摘要:

Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option.Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus.Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier.In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated in the clinical setting. Gene therapy also may play a role in local drug delivery with the use of adenovirus, adeno-associated virus, herpesvirus or other delivery vectors to induce brain cells to produce local modulatory substances.New delivery systems should significantly improve the therapeutic/toxic ratio of AEDs.

ISSN:1172-7047    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The CNS serves as an important sanctuary site for HIV replication. The presence of HIV in this compartment may contribute to neurological complications in individuals infected with HIV. Understanding the CNS penetration capabilities of available antiretroviral agents may help clinicians to design treatment regimens with neuroprotective effects. Although numerous clinical studies and anecdotal reports have examined CSF antiretroviral drug exposure as a marker of CNS penetration, understanding the clinical relevance of these findings is difficult. Challenges with study design and subject recruitment often limit the investigator's ability to collect comprehensive data. Upon review of available data, the antiretroviral agents zidovudine, stavudine, lamivudine, nevirapine, efavirenz and indinavir demonstrate consistent penetration into the CSF. Zidovudine-, stavudine-, lamivudine-, didanosine- and protease inhibitor−based regimens also appear to suppress CSF viraemia or improve HIV neurological disease. These agents may be appropriate candidates for neuroprotective antiretroviral treatment regimens. Despite these data, several unanswered questions about the CSF antiretroviral drug exposure-response relationship still remain. Prospective, controlled studies examining this relationship are needed before absolute clinical recommendations are founded.

ISSN:1172-7047    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Frequent, severe and long-lasting migraine attacks require prophylaxis. Established drugs used for the prevention of migraine such as β-adrenoceptor antagonists (β-blockers), calcium channel antagonists, antidepressants and others have an unknown mode of action in migraine. Their prophylactic effect in migraine was discovered by chance in clinical practice when these drugs were used for other purposes. Recently, research into the mechanisms of migraine and the progressive recognition that cortical hyperexcitability and an imbalance between neuronal inhibition [mediated by γ-aminobutyric acid (GABA)] and excitation (mediated by excitatory amino acids) may play an important role in migraine pathophysiology have lead to the identification of potential new agents for the prevention of migraine attacks. This paper reviews the recent literature on these new agents.A search was conducted using MEDLINE from 1998 to November 2001 with the following search terms: migraine, preventive, prophylactic and treatment. Headache textbooks edited in 2000 and 2001 were also used.After analysing the available controlled and uncontrolled clinical studies as well as abstracts, divalproex sodium (valproate semisodium) can be recommended for the prevention of migraine. Lamotrigine may be useful for preventing aura associated with migraine, and topiramate seems a promising option pending trials with more patients, which are currently underway. Riboflavin (which is possibly involved in improving neuronal energy production) appears to be a promising agent, although comparisons with established prophylactic medications are needed. Gabapentin, magnesium, lisinopril and botulinum toxin A have recently been suggested to be effective; however, at present, there are insufficient rigorous and reliable controlled data on these drugs for them to be indicated for such use. Emerging options such as tiagabine, levetiracetam, zonisamide and petasites may all be useful, but controlled data are required to confirm their efficacy. The anti-asthma medication montelukast was found to be effective in an open trial, but ineffective in a recently completed controlled trial.There is an expectation that modern neuroscience will soon provide more efficacious and better tolerated prophylactic medications for migraine.

ISSN:1172-7047    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectivesThe aim of this study was to evaluate the clinical effectiveness and tolerability of nefazodone for the treatment of depression in elderly patients in clinical routine practice.Patients and study designSeventy-nine patients with a mean age of 72.81 years, who had major depression or dysthymia according to DSM-IV criteria, were enrolled into this open label study. Patients were prescribed nefazodone starting at 50 mg/day, increasing every 4 days until a dosage of 200 mg/day was attained, and subsequently upward to 600 mg/day if no dose-limiting adverse effects appeared. Effectiveness was evaluated at the end of weeks 2, 4, 8 and 12 by completion of the Hamilton Depression Rating Scale (HAM-D), the Geriatric Depression Scale (GDS) and the Clinical Global Impressions scale. The Hamilton Anxiety Rating Scale (HAM-A), the sleep satisfaction item of the Oviedo Sleep Questionnaire (OSQ) and the Short Portable Mental Status Questionnaire (SPMSQ) were used to assess the patients at the end of week 12. Primary efficacy analysis was based on an intention-to-treat, last-observation-carried-forward data set.ResultsHAM-D scores decreased progressively from a baseline mean of 22.3 to 14.2 at the study endpoint; although this was a significant reduction, the endpoint score indicates that a significant residual symptomatology remained in the patients. Similarly, the GDS and HAM-A scores had decreased significantly by week 12. Response and remission rates were 47 and 37.5%, respectively. The percentage of patients who were satisfied, much satisfied or very much satisfied with their sleep according to the OSQ increased from 4.2% at baseline up to 62.2% at the study endpoint. A significant reduction in the SPMSQ total score was observed at the study endpoint, although the clinical relevance of this finding is doubtful. Forty-two (53.2%) patients completed the study. The most common reasons for withdrawal from the study were a lack of efficacy and adverse effects. Most adverse reactions were mild to moderate in severity and included dizziness, dry mouth, gastrointestinal distress, sedation, anxiety and malaise.ConclusionOur results suggest that nefazodone may be a well tolerated and effective alternative for treating elderly patients with depression. Although the HAM-D score at study endpoint indicated significant residual symptomatology, a similar finding has been described in several meta-analyses of antidepressant treatment in the elderly. Further research is needed to evaluate a different nefazodone dose regimen, especially a slower dose titration rate, which could result in a reduced discontinuation rate and thus a better treatment outcome.

ISSN:1172-7047    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects.The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day.Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia.In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated.Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis.ConclusionsZiprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.

ISSN:1172-7047    

出版商:ADIS    

年代:2002

数据来源: ADIS