Pharmacology of : Where Is the “Golden Bullet”?

Kathryn Beauchamp,1* Haitham Mutlak,2,3* Wade R Smith,4 Esther Shohami,5 and Philip F Stahel 4

1Division of Neurosurgery, Department of Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, Colorado, United States of America;2Department of Anesthesiology, University Hospital Grosshadern, Ludwigs Maximilian University of Munich, Munich, Germany; 3Department of Anesthesiology, Clinical Research and Development, University of Colorado Health Sciences Center, Denver, Colorado, United States of America; 4Department of Orthopedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, Colorado, United States of America; 5Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Israel

Traumatic brain injury (TBI) represents a major health care problem and a significant socioeconomic challenge worldwide. In the United States alone, approximately 1.5 million patients are affected each year, and the mortality of severe TBI remains as high as 35%–40%. These statistics underline the urgent need for efficient treatment modalities to improve posttraumatic morbidity and mortality. Despite advances in basic and clinical research as well as improved neurological intensive care in recent years, no spe- cific pharmacological therapy for TBI is available that would improve the outcome of these patients. Understanding of the cel- lular and molecular mechanisms underlying the pathophysiological events after TBI has resulted in the identification of new po- tential therapeutic targets. Nevertheless, the extrapolation from basic research data to clinical application in TBI patients has invariably failed, and results from prospective clinical trials are disappointing. We review the published prospective clinical trials on pharmacological treatment modalities for TBI patients and outline future promising therapeutic avenues in the field. Online address: http://www.molmed.org doi: 10.2119/2008-00050.Beauchamp

INTRODUCTION primary insult, secondary brain injuries brain injuries. The evidence-based Traumatic brain injury (TBI) is the evolve over time. These are characterized guidelines for the treatment of TBI pa- leading cause of death and disability in by a complex cascade of molecular and tients were recently published in revised young people (1,2). Despite advances in biochemical events that lead to neuroin- form by the Brain Trauma Foundation research and improved neurological in- flammation, brain edema, and delayed (8). Interestingly, most recommendations tensive care in recent years, the clinical neuronal death. Early hypoxia and hy- in these published guidelines are based outcome of severely head-injured pa- potension induce and perpetuate cere- on class II or III evidence, owing to a tients is still poor. Evaluation of direct bral ischemia and reperfusion injuries persistent lack of class I evidence–based and indirect costs reveals that TBI is a 60 and are independent predictors of ad- data on treatment strategies for TBI (8). billion dollar “industry” in the United verse outcome after TBI (7) (Figure 1). No specific pharmacological therapy is States (3–6). Posttraumatic brain damage In the past decade, our understanding currently available that prevents the de- is determined by a combination of pri- of the cellular and molecular changes velopment of secondary brain injuries, mary and secondary insults. Primary that occur after TBI has significantly in- and most therapeutic strategies have damage results from mechanical forces creased. A number of new potential ther- failed in translation from “bench to bed- applied to the skull and brain at the time apeutic targets have been identified that side.” We present a review of the current of impact, leading to focal or diffuse may enable prevention of the onset or literature on prospective clinical trials of brain injury patterns. In contrast to the reduction of the extent of secondary pharmacological treatment modalities in TBI patients.

*KB and HM contributed equally to this paper. METHODS Address correspondence and reprint requests to Philip F Stahel, Department of Orthopae- Comprehensive online literature dic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, searches were performed using the in- 777 Bannock Street, Denver, CO 80204; Phone: (303) 653-6463; Fax: (303) 436-6572; E-mail: dexed databases MEDLINE/PubMed [email protected]. and the Cochrane Library. The primary Submitted April 25, 2008; Accepted for publication August 18, 2008; Epub (www.molmed. intention of these searches was to iden- org) ahead of print August 18, 2008. tify prospective randomized controlled

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sulted in marked clinical improvement, and glucocorticoids were found to be beneficial when administered in the peri- operative phase of intracranial tumor sur- gery. became commonplace in the treatment of TBI in the 1970s owing to assumed beneficial effects when used in high doses (9,10). However, multiple clinical studies from the 1980s and 1990s were not able to provide definitive proof of a beneficial effect of steroids in TBI pa- tients. This lack of adequate scientific knowledge led to the design of the largest clinical trial on head injury, aimed at prospectively recruiting 20,000 pa- tients. This large-scale Corticosteroid Randomization after Significant Head In- jury (CRASH) trial, a prospective, ran- domized, placebo-controlled multicenter trial, was designed to determine with high scientific accuracy whether there is a potential benefit of administering high- Figure 1. Pathophysiological mechanisms of secondary brain injury and selected points of dose methylprednisolone in TBI patients action of pharmacological compounds discussed in this review. See text for details and (11). The CRASH trial had to be aborted, explanations. however, after enrollment of just 50% of the patients (n = 10,008), because of the finding of an unexpected increased mor- trials (RCTs), nonrandomized controlled from September 1, 1988 to July 1, 2008. tality in head-injured patients treated trials (NRCTs), and published systematic This defined search led to the following with corticosteroids (11). The authors re- reviews. Medical Subject Heading (MeSH) pharmacological agents of interest, ported that the “verum” cohort of high- thesaurus keywords were applied as a which are described in the present dose methylprednisolone (n = 5007) had standardized use of language to unify paper, steroids and derivatives, a significantly increased mortality com- differences in terminology (Table 1). Ap- N-methyl-D-aspartate (NMDA) receptor pared with the placebo control group propriate MeSH headings and subhead- antagonists, endocannabinoids, mono- (n = 5001) during the first 14 d after ings for each question were selected and aminergic substances, cyclosporine, trauma (21.1% versus 17.9%, P < 0.001) modified on the basis of search results. calcium-channel blockers, and modula- (11). These shocking results indicated Searches were limited to human studies, tors of the kinin/kallikrein system that the “pan”-inhibition of the immune but not to sex or age. Original publica- (Table 1). The last online search was up- response by the use of high-dose steroids tions were evaluated for abstracts that dated on July 1, 2008. is too broad and nonspecific for control- were deemed relevant. If an acceptable ling posttraumatic inflammation. The systematic review or metaanalysis was STEROIDS negative results from the CRASH trial identified, searches to update the data led to a highly provocative editorial in were typically limited to the time period Corticosteroids: A “CRASH” Landing in The Lancet, suggesting that the uncritical, following the search cutoff date reported TBI anecdotal administration of cortico- in the review. Pharmacological agents The problem of extrapolating knowl- steroids to head-injured patients may were selected for analysis based on the edge derived from experimental studies have caused more than 10,000 deaths operational strategy of positive yields on from bench to bedside with regard to during the 1980s and earlier (12). The 1:1 the literature searches (MEDLINE/ pharmacological strategies in TBI is most extrapolation of these negative data from PubMed) using the restriction of human explicitly exemplified by the role of the CRASH trial must be judged cau- pharmacological trials in head injury steroids. Corticosteroids were introduced tiously, however, owing to some weak- (RCTs and NRCTs) and systematic meta- in the early 1960s as a treatment for brain nesses in the study design. Nevertheless, analyses (Cochrane and MEDLINE/ edema. The administration of glucocorti- current TBI treatment recommendations PubMed) published in the last 20 years, coids in patients with brain tumors re- do not include the use of steroids, which

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Table 1. Medical subject heading (MeSH) thesaurus keywords used for online literature searches in PubMed and Cochrane databases. The last online search was performed on 07/01/2008.

Compound MeSH-Terms

Cannabinoids “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Endocannabinoids” OR “Dexabinol” OR “Cannabinoids” OR “Anandamide” Glutamate (NMDA) Receptor Antagonists “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “EAA” OR “Excitatory Amino Acid” OR “Neuroprotective Agent” OR “NMDA” OR “N-Methyl-D-Aspartate”

Magnesium sulfate (MgSO4) “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Magnesium-Chloride” OR “Magnesium Compounds” OR “ Magnesium” OR “Magnesiumsulfate” Corticosteroids “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Steroids” OR “Glucocorticoids” OR “Corticosteroids” OR “Cortisone” OR “Prednisolone” OR “Dexamethasone” OR “Methylprednisolone” Aminosteroids “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Aminosteroids” OR “Tirilazad” OR “Lazaroid” “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Progesterone” OR “Sexual Hormones” Monoaminergic substances “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Amphetamine” OR “Dopamine” OR “Methylphenidate” OR “Dextroamphetamine” Cyclosporine “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Cyclosporine” OR “Immunosuppressant” OR “Cyclosporine A” OR “ CsA” Ca-Channel Blockers “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Calcium Channel Blocker” OR “Calcium Antagonist” OR “Nifedipine” OR “Verapamil” OR “Nicardipine” OR “Nimodipine” OR “Amlodipine” OR “Felodipine” OR “Diltiazem” Inflammatory Modulators “Traumatic Brain Injury” OR “Closed Head Injury” OR “Brain Injury” OR “TBI” OR “Brain Damage” AND “Kallikrein-Kinin” OR “Bradykinine Receptor Antagonists” OR “Kinins” OR “Bradycor” OR “Anatibant” are considered obsolete and potentially (21). One randomized clinical study in- United States trial reported by Marshall harmful for the patient (13). vestigating the effect of tiralazad mesy- et al. The risk of death in patients given late in the setting of TBI has been re- tirilazad mesylate was nearly identical to Aminosteroids ported (22). This study enrolled 1120 that in patients given placebo, relative Lipid peroxidation is the free-radical– patients with moderate (15%) to severe risk (RR) = 1.05 (95% confidence interval mediated formation of lipid peroxides. (85%) TBI. Patients received tirilazad [CI] 0.86 to 1.29). The risk of disability in Once initiated, peroxidation is consid- mesylate or placebo every 6 h for a pe- patients treated with tirilazad mesylate ered to be a self-propagating process riod of 5 d. Primary outcomes were mor- was also almost identical to the risk in that leads to cell membrane damage and tality and Glasgow Outcome Scale patients given placebo, RR = 1.07 (95% cell death (14). Oxygen radical formation (GOS) 6 months after TBI. There were no CI 0.93 to 1.23). These results indicate and lipid peroxidation start early after significant differences in either category that there is no evidence to support the TBI and lead to ischemia and hypoxia. at 6 months after injury. Subgroup anal- routine use of aminosteroids in the man- Free radicals in TBI are generated by mi- ysis suggested that tirilazad mesylate agement of TBI. Future studies should tochondrial damage (15–20). Tirilazad may be effective in reducing mortality investigate titration of the optimal time- mesylate is a 21-aminosteroid that has rates in males suffering from severe window of drug delivery, a variable that been shown to inhibit lipid peroxidation head injury with accompanying trau- appears to be crucial for potential benefi- in experimental animals (14). Tirilazad matic subarachnoid hemorrhage. cial effects in TBI patients. Administering mesylate penetrates the intact blood- In a Cochrane Review, Roberts (23) cal- the agent only in the first 7 d after injury brain-barrier poorly but has a strong culated the risk of death in patients may miss the optimal treatment period, affinity for the vascular endothelium treated with tirilazad mesylate in a thus leading to inaccurate assessment of

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potential treatment benefits. One can rating-scale scores. Survivors of moder- Na+ and K+ gradients are reduced during argue that the antioxidants are poten- ate TBI who received progesterone were cerebral ischemia and TBI (41). Gluta- tially beneficial when they are present at more likely to have a moderate-to-good mate plays a pivotal role in neuronal dif- the site and time of reactive oxygen outcome than those randomized to pla- ferentiation, migration, and survival in species (ROS) formation. Because of the cebo. In addition, results of a recently the developing brain (42). short half-life of these ROS, however, the published randomized controlled trial in- In TBI it is evident that extracellular drug may just miss the target. dicate that progesterone improves the glutamate levels are markedly increased, outcome in patients with severe TBI (35). resulting in glutamate-receptor overstim- Progesterone In this study, 159 TBI patients with a ulation. This can lead to secondary ad- A substantial amount of data indicate GCS ≤8 were enrolled prospectively verse events and neuronal cell death that progesterone, a gonadal hormone within 8 h of trauma. Of these patients, (43,44). At the cellular level, prolonged and neurosteroid naturally distributed in 82 were randomized to receive proges- depolarization and subsequent ionic im- human brains, has potent neuroprotec- terone, whereas 77 were randomized to balance (that is, increased intracellular tive properties (24,25). In animal studies, the placebo control group. Patients calcium levels) can contribute to cerebral progesterone reduced cerebral edema, treated with progesterone had lower edema, which in turn can increase in- neuronal loss, and behavioral deficits by mortality and more favorable outcomes, tracranial pressure, leading to vascular inhibiting secondary injury cascade as measured by the GOS and the modi- compression and possible brain hernia- (26–32). This finding led to further inves- fied Functional Independence Measure tion (45). These findings were confirmed tigation in phase I and II clinical studies. Score at 3- and 6-month follow-up (35). by Bullock et al. (43) in a clinical study in Phase I, a single-center, double-blinded These promising data indicate that prog- which sustained elevated intracranial study, showed that stable progesterone esterone may be one of the few pharma- pressure combined with poor patient levels could be achieved rapidly and cological “golden bullets” for patients outcome was significantly associated safely by use of a two-phase intravenous with severe TBI. However, this notion with increased levels of glutamate in the infusion following TBI (33). Recently, re- warrants further validation in future brain. The knowledge of these patho- sults of the ProTECT (Progesterone for clinical trials. physiological circumstances has led to Traumatic Brain Injury, Experimental the development of agents that modulate Clinical Treatment) study were published NMDA-RECEPTOR ANTAGONISTS glutamate transmission. The NMDA re- (34). In this phase II, single-center, dou- Glutamate is the principal excitatory ceptor is the pharmacological target of ble-blinded, placebo-controlled clinical neurotransmitter in the brain. It acts numerous treatments in a variety of neu- pilot study, the safety and potential bene- postsynaptically on three families of in- rological diseases (38). Summarization fit of progesterone administration to pa- otropic receptors that are named after studies in animal models have provided tients with TBI was investigated in a their agonists, NMDA, α-amino-3- a large body of evidence that glutamate level I trauma center. The primary mea- hydroxy-5-methyl-4-isoxazoleproionic accumulation in the synaptical fissure is sure of benefit was the dichotomized acid, and kainite (36,37). Another recep- a main cause of cell death. Reduction of GOS 30 d after injury, and primary safety tor class is the metabotropic glutamate glutamate levels or neurotransmission measures were differences in adverse receptor (mGluR), which acts via a mes- via different pharmacological agents can event rates and 30-d mortality. In this senger (G proteins) to modulate bio- ameliorate such effects (43,46–48). study, 100 patients who arrived within chemical pathways and ion channels. A Cochrane analysis identified a total 11 h of injury with a Glasgow Coma Three subgroups of mGluRs have been of seven completed, randomized con- Scale (GCS) score of 4–12 were enrolled characterized, group I (mGluRs1, trolled trials in patients with TBI. There and randomized on a 4:1 basis to receive mGluRs5), group II (mGluRs2, mGluRs3), were another two randomized clinical either intravenous progesterone or pla- and group III (mGluRs 4–8). In contrast trials with three different compounds cebo; 77 patients received progesterone; to inotropic receptors, mGluRs modulate available for this review. 23 received placebo. No serious adverse the release of neurotransmitters (38). events were attributed to progesterone. mGluRs are activated by prolonged or el- Selfotel Adverse and serious adverse event rates evated glutamate release in case of Selfotel (GCS 19755) is a competitive were similar in both groups, except that seizures and trauma (39). Glutamate is glutamate antagonist that has been tested patients randomized to progesterone had released from vesicles in presynaptic ter- in two separate multicenter, double- a lower 30-d mortality rate than controls minals by a Ca++-dependent mechanism, blind, controlled phase III clinical trials (RR = 0.43; 95% CI 0.18 to 0.99). Thirty involving voltage-dependent Ca++ chan- in patients with severe TBI (49). These days after injury, the majority of severe nels (36,40). Glutamate may also be re- trials were conducted simultaneously in TBI survivors in both groups had rela- leased by reverse operation of glutamate the United States, Israel, and Europe, tively poor GOS extended and disability transporters, a process that occurs when with 93 medical centers participating.

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Inclusion criteria were a GCS score of D-CCP-ene (EAA 494) (63) confirmed no improvement in out- 4–8, at least one reactive pupil, and an D-CCP-ene (EAA 494) is a competitive come with administration of magnesium abnormal computed tomographic scan NMDA agonist that has been tested in a in TBI. Primary outcome parameters demonstrating intracranial injury. The double-blind, placebo-controlled, phase were survival, seizure occurrence, and protocol required a cerebral perfusion III trial. Results of this trial have not neurobehavioral functioning 6 months pressure >60 mmHg and intracranial been published but were discussed in after TBI. The initial serum level target of pressure >20 mmHg. The primary end- Narayan et al. (53). A total of 920 patients magnesium was 1.25–2.4 mmol/L, but point was a demonstration of 10% im- were recruited in 51 European treatment owing to concerning trends in deaths and provement in the GOS measured 6 centers. Patients received either D-CCP- blood pressure the study was restarted months after injury. Patients received ene twice a day for a period of 5 d or with a lower target concentration of 5 mg/kg selfotel or placebo daily for placebo. The primary endpoint was the 1.0–1.85 mmol/L. A loading dose of mag- 4 d. Initial treatment was within 8 h of GOS score 6 months after TBI. Patients in nesium was administered within the first injury. A total of 693 patients were en- the treatment group had a slightly, non- 8 h of injury. There was higher mortality rolled. Comparison of the two treatment statistically significant, worse outcome in the higher magnesium dose group than groups showed no difference in mortal- than patients in the placebo group. with the placebo. These studies suggested ity rate, with a slight trend in the selfotel Therefore, D-CCP-ene is not recom- that magnesium may not be neuroprotec- group toward worse outcome. The study mended in the treatment of TBI. tive and in fact may be harmful. was prematurely stopped owing to an In summary, excessive activation, fol- interim analysis indicating that achieve- Magnesium Sulfate (MgSO4) lowed within a relatively short time by ment of improved GOS was highly un- Magnesium is an intracellular cation desensitization and loss of functional likely. Additionally, data indicated a sig- that is known to modulate NMDA- NMDA receptors, may explain the pre- nificant increase of serious adverse receptor permeability to calcium and clinical and clinical experience with effects and high mortality rate in the sodium. Furthermore, magnesium is a po- NMDA-receptor antagonists, as well as selfotel treatment group. tent calcium-channel blocker that modu- suggest alternative modes of treatment. lates intracellular calcium activity by a This hypothesis was tested in a mouse Traxoprodil (CP-101.606) noncompetitive NMDA-receptor channel model of closed head injury and the re- Traxoprodil (CP-101.606) is a substi- block (54). Low levels of magnesium can sult not only confirmed the hypothesis, tuted 4-phenylpiperidine noncompetitive generate an impairment of the ATPase showing approximately 50% lower levels NMDA antagonist with good brain pene- pump function (55), leading to a reduc- of NMDA receptor at 7 d after injury, but tration. Additionally, traxoprodil acts as tion of intracellular ATP and thus increas- also demonstrated that the activation of a postsynaptic NMDA antagonist with a ing the intracellular calcium levels. Head- these receptors (not inhibition) at 24 h high affinity for receptors containing the injured patients are at high risk of after injury led to remarkably improved NR2B-subunit, which is distributed in developing hypomagnesaemia, which can function (64,65). forebrain areas vulnerable to injury re- persist for several days (56,57). Animal sulting from trauma or ischemia (50). A head-injury models have demonstrated SYNTHETIC CANNABINOIDS phase II clinical study published by Mer- that this reduction in magnesium levels is In the last decade the endocannabinoid chant et al. (51) investigated pharmacoki- associated with poor neurological out- system has been examined for its poten- netics, safety, and tolerability of traxo- come and increased mortality (58). Restor- tial neuroprotective role. This system con- prodil in 53 patients (45 patients with ing these levels reduces brain edema and sists of two receptors, CB1 and CB2, and mild-to-moderate TBI, 8 with hemor- improves neurological and cognitive out- three types of endocannabinoid ligands. rhagic stroke). Outcome measures in- comes. Magnesium has been shown to be All known types of endogenous cannabi- cluded a battery of neurobehavioral tests. neuroprotective in experimental TBI in ro- noids are derivates of arachidonic acid. Although there were no adverse effects dent models (59–61). This potential for The CB1 receptor is present mainly in the reported, there were no statistical differ- improved outcome led to randomized, central nervous system (CNS) and in nu- ences in outcome. A more recent, double- controlled clinical trials. Arrango et al. re- merous peripheral tissues, whereas CB2 blind, placebo-controlled phase III trial cently published a systematic review is found mostly in organs of the immune (52) included 444 patients who received identifying two studies with 75 random- system but not in the brain (66–69). taxoprodil or placebo infusion within 8 h ized patients (62). GOS results at 6 Arachidonoylethanolamide (anandamide) of severe TBI. Outcome measures were months indicated that there is no role for was the first endocannabinoid to be iden- function at 6 months after TBI. Although MgSO4 in the treatment of TBI. A subse- tified (70), followed by 2-arachidonoyl this study yielded intriguing results, it quent double-blind, monocentric, clinical glycerol (71). A third endocannabinoid, did not lead to definitive recommenda- phase II trial that included 499 patients 2-arachidonyl glyceryl ether (noladin tions for treatment. with mild to severe TBI (GCS total 3–12) ether), was reported in 2001 (72). Unlike

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the classic neurotransmitters, such as could not be replicated. There was no dif- (GCS 9–12) were treated with 0.3 mg/kg dopamine, serotonin, and norepinephrine, ference in outcome after 6 months in the methylphenidate per dose by the second the endocannabinoid anandamide is pres- HU-211 treatment group (odds ratio 1.04; day after TBI and were treated until dis- ent in very low concentrations in the brain 95% CI 0.79 to 1.36). Improvement in in- charge. Methylphenidate was associated and is formed on demand from a precursor, tracranial pressure control was not re- with reductions in ICU and hospital N-arachidonoylphosphatidylethanolamine corded, and subgroup analysis showed length of stay by 23% in severe TBI pa- (73). In most of their pharmacological ac- no benefits of HU-211 treatment. tients (P = 0.06 for ICU and P = 0.029 for tivities, these body constituents parallel hospital stay). In the moderate TBI group the effects of Δ9 tetrahydrocannabinol, MONOAMINERGIC SUBSTANCES only the ICU duration was significantly the active constituent of marijuana, but Monoaminergic substances are thought shorter (P = 0.05). Currently a phase III the effect of endocannabinoids is shorter to modulate functional recovery after es- clinical trial is being conducted to evalu- in duration because of their quick cellular tablished brain injury. The etiology is ate the effects of methylphenidate in the uptake and hydrolysis by fatty acid multifactorial (87). Previous studies have setting of TBI in children. amide hydrolase (74). focused on prevention of secondary in- The neuroprotective effects of cannabi- jury, whereas the focus of this substance CYCLOSPORINE noids include inhibition of the release of is on repair once secondary injury has Cyclosporine A (CsA) may be a poten- glutamate and inflammatory cytokines. occurred. In animal models after experi- tial neuroprotective treatment following Cannabinoids also counteract the vaso- mental head injury, levels of norepineph- acute TBI. In animal models it has been constrictive effect of endothelin-1. These rine, dopamine, and epinephrine are shown that administration of CsA fol- effects have been demonstrated in cell markedly increased. Additionally, ad- lowing acute, severe TBI reduces the culture and animal models and exten- ministration of amphetamine after TBI in amount of damaged tissue when given sively described in reviews (75,76). a rat model showed improved neurologi- following the event (94–97). The exact A synthetic, nonpsychotropic cannabi- cal outcome (88). mechanism of action responsible for neu- noid is HU-211 (dexanabinol). This com- Methylphenidate (Ritalin) is a dopa- roprotection remains unclear. CsA in- pound was found to exhibit pharmaco- mine reuptake inhibitor that has been hibits mitochondrial dysfunction in the logical properties characteristic of a tested in the treatment of neurobehav- CNS, preventing calcium efflux. By inter- noncompetitive NMDA-receptor antago- ioral disorders following TBI (89). The fering with calcium release from mito- nist (77,78). HU-211 also blocks tumor- exact mechanism of action is not yet fully chondria, the secondary cascade of necrosis factor synthesis and has antioxi- understood, but methylphenidate seems events leading to persistent damage dant properties, inhibiting release of ROS to act by altering the reuptake and conse- within the CNS is presumed to be inter- (79–81). Because glutamate, ROS, and quently the efficacy of different aminergic rupted (98–100). Defining the optimal tumor-necrosis factor are well known to CNS neurotransmitters. The presumed dosing to achieve therapeutic concentra- be involved in the pathophysiology of mechanism is interference with dopa- tions in the brain with minimal systemic brain injury (82,83), the above observa- mine reuptake. The potency of blocking consequences is important. CsA is me- tions led to clinical trials. Phase I and II the norepinephrine transporter is lower tabolized by the hepatic cytochrome trials demonstrated (84,85) that HU-211 (90). Methylphenidate has proven clinical P-450 3A enzyme into more than 18 significantly improves the neurological safety and has been safely administered metabolites (101). Results of a phase II outcome of head-injured patients. Results to patients following TBI (91,92). Prelimi- clinical trial (102) have been published of a multicenter, placebo-controlled, phase nary results show that patients have im- recently. In this prospective, randomized, III clinical trial have been published re- proved recovery and cognitive skills after placebo-controlled clinical trial a dose es- cently (86). In this study, patients were TBI. A recent published Cochrane Data- calation was performed to obtain data re- randomized to receive a single dose of in- base Review mentioned that there is in- garding CsA effects in TBI patients as travenous HU-211 (dexanabinol) (150 mg) sufficient evidence to support the admin- well as to identify optimal dosage in 30 or placebo. A total of 846 patients were istration of methylphenidate or other patients with severe TBI (GCS 4–8). It prospectively enrolled and randomized related agents (for example, ) was shown that patients with severe TBI into the HU-211 and placebo-control in TBI. None of the cited references met demonstrate a rapid clearance and larger treatment groups. Of the entire patient the inclusion criteria (87). One study (93) distribution volume of CsA. This effect population, an equal number of patients investigated the effect of methylphenidate will need to be accounted for in future showed an unfavorable outcome at 6 on hospital and intensive care unit (ICU) safety and efficacy studies. months, as determined by the extended length of stay in patients with TBI. In this GOS as the primary outcome parameter prospective, randomized, double-blind CALCIUM-CHANNEL BLOCKERS in this study (86). The promising results clinical study 40 patients with severe Calcium-channel blockers reduce the from previous phase I and II clinical trials (GCS 5–8) and 40 patients with mild TBI influx of calcium into the cell by blocking

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the calcium channels. In the setting of thought to be involved in the inflamma- (3.75 or 22.5 mg) subcutaneously within experimental TBI, a rapid increase of ex- tory response. Bradykinin is a potent 8–12 hours after TBI. The objective was to tracellular calcium is observed based on stimulator of nitric oxide formation, cy- test the pharmacokinetics of anatibant in increased Ca2+ permeability and mito- tokines, free radicals, and excitatory the setting of severe TBI. GOS at 3 and 6 chondrial Ca2+ release. There is still un- amino acids as well as a stimulator of in- months indicated a positive trend toward certainty about the consequences, but it is creased intracellular Ca2+ (113,114), the higher concentration, but small sam- suggested that ROS are created, inducing which can lead to blood-brain–barrier ple size (anatibant n = 10 per group, pla- cellular damage and death (103–105). dysfunction (113,115). Two G-protein (B1 cebo n = 5) are limiting factors for inter- Calcium-channel blocker use has been and B2)-coupled receptors are known to pretation of the results. suggested for prevention or treatment of mediate the effects of kinins. Bradykinin cerebral vasospasm after acute traumatic acts via the B2-receptor (116). Bradykinin CONCLUSION brain injury. The known side effects of receptor antagonists given after experi- The golden bullet in the treatment of the drugs (induced hypotension, cerebral mental TBI resulted in improved neuro- acute TBI has not yet been determined. vasodilatation, and impaired cerebrovas- logical outcome in animal models Unfortunately, most of the promising cular reactivity) call into question the (117,118). therapeutic strategies derived from ex- utility of calcium-channel blockers in TBI. perimental animal studies have failed in Nimodipine is known for prevention of Bradycor (CP-0127) translation to the clinical setting of TBI. vasospasm in aneurysmal subarachnoid Bradycor (Delbitant), a peptide com- The rationale for this disappointing fail- hemorrhage and has been shown to have pound B2-, was ure is likely multifactorial. Pharmacolog- neuroprotective properties (103). In the tested in a pilot, single-blind clinical ical compounds that are currently in clin- early 1990s, HIT (Head Injury Trial) I and study in 20 patients (119). Results ical use may be missing their target, both II (106–110) performed in unselected TBI showed reduction of intracranial pres- from a morphological perspective by not patients in Europe indicated a 4% ab- sure and significant prevention in deteri- reaching an adequate concentration solute improvement and 8% relative im- oration of GCS . In a multicenter ran- within the intracranial compartment, and provement for favorable outcome in ni- domized, placebo-controlled trial (120) from a kinetic point of view, by missing modipine-treated patients. These results with 139 patients, bradycor-treated pa- the appropriate timing for the therapeu- were not statistically significant. A sys- tients showed improvement in GOS tic window of opportunity. tematic Cochrane Database Review in- measured 3 months after trauma. Re- Future therapeutic protocols should be cluded all six existing clinical trials (111). sults appeared promising, indicating a designed to allow for prehospital care These were RCTs with a total of 1862 par- positive trend in intracranial pressure, personnel to administer specific pharma- ticipants. Risk of death was reported in neuropsychological tests, GOS score, cological agents at the accident site. In five trials, and the pooled odds ratio (OR) and death rate, although none of the re- addition, there is an ongoing need for of these trials was 0.91 (95% CI 0.70 to sults were statistically significant com- continuing high-quality basic research 1.16). For the six trials reporting death pared to the placebo-treated group. A studies in search of new therapeutic and severe disability (unfavorable out- larger randomized study is needed to compounds. The unexpected failure of come), the pooled OR was 0.97 (95% CI confirm and define this promising result. the CRASH trial in 2004, which revealed 0.81 to 1.18). For two RCTs reporting the that complete inhibition of posttraumatic risk of death in a subgroup of traumatic Anatibant (LF16–0687Ma) neuroinflammation by administration of subarachnoid hemorrhage patients, the Anatibant, a nonpeptide B2-receptor high-dose methylprednisolone leads to a pooled OR was 0.59 (95% CI 0.37 to 0.94). antagonist, has been shown to be effective significantly increased mortality after Thus, the role for calcium channel blocker at minimal concentrations (121) and has TBI (11,12), indicates that future antiin- in acute TBI remains unclear. A beneficial been tested in animal models. Potential flammatory strategies will have to be effect of nimodipine in a subgroup of benefits include decreases in brain edema, more subtle and sophisticated. Promising brain injury patients with subarachnoid improved neurological function recovery, new findings have been made in molecu- hemorrhage was shown but further clini- and decreased inflammatory response lar mechanisms of TBI, and many experi- cal phase III studies are needed to ascer- (117,118,122). A phase I clinical trial in mental substances await testing in the tain beneficial effects in TBI versus the healthy volunteers showed no safety is- clinical setting. For example, peroxisome known risks. sues (unpublished data). Recently anati- proliferator-activated receptors have re- bant was investigated in a phase I clinical cently emerged as potent antiinflamma- MODULATORS OF THE study (123) in patients with severe TBI. In tory transcription factors that when used KININ/KALLIKREIN SYSTEM this multicenter, double-blind, random- alone or in combination with endo- Activation of the kallikrein-kinin sys- ized, placebo-controlled trial, patients cannabinoids may prove to be pivotal tem occurs after trauma (112). Kinins are with TBI and GCS <8 received anatibant antiinflammatory and neuroprotective

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agents in the setting of TBI (124,125). In 11. Roberts I et al. (2004) Effect of intravenous corti- flammatory agents that accompany traumatic addition, selective targeting of the innate costeroids on death within 14 days in 10008 adults brain injury. Brain Res. 1049:112–9. with clinically significant head injury (MRC 28. Roof RL, Duvdevani R, Braswell L, Stein DG. immune response after trauma, such as CRASH trial): randomised placebo-controlled (1994) Progesterone facilitates cognitive recovery by pharmacological inhibition of the trial. Lancet 364:1321–8. and reduces secondary neuronal loss caused by complement cascade at various levels of 12. Sauerland S, Maegele M. (2004) A CRASH land- cortical contusion injury in male rats. Exp. its activation pathways, has recently ing in severe head injury. Lancet 364:1291–2. Neurol. 129:64–9. emerged as a new promising therapeutic 13. The Brain Trauma Foundation. (2007) Guidelines 29. Roof RL, Duvdevani R, Heyburn JW, Stein DG. for the management of severe traumatic brain in- (1996) Progesterone rapidly decreases brain strategy in experimental TBI models jury; XV: steroids. J. Neurotrauma 24:S91–5. edema: treatment delayed up to 24 hours is still (126–129). Exciting treatment possibilities 14. Hall ED, Yonkers PA, McCall JM, Braughler JM. effective. Exp. Neurol. 138:246–51. such as these promise a riveting future (1988) Effects of the 21-aminosteroid U74006F on 30. Shear DA, Galani R, Hoffman SW, Stein DG. for research in the treatment of TBI. experimental head injury in mice. J. Neurosurg. (2002) Progesterone protects against necrotic 68:456–61. damage and behavioral abnormalities caused by DISCLOSURE 15. Braughler JM, Pregenzer JF. (1989) The 21- traumatic brain injury. Exp. Neurol. 178:59–67. aminosteroid inhibitors of lipid peroxidation: re- 31. Thomas AJ, Nockels RP, Pan HQ, Shaffrey CI, The authors declare that they have no actions with lipid peroxyl and phenoxy radicals. Chopp M. (1999) Progesterone is neuroprotective competing financial or proprietary inter- Free Radic. Biol. Med. 7:125–30. after acute experimental spinal cord trauma in ests with regard to this publication. Par- 16. Clark WM, Hazel JS, Coull BM. (1995) Lazaroids: rats. Spine 24:2134–8. ticularly, none of the authors have any fi- CNS pharmacology and current research. Drugs 32. Wright DW, Bauer ME, Hoffman SW, Stein DG. nancial relationships, interests, or shares 50:971–83. (2001) Serum progesterone levels correlate with 17. Hall ED, Braughler JM. (1989) Central nervous decreased cerebral edema after traumatic brain related to any of the therapeutic agents system trauma and stroke; II: physiological and injury in male rats. J. Neurotrauma 18:901–9. discussed in this manuscript. pharmacological evidence for involvement of 33. 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