with Chronic liver disease (CLD) due to any as soon as a patient presented, before any treatment cause, having grade II to grade IV Hepatic was started. The second sample was drawn on Day 3 Encephalopathy were included in the study after i.e. after the patient received three days of the informed consent. CLD was diagnosed by common Trial-Treatment or Placebo. Clinical improvement in complications like ascites, gastro-oesophagal varices, hepatic encephalopathy was noted by West Haven’s INTRODUCTION conditions associated with excess ammonia with sonographic findings of shrunken liver, splenomegaly, criteria, on day 1 before LOLA infusion and on day III (constipation, protein overload, internal bleeding or portal vein size > 1 cm, deranged clotting profile and after infusion. Data was collected on the prescribed Cirrhosis or end stage liver disease is destruction of sepsis).5 It also explains the reason why some patients and inverse albumin /globulin ratio. Hepatic performa and analyzed using Statistical Package for normal liver parenchyma, replaced by regenerating have marginal elevation of arterial ammonia, despite encephalopathy was diagnosed on the basis of Social Services (SPSS) V 17. Numerical data was nodules and scar tissue, due to various reasons hepatic encephalopathy.6 Therefore reduction in confusion, drowsiness, restlessness, disorientation and recorded as mean and standard deviation, nominal data common causes includes HBV, HCV, and alcoholic liver ammonia levels in the body is important treatment asterixis without any altered explanation of these was recorded as frequency and percentage. Patients on disease. Hepatic Encephalopathy is present in about strategy.7 The L-ornithine L-Aspartate(LOLA) are salts of symptoms. Clinical grading of hepatic encephalopathy treatment with Ornithine - Aspartate infusion and on 50-70% of all patients with cirrhosis.(1) Hepatic naturally occurring aminoacids ornithine and aspartate. was done by West Haven’s criteria.16 Patient having placebo were compared by paired t-test. A p-value of < Encephalopathy is a complex neuropsychiatric syndrome They stimulate urea cycle and glutamine synthesis, sepsis, hepatorenal syndrome, acute/ chronic kidney 0.05 was considered statistically significant. associated with acute or chronic hepato- cellular failure which are major mechanisms of ammonia detoxification.8 disease were excluded from the study because they and porto-systemic shunting of blood. It is one of the Over last 25 years, various studies were carried out might affect ammonia levels. Hypoglycemia and RESULT major complications of cirrhosis. Various neurotoxins regarding efficacy of LOLA in improvement of hepatic respiratory failure was excluded by measuring random have been known to involve in pathogenesis of hepatic encephalopathy, showed controversial results. Blanco blood sugar and arterial blood gases. The estimated Out of 102, two patients were discharged or referred encephalopathy. High levels of ammonia, glutamate, et al compared the standard treatment, with LOLA and sample size was 102 patients, considering 500 annual before collection of data. The remaining patients endogenous benzodiazepines, Gamma Amino butyric concluded that LOLA was effective not only in reducing admissions in our ward. The patients meeting inclusion completed study. Half of the patients (50), received Acid (GABA) have been strongly associated with acute hyperammonemia and the severity of this disease, but criteria were randomly allocated into two groups with 50 L-Ornithine L-Aspartate (LOLA) and half received Placebo hepatic encephalopathy. 2 Among these, raised level of also in improving the patient's perceived quality of life.9 patients in each group. The Trial-Treatment group (50). In LOLA group 20(40%) were female and 30(60%) ammonia is thought to play a major role in pathogenesis Sharma et al conducted a study in 2014and concluded received L-Ornithine L-Aspartate; the Placebo group were male. In placebo group were 22(44%) female and of hepatic encephalopathy. 3,4 In hepatic encephalopat- that LOLA, probiotics and rifxamine were all superior to received normal saline. Both groups continued to 28(56%) male. Mean age was 49.66+ 12.25 SD in trial hy the rate of ammonia metabolism decreases and its placebo, although this study was conducted on patients receive all other standard supportive treatment group and 46.06 +9.83 SD in placebo group. Out of 100 permeability to blood brain barrier increases, resulting with minimal hepatic encephalopathy.10 A meta-analysis including lactulose and metronidazole. The patients people 43 % had HCV, 22 % had HBV, 4 % were non B-C in elevated ammonia levels in brain with variable done in 2009 reviewed four studies and concluded that with precipitating factors such as infection, and 8 % had both B and C virus. (Table: I) On Day I mean changes in blood. This mechanism is also supported by although use of LOLA was associated with decreasing constipation, hypokalemia, dehydration, electrolyte ammonia was 105.2 micromol/l in trial group. (Normal the fact that cirrhotic patients are sensitive to serum ammonia levels, no clinical improvement was

range: 6-47 micromol/l). In placebo group mean to identify two clinical trials. In 2011 Abid et al conducted REFERENCES Tomsik J, Elton TS, Simmons DL. COX-3, a ammonia level was 112.28 micromole /dl on Day a study in Agha Khan university Hospital on 110 patients cyclooxygenase-1 variant inhibited by I.(Table:II) On Day III mean ammonia level in the trial concluded that LOLA was safe and associated with rapid 1. Scher AI, Stewart WF, Lipton RB. Migraine and acetaminophen and other analgesic/antipyretic group was 74.16 micromol/L. In placebo group mean clinical improvement and shorter hospital stay.14 Ahmed et headache: a meta-analytic approach. In: Crombie drugs: cloning, structure, and expression. Proc Natl ammonia level was 110.52 micromol/L .On comparison of al conducted a study in in Shaikh Zyed hospital Lahore on IK (ed) Epidemiology of pain, Seattle: WA, IASP Acad Sci U S A. 2002;15; 99(21):13926-13931. serum ammonia levels before(day 1) and after (day 3) 80 patients in 2008 concluded that ornithine infusion Press. 1999, 159-170. 8. Bolukbası N, Ersanli S, Basegmez C, Ozdemir T, L-ornithine L aspartate therapy ,the difference was was associated with rapid clinical recovery and decrease 2. Siva A. Baş ağrısı epidemiyolojisi. Baş, boyun ve Ozyalcin S. Efficacy of quick-release lornoxicam statistically significant in trial group(p value 0.0013) while serum ammonia.13 Considering the results of our trial and bel ağrıları sempozyum dizisi 2002; 30: 9-14. versus placebo for acute pain management after it was non significant in placebo group.(p value 0.124) other national and international studies and meta 3. Lipton RB, Bigal ME. Migraine: epidemiology, dental implant surgery: a randomised (Table : II) To assess clinical improvement with LOLA, we analysis, we can recommend use of LOLA as addition to impact, and risk factors for progression. placebo-controlled triple-blind trial. Eur J Oral used clinical grading of hepatic encephalopathy. In trial other standard therapies of hepatic encephalopathy since Headache, 2005; 45 Suppl 1:S3-S13. Implantol 2012;5(2):165-173. group, On Day I 10(20%) were in grade II, 17(34%) were ornithine therapy is safe, with mild side effects like 4. Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, 9. Aabakken L, Osnes M, Frenzel W. Gastrointestinal in grade III and 23(46%) were in grade IV hepatic nausea and vomiting and is easily available, can be given Olesen J. Classification of primary headaches. tolerability of lornoxicam compared to that of encephalopathy, while on day III 4(8%) were in grade both orally and parenterally and does not adds significant Neurology, 2004;10(63):427-435. naproxen in healthy male volunteers. Aliment zero, 18(36%) were in I, 20(40% ) were in grade II, cost to treatment of hepatic encephalopathy. Future 5. Mathew NT, Tfelt-Hansen P. General and Pharmacol Ther. 1996;10(2):151-156. 8(16%) in grade III and zero were in grade IV hepatic studies should be directed towards comparison of pharmacological approach to migraine 10. Rosenow DE, Albrechtsen M, Stolke D. A encephalopathy. (Table:III) In placebo group on day I efficacy L ornithine therapy with others drugs used for management. In, Olesen J, Goadsby PJ, Ramadan comprasion of patient-controlled analgesia with 12(24%) % were in grade II, 19(38%) were in grade III, standard treatment of hepatic encephalopathy like NM, Tfelt-Hansen P, Welch KMA (eds.) The lornoxicam versus morphine in patients undergoing 19(38%) were in grade IV hepatic encephalopathy, while lactitol, rifixamine, Zinc supplements and branch chain headaches, 3rd edition. Lippincot Williams & lumbar disk surgery. Anesth Analg. 1998; 86(5): on day III no patient % was in grade zero,10(20%) were in amino acids. Wilkins, Philadelphia, 2006, 433-440. 1045-1050. grade I, 12 (24%) were in grade II, 18(36%) were in 6. Tfelt-Hansen P, Rolan P. Nonsteroidal 11. Loo CY, Tan HJ, Teh HS, Raymond AA. Randomised, grade III and 10(20%) were in grade IV hepatic anti-inflammatory drugs in the acute treatment of open label, controlled trial of celecoxib in the encephalopathy. On Day I clinical difference in grading of CONCLUSION migraines. In, Olesen J, Goadsby PJ, Ramadan NM, treatment of acute migraine. Singapore Med J. hepatic encephalopathy between two groups was Tfelt-Hansen P, Welch KMA (eds.) The headaches, 2007;48(9):834-839. statistically non significant. (p-values > 0.05) while on LOLA is effective in decreasing serum ammonia as well 3rd edition. Lippincot Williams & Wilkins, 12. Ravishankar K, Tayade H, Mandlik R. Sublingual Day III, significant clinical improvement was observed p as causes clinical improvement in patients with hepatic Philadelphia, 2006, 449-457. piroxicam in migraine without aura. J Assoc value < 0.05.(Table: III) encephalopathy. It can be recommended that LOLA 7. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Physicians India. 2011;59:494-497. may be used in the patients with hepatic encephalopathy especially when not responsive to DISCUSSION standard treatment regimen.

In developing countries like Pakistan cirrhosis liver is more Table I: Distribution of patients according to Conflict of Interest: Author declares no conflict of interest. prevalent compared to developed countries.17 In fact both characteristics hepatitis B virus (HBV) and hepatitis C virus (HCV) Funding Disclosure: Nil infections have become endemic in our community.18,19 Author’s contribution: Hepatic Encephalopathy is a common neuro-psychiatric complication in CLD. High levels of ammonia in the body Dr. Murat Cabalar: Study concept and design, protocol writing, data collection, data is a major cause of hepatic encephalopathy, that’s why analysis, manuscript writing, manuscript review most of the treatments are targeted against the detoxification of ammonia. L Ornithine L aspartate (LOLA) Dr. Selcuk Dincer: Data collection, data analysis, manuscript writing, manuscript review stimulates the urea cycle and ammonia utilization that’s why thought to be useful in acute hepatic encephalopathy. Dr. Vildan Yayla: Collection, data analysis, manuscript writing, manuscript review In our study, it was observed that the LOLA has beneficial Dr. Suleyman Ozyalcin: Data collection, data analysis, manuscript writing, manuscript effects not only in clinical improvement of encephalopathy review but also obvious decrease in serum ammonia levels after infusion of LOLA. These results were comparable to other studies. Bai et al concluded after meta-analysis of 8 randomized clinical trials including 646 patients that, LOLA was beneficial in both overt and minimal hepatic encephalopathy, causes both clinical and biochemical detoxification of ammonia.20 Another meta analysis done in 2011 supported the use of LOLA for neuro-psychiatric improvement as well as decreasing levels of ammonia.21 Although regional data is sparse however, it is necessary

PAKISTAN JOURNAL OF NEUROLOGICAL SCIENCES 46 VOL. 10 (3) JUL - SEPT 2015