DOCSLIB.ORG

Baclofen and Other GABAB Receptor Agents Are Allosteric Modulators of the CXCL12 Chemokine Receptor CXCR4

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Baclofen and Other GABAB Receptor Agents Are Allosteric Modulators of the CXCL12 Chemokine Receptor CXCR4 The Journal of Neuroscience, July 10, 2013 • 33(28):11643–11654 • 11643 Cellular/Molecular Baclofen and Other GABAB Receptor Agents Are Allosteric Modulators of the CXCL12 Chemokine Receptor CXCR4 Alice Guyon,1,2,3 Amanda Kussrow,4 Ian Roys Olmsted,4 Guillaume Sandoz,1,2,5 Darryl J. Bornhop,4* and Jean-Louis Nahon1,2,6* 1Universite´ de Nice Sophia Antipolis, 06103 Nice, France, 2Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Mole´culaire et Cellulaire, UMR 7275, 06560 Valbonne, France, 3Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720, 4Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37235-1822, 5Institute of Biology Valrose, CNRS UMR 7277, INSERM UMR 1091, Laboratories of Excellence, Ion Channel Science and Therapeutics, 06103 Nice, France, 6Station de Primatologie—UPS 846—Centre CNRS, RD56, 13790 Rousset sur Arc, France CXCR4, a receptor for the chemokine CXCL12 (stromal-cell derived factor-1␣), is a G-protein-coupled receptor (GPCR), expressed in the immune and CNS and integrally involved in various neurological disorders. The GABAB receptor is also a GPCR that mediates metabotropic action of the inhibitory neurotransmitter GABA and is located on neurons and immune cells as well. Using diverse approaches, we report novel interaction between GABAB receptor agents and CXCR4 and demonstrate allosteric binding of these agents to CXCR4. First, both GABAB antagonistsandagonistsblockCXCL12-elicitedchemotaxisinhumanbreastcancercells.Second,aGABAB antagonistblocksthepotentiationby CXCL12ofhigh-thresholdCa 2ϩ channelsinratneurons.Third,electrophysiologyinXenopusoocytesandhumanembryonickidneycellline293 ϩ cells in which we coexpressed rat CXCR4 and the G-protein inward rectifier K (GIRK) channel showed that GABAB antagonist and agonist modified CXCL12-evoked activation of GIRK channels. To investigate whether GABAB ligands bind to CXCR4, we expressed this receptor in heterologous systems lacking GABAB receptors and performed competition binding experiments. Our fluorescent resonance energy transfer experimentssuggestthatGABAB ligandsdonotbindCXCR4attheCXCL12bindingpocketsuggestingallostericmodulation,inaccordancewith our electrophysiology experiments. Finally, using backscattering interferometry and lipoparticles containing only the CXCR4 receptor, we quantified the binding affinity for the GABAB ligands, confirming a direct interaction with the CXCR4 receptor. The effect of GABAergic agents on CXCR4 suggests new therapeutic potentials for neurological and immune diseases. Introduction roles in several processes involved in ischemic stroke and its sub- CXCR4 is a G-protein-coupled receptor (GPCR) that selectively sequent repair (Wang et al., 2012), brain tumor pathogenesis binds CXCL12 (stromal-cell derived factor; SDF-1␣). This (Rempel et al., 2000), human immunodeficiency virus (HIV) chemokine and its receptor have been found to play important encephalopathy (Li and Ransohoff, 2008), multiple sclerosis, and stem cell migration (Carbajal et al., 2010). CXCR4 is widely ex- Received Nov. 14, 2011; revised May 8, 2013; accepted June 5, 2013. pressed in a variety of cell types including leukocytes, where it Author contributions: A.G., A.K., D.J.B., and J.-L.N. designed research; A.G., A.K., I.R.O., and G.S. performed promotes migration, recruitment, and activation (Bonavia et al., research; A.G., A.K., and D.J.B. contributed unpublished reagents/analytic tools; A.G., A.K., I.R.O., G.S., and D.J.B. 2003; Salcedo and Oppenheim, 2003; Juarez et al., 2004; Choi and analyzed data; A.G., D.J.B., and J.-L.N. wrote the paper. An, 2011; Comerford and McColl, 2011); neurons, where it mod- ThisworkwassupportedbyCentreNationaldelaRechercheScientifique(CNRS)(INSB),ANR-MNPs-018-01,Fondation FranceParkinson,FondationdelaRechercheMe´dicale,andtheNationalScienceFoundation(GrantCHE-0848788).G.S.was ulates electrical activity (Banisadr et al., 2002; Guyon and Nahon, supportedbytheAtip-AvenirfundfromtheCNRSandINSERM.WearegratefultoRichardMillerforgenerouslyprovidingus 2007; Roste`ne et al., 2011); and various cancers and metastases withtheratCXCR4cloneandforallhisadvice.WethankEhudIsacoffforhisgenerouswelcome.Wegreatlyappreciatedthe (Wang et al., 2006), where it is involved in tumor progression assistance of Dr. Shashank Bharill, Dr. Ryan Arant, and Dr. Hitomi Okada. We thank Dr. Josh Levitz for providing us with GIRK1-F137S and Drs. Thomas Berger, Zhu Fu, Benji Gaub, Grant Kauwe, Susy Kohout, Andreas Reiner, Sasha Shekhar, (Liu et al., 2006; Gao et al., 2010; Zhao et al., 2010). CXCR4 also Sandra Wiese, and all the Isacoff lab for fruitful discussions and technical support. We thank Dr. Piotr Bregestovski, Dr. binds the HIV-1 viral envelope glycoprotein, gp120 (Doranz et Gregory Conductier, and Dr. Brice Flammang for their advice on experiments. We thank Audrey Recouly, Fabienne Cheval- al., 1997; Gabuzda and Wang, 2000). Thus CXCR4 is an impor- lier, and Florence Servent from Cisbio Bioassays, Codolet, France, for the receptor-ligand binding assay using the Tag-lite tant therapeutic target for stroke, inflammation, neuromodula- technology. We thank Dr. Joseph Rucker from Integral Molecular for generously providing the lipoparticles. We acknowl- edge Ann Fischer and Michelle Richner from the University of California Berkeley MCB Tissue Culture Facility for cell culture tion, cancer, and in the prevention of HIV infection. support;Dr.FranckBihlfromIPMC,France;andDrs.VictoriaVinaderandKamyarAfarinkiafromtheUniversityofBradford, CXCR4 couples to the Gi family of proteins activating multiple UK, for their advice on chemotactic assay. We acknowledge Michelle Sexton for help in preparation of this manuscript and G-protein-dependent and -independent pathways (Lazarini et al., 2003; Franck Aguila for artwork. The following reagents were obtained through the National Institute of Health (NIH) AIDS Busillo and Benovic, 2007). In neurons, CXCR4 stimulation has been Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), ϩ NIH: Recombinant HIV-1 IIIB gp120 (CHO), cat#11784 from DIAIDS and NIAID (Immunodiagnostics) and Recombinant showntoactivateaG-proteininwardrectifierK (GIRK)andavoltage- Soluble Human CD4, cat#4615, from Progenics Pharmaceuticals. gated K channel Kv2.1 associated to neuronal survival, and to increase *D.J.B. and J.-L.N. contributed equally to this work. high voltage-activated (HVA) Ca 2ϩ currents (Guyon and Nahon, 2007; Correspondence should be addressed to Alice Guyon, Centre National de la Recherche Scientifique, Institut de Shepherd et al., 2012). Pharmacologie Mole´culaire et Cellulaire, 06560 Valbonne, France. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.6070-11.2013 The GABA type B (GABAB) receptor is also a GPCR activated Copyright © 2013 the authors 0270-6474/13/3311643-12$15.00/0 by GABA, the chief neuro-inhibitory neurotransmitter in mam- • 11644 • J. Neurosci., July 10, 2013 • 33(28):11643–11654 Guyon et al. GABABR Agonists and Antagonists Interact with CXCR4 ؉؉ malian systems. GABAB receptors are obligatory heterodimers 100 nM CXCL12 ( ). Control agarose solutions were prepared by sub- Ϫ ϪϪ with two homologous subunits (GB1 and GB2) required for func- stituting same volumes of water for CXCL12 (Solutions and ). tioning, are widely expressed and distributed in the CNS (Kaup- Four independent drops (10 ␮l, ϳ2 mm diameter) of the four solutions mann et al., 1998), and can activate diverse intracellular pathways (maintained at 40°C) were pipetted onto the base of a sterile 20 mm (Guyon and Leresche, 1995; Laviv et al., 2011). GABA receptors diameter glass-bottomed cell culture dish (MatTek Corporation; see Fig. B 1C). The dishes were then cooled for 5 min at 4°C to allow the agarose are also expressed on cells of the immune system with a possible spot to solidify. MDA-MB-231 cells were trypsinized and resuspended to link to the inflammatory response (Tian et al., 2004; Rane et al., a final concentration of 10 5 cells/ml in RPMI 1640 supplemented with 2005). As a consequence, there is a rich pharmacology aimed at 10% FBS, 1 mM sodium pyruvate, and 2 mML-glutamine. Cells were then targeting GABAB receptors, with numerous compounds cur- exposed to AMD3100 (2 ␮M), gp120 and CD4 (300 nM each), CGP 55845 rently being used with the presumption that they are highly se- (5 ␮M), CGP 54626 (5 ␮M), GABA (100 ␮M), baclofen (100 ␮M), or lective for these receptors (Bowery, 1993; Froestl, 2010). Given control PBS with no drug. Following this incubation, cells were added to that CXCR4 and GABA have coexpression on immune cells and the dishes containing the agarose spots (1 ml per plate at a final concen- B Ϫ neurons, and the evidence for possible cross talk between these tration of 10 5 cells.ml 1) and then incubated for4hat37°C to allow the cells to adhere. The culture media was replaced with RPMI medium receptors, we hypothesized that ligands binding GABAB are in- volved in allosteric or direct interaction with CXCR4. Here we containing 0.1% FBS and the drugs or control, and the dish incubated at 37°C in 5% CO overnight. The degree of cells invading underneath the describe the experiments that test our hypothesis. First we show 2 agarose spot was analyzed by collecting pictures under an inverted mi- inhibition of CXCL12-induced migration of cancer cells by croscope Olympus IX91 using a ϫ10 objective equipped with an Andor GABAB
Load more

Recommended publications
  • Baclofen Overdose D
    Postgraduate Medical Journal (February 1980) 56, 108-109 Postgrad Med J: first published as 10.1136/pgmj.56.652.108 on 1 February 1980. Downloaded from Baclofen overdose D. J. LIPSCOMB* T. J. MEREDITHt M.B.. M.R.C.P. M.A., M.R.C.P. *Department of Medicine, Peterborough District Hospital, Peterborough PE3 6DA, and tPoisons Unit, Guy's Hospital, London SE] 9RT Summary Case report A 57-year-old woman suffering from multiple sclerosis A 51-year-old woman, who had suffered from took an estimated 1500 mg of baclofen. She became multiple sclerosis for 15 years, was prescribed baclo- deeply unconscious with generalized flaccid muscle fen 40 mg daily as part of her treatment for spastic paralysis and absent tendon reflexes. Toxicological paraplegia. One morning, she was found lying in analysis confirmed the presence of baclofen together bed unconscious and was admitted to hospital. with small amounts of paracetamol and glutethimide. Information given by her husband suggested that an Supportive therapy, including assisted ventilation for overdose of baclofen (consisting of 152 10-mg 3 days, led to complete recovery; anticonvulsant tablets) had been taken about 2 5 hr before being drugs were necessary for the treatment of grand mal found unconscious. On arrival in hospital 90 min fits. The clinical features and treatment of baclofen later, she was deeply unconscious and unresponsive overdose are discussed. to painful stimuli. Respiration was depressed and the cough reflex was absent. She was intubated without Introduction resistance and ventilated; gastric lavage was per-Protected by copyright. Baclofen (Lioresal, Ciba) is widely used in the formed but no tablets were returned in the lavage treatment of muscle spasticity.
    [Show full text]
  • The Use of Intravenous Baclofen As Therapy for the Γ-Hydroxybutyric Acid Withdrawal Syndrome
    Research Article Remedy Open Access Published: 12 Jun, 2017 The Use of Intravenous Baclofen as Therapy for the γ-hydroxybutyric Acid Withdrawal Syndrome Marc Sabbe1*, Francis Desmet1 and Sabrina Dewinter2 1Department of Emergency Medicine, University Hospitals, Catholic University of Leuven, Belgium 2Department of Pharmacy, University Hospitals, Catholic University of Leuven, Belgium Abstract Introduction: In this case series with three patients, we introduced baclofen, a γ-aminobutyric acid type B(GABA-B) receptor agonist, for treatment of the γ-hydroxybutyric acid (GHB) withdrawal syndrome. Materials and Methods: Single center case series performed on three patientswith a GHB withdrawal syndrome. They initially received massive doses of benzodiazepines, without sufficient effect. Two patients also received an unsuccessful continuous dexmedetomidine drip. In all patients, intravenous baclofen was started, with an intravenous loading dose between 0.5 and 2 milligrams (mg) to achieve a therapeutic level. Thereafter a continuous intravenous dose between 0.5 and 1 mg per hour for 12 h was administered to maintain a steady state. After that, baclofen was substituted orally with a daily oral dose varying between 20 mg and 40 mg which could be downgraded and stopped over the next days. They all continued to receive a standard benzodiazepine regimen during the baclofen trial. Results and Discussion: Main outcome measurements were the degree of withdrawal symptoms and the need for benzodiazepines during baclofen treatment. In all patients, a significant reduction of the GHB withdrawal syndrome was noted. A standard daily regimen of baseline benzodiazepine dosing between 40 mg and 80 mg diazepam was sufficient. Adverse effects of baclofen use were absent.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Gastroparesis: 2014
    GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #1 Richard W. McCallum, MD, FACP, FRACP (Aust), FACG Status of Pharmacologic Management of Gastroparesis: 2014 Richard W. McCallum Joseph Sunny, Jr. Gastroparesis is characterized by delayed gastric emptying without mechanical obstruction of the gastric outlet or small intestine. The main etiologies are diabetes, idiopathic and post- gastric and esophageal surgical settings. The management of gastroparesis is challenging due to a limited number of medications and patients often have symptoms, which are refractory to available medications. This article reviews current treatment options for gastroparesis including adverse events and limitations as well as future directions in pharmacologic research. INTRODUCTION astroparesis is a syndrome characterized by documented gastroparesis are increasing.2 Physicians delayed emptying of gastric contents without have both medical and surgical approaches for these Gmechanical obstruction of the stomach, pylorus or patients (See Figure 1). Medical therapy includes both small bowel. Patients can present with nausea, vomiting, prokinetics and antiemetics (See Table 1 and Table 2). postprandial fullness, early satiety, pressure, fullness The gastroparesis population will grow as diabetes and abdominal distension. In addition, abdominal pain increases and new therapies will be required. What located in the epigastrium, and distinguished from the do we know about the size of the gastroparetic term discomfort, is increasingly being recognized population? According to a study from the Mayo Clinic as an important symptom. The main etiologies of group surveying Olmsted County in Minnesota, the gastroparesis are diabetes, idiopathic, and post gastric risk of gastroparesis in Type 1 diabetes mellitus was and esophageal surgeries.1 Hospitalizations from significantly greater than for Type 2.
    [Show full text]
  • Guideline for Preoperative Medication Management
    Guideline: Preoperative Medication Management Guideline for Preoperative Medication Management Purpose of Guideline: To provide guidance to physicians, advanced practice providers (APPs), pharmacists, and nurses regarding medication management in the preoperative setting. Background: Appropriate perioperative medication management is essential to ensure positive surgical outcomes and prevent medication misadventures.1 Results from a prospective analysis of 1,025 patients admitted to a general surgical unit concluded that patients on at least one medication for a chronic disease are 2.7 times more likely to experience surgical complications compared with those not taking any medications. As the aging population requires more medication use and the availability of various nonprescription medications continues to increase, so does the risk of polypharmacy and the need for perioperative medication guidance.2 There are no well-designed trials to support evidence-based recommendations for perioperative medication management; however, general principles and best practice approaches are available. General considerations for perioperative medication management include a thorough medication history, understanding of the medication pharmacokinetics and potential for withdrawal symptoms, understanding the risks associated with the surgical procedure and the risks of medication discontinuation based on the intended indication. Clinical judgement must be exercised, especially if medication pharmacokinetics are not predictable or there are significant risks associated with inappropriate medication withdrawal (eg, tolerance) or continuation (eg, postsurgical infection).2 Clinical Assessment: Prior to instructing the patient on preoperative medication management, completion of a thorough medication history is recommended – including all information on prescription medications, over-the-counter medications, “as needed” medications, vitamins, supplements, and herbal medications. Allergies should also be verified and documented.
    [Show full text]
  • Drug Effects on EEG
    REVIEW ARTICLES Drug Effects on EEG Warren T. Blume Abstract: Although excess beta activity and a mild theta increase may SPECIFIC MODIFICATIONS be the most common EEG alterations associated with medication, more Beta remarkable changes may also appear. Although changes such as diffuse An augmentation of voltage, field distribution, and persis- delta, triphasic waves, bisynchronous spikes or polyspikes, burst sup- tence of normally appearing 15 to 25 Hz Beta activity most pression or electrocerebral inactivity may indicate a dismal prognosis commonly indicates the presence of a medication effect on the under many circumstances; these patterns may fully resolve to a normal EEG (Figs. 1–3). Barbiturates and benzodiazepines most prom- EEG if drug administration is the unique or principal cause. inently produce this effect ( G. Bauer and R. Bauer, 2005; Van Cott and Brenner, 2003). Greater than usual theta activity may Key Words: Drug effects, EEG, Prognosis. accompany such beta excess (Blume et al., 2002). Central (J Clin Neurophysiol 2006;23: 306–311) nervous system stimulants such as cocaine, amphetamines, and methylphenidate as well as tricyclic antidepressants may evoke greater beta activity at low voltage (G. Bauer and R. Bauer, s a substantial proportion of patients undergoing electro- 2005; Van Cott and Brenner, 2003). Withdrawal from alcohol Aencephalography (EEG) take one or more medications of and barbiturates may produce a similar low voltage EEG with various kinds, the electroencephalographer must bear their beta activity. effects in mind when reading the EEG and phrasing its clinical Beta activity is more abundantly expressed by medication interpretation. Moreover, an asymmetry of drug effects may in children than in adults and with acute rather than chronic reflect a focal or hemispheric lesion whose EEG effects may not administration.
    [Show full text]
  • AUD-Patient AD-Baclofen-HCV
    What are some side effects How long do I have to take of baclofen? baclofen? Common What Can I Do if I You and your provider will decide on Side Effects Experience This? your treatment plan. Drowsiness Most common side Most take baclofen for at least effect. Your body will 6 months and often longer. likely adjust over time Headache You may take a non- opioid pain reliever For more information about drinking if recommended by and Hepatitis C visit the VA’s website: your provider Nausea • Take with food http://www.hepatitis.va.gov/ or Upset • Eat plain rice, toast, patient/daily/alcohol/index.asp Stomach or crackers Dizziness Rise slowly to prevent falls Veteran's Crisis Line 1-800-273-TALK (8255) or Do not drive, use machinery, or do Text - 838255 anything that may be dangerous until you know how the medicine affects you. U.S. Department of Veterans Affairs Notify your provider if you experience: Veterans Health Administration VA PBM Academic Detailing Service ¡ Allergic reactions (skin rash, hives, swelling of lips) Baclofen ¡ Chest pain Contact info: ¡ Hallucinations Using Medications to ¡ Seizures Help Manage Alcohol Use All medicines can have side effects. Disorder with Hepatitis C Not everyone has side effects though. They usually get better as your body gets used to the new medicine. Talk with your provider or pharmacist if May 2017 PBM Academic Detailing Service any of the above side effects trouble you. IB 10-949, P96831 www.va.gov How can baclofen help me What do I need to know before Drinking and Hepatitis C cut down or stop drinking? starting baclofen? If you have Hepatitis C, drinking Baclofen is a medication that reduces alcohol can be the single biggest your urge or craving to drink, and can threat to your health.
    [Show full text]
  • Information for the Patient Nicardipine 10 Mg/10 Ml Solution for Injection Nicardipine Hydrochloride
    Package leaflet: Information for the patient Nicardipine 10 mg/10 ml solution for injection Nicardipine hydrochloride Read all of this leaflet carefully before you are given this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or nurse. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. The name of your medicine is “Nicardipine 10 mg/10 ml solution for injection” but in the rest of the leaflet it will be called as ‘Nicardipine solution for injection’. What is in this leaflet 1. What Nicardipine solution for injection is and what it is used for 2. What you need to know before you are given Nicardipine solution for injection 3. How to take Nicardipine solution for injection 4. Possible side effects 5. How to store Nicardipine solution for injection 6. Contents of the pack and other information 1. What Nicardipine solution for injection is and what it is used for Nicardipine solution for injection contains the active substance Nicardipine hydrochloride, which belongs to a group of medicines called calcium channel blockers. Nicardipine solution for injection is used to treat very severe high blood pressure. It can also be used to control high blood pressure after an operation. You must talk to a doctor if you do not feel better or if you feel worse. 2. What you need to know before you are given Nicardipine solution for injection Do not take Nicardipine solution for injection: • If you are allergic to Nicardipine or any of the other ingredients of this medicine (listed in section 6) • If you have chest pain • If your high blood pressure is because of narrowing of a heart valve or other defects in the heart • If you have had a heart attack in the last eight days • If you have been told by your doctor that you have an intolerance to some sugars.
    [Show full text]
  • Complications of Baclofen Overdosage K
    Postgrad Med J: first published as 10.1136/pgmj.56.662.865 on 1 December 1980. Downloaded from Postgraduate Medical Journal (December 1980) 56, 865-867 Complications of baclofen overdosage K. GHOSE K. M. HOLMES Ph.D., M.R.C.P. M.R.C.P. K. MATTHEWSON M.B. B.S. The Cumberland Infirmary, Carlisle, Cumbria CA2 7HY Summary 45 baclofen tablets (450 mg) which had been taken A 39-year-old female patient who had been receiving about 8-10 hr previously. She had been prescribed 30 mg of baclofen daily for 5 months was admitted to this medication for muscle spasticity associated with the hospital about 12 hr after an overdose of this basilar impression due to an arachnoid cyst of the drug (450 mg). On admission, she was comatose, posterior fossa about 5 months before this incident. flaccid, and in respiratory failure. Later she developed On admission, she was comatose, hypotonic, and muscle twitchings and had several epileptic fits. She all reflexes were absent. Pupils were dilated and Protected by copyright. was treated symptomatically and became conscious fixed but there was no evidence of papilloedema or within 36 hr. However, approximately 65 hr after the pulmonary oedema. Her BP was 110/70mmHg overdose she developed sinus tachycardia which was and a routine ECG was normal with a heart rate of successfully treated with oral propranolol. Plasma 80/min. However, she had central cyanosis and her concentrations, as measured on days 2 and 3, were respiration was slow, irregular and shallow. She within the therapeutic range but the elimination was ventilated and treated with various supportive half-life was prolonged.
    [Show full text]
  • Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved ADME
    JPET Fast Forward. Published on June 5, 2009 as DOI: 10.1124/jpet.108.149773 JPETThis Fast article Forward. has not been Published copyedited and on formatted. June 5, The 2009 final asversion DOI:10.1124/jpet.108.149773 may differ from this version. JPET#149773 Arbaclofen Placarbil, A Novel R-Baclofen Prodrug: Improved ADME Properties Compared to R-Baclofen. Ritu Lal, Juthamas Sukbuntherng, Ezra H.L. Tai, Shubhra Upadhyay, Fenmei Yao, Mark S. Warren, Wendy Luo, Lin Bu, Son Nguyen, Jeanelle Zamora, Ge Peng, Tracy Dias, Ying Bao, Maria Ludwikow, Thu Phan, Randall A. Scheuerman, Hui Yan, Mark Gao, Downloaded from Quincey Q. Wu, Thamil Annamalai, Stephen P. Raillard, Kerry Koller, Mark A. Gallop, and Kenneth C. Cundy jpet.aspetjournals.org XenoPort, Inc., Santa Clara, CA, U.S.A. at ASPET Journals on September 26, 2021 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on June 5, 2009 as DOI: 10.1124/jpet.108.149773 This article has not been copyedited and formatted. The final version may differ from this version. JPET#149773 Running Title: Arbaclofen Placarbil: ADME and Pharmacokinetics Corresponding Author: Ritu Lal, Ph.D. XenoPort, Inc. 3410 Central Expressway Santa Clara, CA 95051 Phone: 408-616-7199 FAX: 408-616-7212 Downloaded from E-mail: [email protected] jpet.aspetjournals.org Number of text pages: 40 Number of Tables: 8 Number of Figures: 5 at ASPET Journals on September 26, 2021 Number of References: 22 Number of words in Abstract: 214 Number of words in Introduction: 478 Number of words in Discussion: 1494 List of Abbreviations: AUC, area under the blood concentration versus time curve; AUC(0-inf), area under the blood concentration versus time curve extrapolated to infinity; C0, concentration in blood extrapolated to time zero following intravenous administration; Cmax, maximum concentration in blood; Caco-2, human colonic adenocarcinoma cell line; CSF, cerebrospinal fluid; GABAB, gamma-aminobutyric acid-B; GERD, gastroesophageal 2 JPET Fast Forward.
    [Show full text]
  • Compounding for Vulvar Conditions
    Multidisciplinary Evaluation and Treatment of Vulvar Disorders The Role of Compounding Pharmacy Tara Thompson PharmD., RPh. Innovation Compounding Pharmacy Disclosures • Innovation Compounding Pharmacy – Kennesaw, GA Objectives • To understand the purpose of a compounding pharmacy • To familiarize the benefits & drawbacks of compounding • To delineate compounding options for the vulvar region • To determine appropriate formulations for commonly prescribed vulvar preparations What is Compounding? • Compounding pharmacists work directly with prescribers including physicians, NP/PAs, physical/sex therapists, and other clinicians to create customized medication solutions for patients whose healthcare needs cannot be met by manufactured medications. • 5000 year old profession, the oldest form of pharmacy • Regulated by State Boards of Pharmacy and Accreditation Boards • “Thinking outside of the box” • Manipulating the dosage form! • Customized, individualized medicine tailored to the patient’s specific need How Do I Choose a Compounding Pharmacy? • Licensed in your State • Pharmacist Knowledge and Access • Adherence to USP Guidelines, Testing • USP <795> - Non-Sterile Compounding • USP <797> - Sterile Compounding • Diversity of Portfolio to your Practice Needs • Pelvic Health/FSD/IC • Pricing and Patient Care/Access • Reputation • Compounding Ability and Dosage Form Assortment • Most Important – Accreditation and Inspection!! PCAB – Pharmacy Compounding Accreditation Board • A service of the Accreditation Commission for Healthcare (ACHC) •
    [Show full text]
  • Psychological and Emotional Effects of the Use of Oral Baclofen: a Preliminary Study
    Paraplegia 32 (1994) 349-353 © 1994 International Medical Society of Paraplegia Psychological and emotional effects of the use of oral baclofen: a preliminary study A Jamous MD MSc (Oxon), P Kennedy MSc C Psychol AFBPsS, N Grey BA (Cantab) National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, Bucks HP21 8AL, UK. Spasticity is a common problem following spinal cord injury. The drug of choice to control spasms is baclofen. There would appear to be no reported studies which have evaluated the psychological and emotional effect of this drug. This preliminary study investigated a number of such effects, including depression, anxiety and general mood state. First, we examined 10 subjects before and during the administration of baclofen. They were then compared to a control group of 12 subjects. A second cohort of 12 subjects taking baclofen were compared to a control group of nine subjects at a specific time after injury. Results indicated that whilst some significant differences were found, suggesting an increase in fatigue with use of baclofen, no major adverse psychological effects were noted. The implications of these results were discussed and suggestions for further research were highlighted. Keywords: spinal cord injury; spasms; baclofen; psychology; adverse side effects. Introduction ways. First, by within-subject comparison of ratings taken before and during the use For years, oral baclofen has been one of the of oral baclofen. Secondly, by a between­ main drugs for the treatment of spasticity subject comparison of ratings at a fixed after spinal cord injury. It is usually well point in time after injury of a group of tolerated, but with common adverse side subjects taking baclofen at that time and a effects such as sedation, confusion and control group who used no antispasticity fatigue.
    [Show full text]