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PubMed2005

Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity.

Perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive N-methyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose- and time-dependently blocked prostaglandin E(2) (PGE(2))- and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE(2)-induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.

Analgesics↗
PubMed2005

Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity.

Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-d-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and alpha-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury.

Animals↗
PubMed1994

Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin.

The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1 beta, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelman, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of > or = 300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides new insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.

AIDS Dementia Complex↗
PubMed1996

Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study.

OBJECTIVE: A group of 27 patients with Friedreich's ataxia and another group of 30 patients with olivopontocerebellar atrophies were each randomly divided into two subgroups, one receiving placebo and the other amantadine hydrochloride (AH; 200 mg daily) for three to four months. METHODS: The effect of double blind treatment was evaluated by simple visual and auditory reaction time (RT) and movement time (MT) for both right and left hands. RESULTS: The subgroup with olivopontocerebellar atrophies receiving AH showed significant improvement on seven out of eight variables studied by analysis of covariance. In patients with Friedreich's ataxia, improvement was definitely less. Treatment remained contraindicated for those with cardiomyopathies or drug intolerance. CONCLUSION: The rationale of AH use in heredodegenerative ataxias can be explained by its replacement effect (dopamine release) and by direct involvement of N-methyl-D-aspartate (NMDA) in glutamate mediated neurotoxicity in cerebellar granular cells; memantine, an AH analogue, is a potent blocker of NMDA receptors.

Adult↗
PubMed2005

Mechanisms of mechanotransduction by specialized low-threshold mechanoreceptors in the guinea pig rectum.

The guinea pig rectum, but not the colon, is innervated by a specialized class of distension-sensitive mechanoreceptors that have transduction sites corresponding to rectal intraganglionic laminar endings (rIGLEs). Rectal mechanoreceptors recorded in vitro had low threshold to circumferential stretch, adapted slowly, and could respond within 2 ms to mechanical stimulation by a piezo-electric probe. Antagonists to ionotropic N-methyl-D-aspartate (NMDA; CGS 19755, memantine) and non-NMDA (6,7-dinitroquinoxaline-2,3-dione) glutamate receptors did not affect mechanotransduction. In normal Krebs solution, the P2X purinoreceptor agonist alpha,beta-methylene ATP reduced mechanoreceptor firing evoked by distension but simultaneously relaxed circular smooth muscle and inhibited stretch-induced contractions. Neither ATP nor alpha,beta-methylene ATP affected mechanotransduction when transduction sites were directly compressed with von Frey hairs. The P2 purinoreceptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid did not affect stretch-induced firing but reduced the inhibitory effect of alpha,beta-methylene ATP on stretch-induced firing. Under isometric conditions, blocking synaptic transmission in Ca2+-free solution reduced stretch-evoked firing but not when basal tension was restored to control levels. Under isotonic condition, Ca2+-free solution did not significantly affect load-evoked firing. The blockers of mechanogated and/or transient receptor potential channels, benzamil, Gd3+, SKF 96365, and ruthenium red inhibited stretch-induced firing but, in parallel, significantly reduced stretch-induced contractions. Benzamil and SKF 96365 were able to inhibit mechanotransduction when transduction sites were compressed with von Frey hairs. The results show that mechanotransduction is rapid but does not depend on fast exocytotic release of mediators. It is likely that stretch-activated ion channels on rIGLEs are involved in direct, physical mechanotransduction by rectal low-threshold mechanoreceptors.

Adenosine Triphosphate↗
PubMed2006

Current and emerging pharmacological treatment options for dementia.

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.

Acetylcholine↗
PubMed2004

Emerging therapies for vascular dementia and vascular cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD). SUMMARY: Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence. CONCLUSIONS: From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Carbamates↗
PubMed2004

Transcranial magnetic stimulation: applications for neuropsychopharmacology.

Transcranial magnetic stimulation (TMS) provides new possibilities for studying localized changes in the electrical properties of the human cortex. TMS combined with electromyography (EMG) has revealed that drugs blocking Na(+) or Ca(2+) channels such as phenytoin, lamotrigin or carbamazepine change the motor threshold without affecting intracortical inhibition or facilitation. Gabaergic agents vigabatrin, lorazepam, diazepam, baclofen and ethanol do not affect the motor threshold, but increase intracortical inhibition and decrease facilitation. N-methyl-D-aspartate receptor antagonists riluzole, dextromethorphan and memantine have similar effects. Dopamine receptor antagonists such as haloperidol, but not sulpiride, decrease intracortical inhibition and increase intracortical facilitation. Other monoamines, such as serotonin and noradrenaline, may have some modulating effect on the cortical excitability. However, TMS combined with EMG gives only indirect evidence about the excitability of the motor cortex because spinal mechanisms may contribute to the results. Cortical excitability can be studied directly by combining TMS with brain imaging methods such as electroencephalography (EEG). Motor and non-motor areas can be stimulated and subsequent brain activity can be measured. Ethanol has been shown to modulate EEG responses evoked by motor-cortex TMS, the effects being largest at the right prefrontal cortex, meaning that ethanol would have changed the functional connectivity. Furthermore, alcohol decreases amplitudes of EEG responses after the left prefrontal stimulation mainly in anterior parts of the cortex, which may be associated with the decrease of the prefrontal cortical excitability. Taken together, TMS provides a new insight to the actions of central nervous system drugs at the cortical level.

Electric Stimulation Therapy↗
PubMed1997

Pharmacotherapy of HIV dementia.

OBJECTIVE: To review the clinical presentation and management of cognitive impairment associated with central nervous system HIV type 1 (HIV-1) infection. DATA SOURCES: A MEDLINE search pertaining to HIV-related dementia (HIV-D) and pharmacologic management was performed. Additional literature was obtained from reference lists of the identified articles. STUDY SELECTION AND DATA EXTRACTION: All clinical trials and case reports evaluating pharmacologic efficacy in terms of clinical response, cerebrospinal fluid (CSF) changes, and neuropathology were considered for inclusion. Selection was not restricted by study design because most information consists of open uncontrolled trials and case reports. DATA SYNTHESIS: HIV-D is characterized by a triad of disturbances in cognition, motor performance, and behavior in adults. Children present with developmental delay, cognitive impairment, poor brain growth, and other neurologic symptoms. The exact pathophysiologic mechanisms of HIV-D are not known. Numerous pharmacologic agents (e.g., nucleoside reverse transcriptase inhibitors, pentoxifylline, nitroglycerin, memantine, nimodipine, peptide T) are under investigation for management of HIV-D. Zidovudine is the most thoroughly investigated medication, with patients developing HIV-D less frequently and showing improvement on neuropsychological, CSF, and neuropathologic evaluations. Sustained response to zidovudine lasts 6 months to 1 year and optimal response is achieved at higher, but less tolerated, dosages. HIV-D patients frequently have comorbid psychiatric disorders requiring psychopharmacologic agents and are sensitive to the adverse effects of these medications. CONCLUSIONS: HIV-D is a devastating complication of HIV-1 infection. Zidovudine is the therapy of choice for prevention and management of cognitive impairment in symptomatic HIV-infected patients and patients with AIDS. Recommendations for other medications cannot be made secondary to lack of data. The management of HIV-D may include multiple agents as more data become available regarding combination therapy. Well-designed controlled trials are needed to evaluate the efficacy of established treatments and investigational medications in the management of HIV-D.

AIDS Dementia Complex↗
PubMed2006

QEEG monitoring of Alzheimer's disease treatment: a preliminary report of three case studies.

Previous research has shown that quantitative electroencephalography (qEEG) can monitor treatment of Alzheimer's Disease (AD). This study investigated the ability of a qEEG measure based on EEG variance, combined with a delayed recognition memory task, to measure treatment effects on patients with AD. Three AD patients with very mild AD (CDR=0.5, FAST stage 3) were monitored with task specific EEG at multiple time points before and after medication treatment. Patients had their EEG recorded while performing a recognition memory task. A measure of (normalized) variance was applied to the EEG data. To the extent possible, the subjects received this treatment monitoring multiple times. These patients were monitored a total of 14 times, which yielded 11 measurements of qEEG change during the course of treatment. The direction of change in patients' qEEG values agreed with patients' medication treatment on 10 out of 11 occasions, p < 0.006 (binomial test) and was more accurate than monitoring with the relative theta power, p < 0.05. The results of this monitoring also showed that the qEEG measure accurately reflected treatment in a dose dependent manner. These results were independent of the specific medication monitored; Galantamine, Memantine, Nicotine, and Rivastigmine. In conclusion, this qEEG method may be useful for measuring AD treatment responses.

Aged↗
PubMed2005

Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases.

The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.

Aging↗
PubMed2006

Neuroprotective agents for clinical trials in ALS: a systematic assessment.

BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2004

[Current status and perspectives on the development of therapeutic agents for Alzheimer's disease].

Acetylcholinesterase inhibitors have beneficial effects to improve the cognitive impairment in patients with mild to moderate Alzheimer's disease (AD). In addition, a channel blocker of N-methyl-D-aspartate receptor, memantine hydrochloride, was approved as a therapeutic agent for patients with moderate to severe AD in both EU countries in 2002 and USA in 2003, while the clinical development is still ongoing in Japan. In contrast, the pharmacotherapy for a prime cure against AD is not available in the market, although there has been a worldwide search for novel compounds. The most plausible mechanism for the treatment of AD is the reduction of the amyloid beta-peptide (Abeta) plaques, one of the pathological markers of AD, in the brain. For this purpose, the inhibitors of beta-secretase and gamma-secretase, which cleave amyloid precursor protein (APP) to release Abeta, has been developed to interfere with APP processing. The beta-sheet breaker and metal chelators for the breakdown of aggregated Abeta have also been synthesized as well as the immunotherapeutic approach using Abeta vaccine. On the other hand, some nonsteroidal anti-inflammatory drugs, such as ibuprofen and sulindac, noncompetitively inhibited Abeta production but not Notch cleavage. The development of Abeta-lowering drugs is highly expected for the treatment of AD.

Alzheimer Disease↗
PubMedDate not supplied

New drugs of 2003.

OBJECTIVES: To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. DATA SOURCES: Product labeling supplemented selectively with published studies and drug information reference sources. STUDY SELECTION: By the author. DATA EXTRACTION: By the author. DATA SYNTHESIS: The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

Drug Approval↗
PubMed2005

Can olanzapine cause delirium in the elderly?

OBJECTIVE: To report a case of delirium probably caused by the atypical antipsychotic olanzapine in a 74-year-old man with dementia. CASE SUMMARY: A 74-year-old white man with a diagnosis of severe dementia of mixed etiology with behavioral disturbances was admitted to an urban teaching hospital for increasing agitation in the context of worsening dementia. Olanzapine 2.5 mg each evening was started for agitation, and the dose was titrated to 5 mg each evening with additional emergent doses. Memantine, an N-methyl-D-aspartate antagonist, was increased from the admission dose of 10 mg/day to 15 mg/day. The patient developed symptoms of delirium on hospital day 4. Neuroleptic malignant syndrome and other causes of delirium were ruled out. Discontinuation of olanzapine resulted in resolution of the delirium. DISCUSSION: Antipsychotic medications are commonly used to treat symptoms of delirium. Atypical antipsychotics are better tolerated in the elderly because of their fewer adverse reactions compared with other antipsychotics. Olanzapine has been successfully used in the treatment of delirium. However, there have been case reports of delirium associated with olanzapine, probably related to its intrinsic anticholinergic effect. Application of the Naranjo probability scale indicated a probable relationship between the onset of delirium and the use of olanzapine in this patient. As of December 1, 2005, this was the second such report of a case in the elderly. CONCLUSIONS: Although olanzapine is useful in the treatment of delirium, elderly patients treated with this drug can develop delirium and hence should be closely monitored.

Aged↗
PubMed2004

Open-channel blockers of the NMDA receptor complex.

A variety of compounds have been shown to limit or prevent excitotoxicity by blocking N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. However, many first-generation NMDA antagonists did not live up to clinical expectations in trials of acute brain injury because of the manifestation of multiple side effects. In spite of this, development of NMDA antagonists continues, where some of the newer agents block excitotoxicity through alternative mechanisms. For example, blockers selective to the NR2B subunit or agents that block metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are currently under investigation. Several years ago, the arylalkylamine spider toxins were demonstrated to function as open-channel blockers similar to memantine, which was very recently approved by the U.S. FDA for use in patients with Alzheimer's dementia. With this said, programs focusing on NMDA antagonism via alternative mechanisms may still hold promise for treating acute injury and even chronic forms of dementia.

Animals↗
PubMed2000

Perspectives in the treatment of vascular dementia.

The diagnosis and treatment of vascular dementia (VaD) are particularly challenging because of its multiple causal lesions and the variety of its clinical presentations. Even poststroke dementia cases may be due to preexisting Alzheimer's disease. Diagnostic criteria for clinical trials have been implemented quite recently. Of the vasodilator agents, only the ergoloid mesylates have shown mild benefit. The calcium channel blocker nimodipine appears to be useful in subcortical VaD. Of the nootropic agents, memantine appears to be promising. Pentoxifylline produced significant improvement in multi-infarct VaD. Aspirin, triflusal and Ginkgo biloba extract were associated with some stabilization of dementia progression, perhaps due to their antiplatelet effects. Acetyl-cholinesterase inhibitors appear to be useful in improving memory and activities of daily living in VaD. Results of a large trial of donepezil in VaD should be available soon. Hyperbaric oxygen has been reported to be effective in Binswanger's disease. From the public health perspective, stroke prevention, particularly in atrial fibrillation, and the early and adequate treatment of arterial hypertension clearly decrease the incidence of VaD.

Journal Article↗
PubMed2005

Analgesic therapy in postherpetic neuralgia: a quantitative systematic review.

BACKGROUND: Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN. METHODS AND FINDINGS: We systematically searched databases (MEDLINE 1966-2004, EMBASE 1988-2004, CINAHL 1982-2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat. Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25. This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, "strong" opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated. Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as "not yet adequately tested" rather than demonstrating "no evidence of efficacy." Topical aspirin/diethyl ether has not been adequately tested. CONCLUSION: The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.

Analgesics↗