Posts Tagged Drug development
The purpose of this review is to highlight the pharmacological barrier to drug development for traumatic brain injury (TBI) and to discuss best practice strategies to overcome such barriers. Specifically, this article will review the pharmacological considerations of moving from the disease target “hit” to the “lead” compound with drug-like and central nervous system (CNS) penetrant properties. In vitro assessment of drug-like properties will be detailed, followed by pre-clinical studies to ensure adequate pharmacokinetic and pharmacodynamic characteristics of response. The importance of biomarker development and utilization in both pre-clinical and clinical studies will be detailed, along with the importance of identifying diagnostic, pharmacodynamic/response, and prognostic biomarkers of injury type or severity, drug target engagement, and disease progression. This review will detail the important considerations in determining in vivo pre-clinical dose selection, as well as cross-species and human equivalent dose selection. Specific use of allometric scaling, pharmacokinetic and pharmacodynamic criteria, as well as incorporation of biomarker assessments in human dose selection for clinical trial design will also be discussed. The overarching goal of this review is to detail the pharmacological considerations in the drug development process as a method to improve both pre-clinical and clinical study design as we evaluate novel therapies to improve outcomes in patients with TBI.
[ARTICLE] Postoperative seizure outcome and timing interval to start antiepileptic drug withdrawal: A retrospective observational study of non-neoplastic drug resistant epilepsy – Full Text
This study aimed to investigate the impact of timing interval to start AED withdraw (TIW) after surgery on the seizure outcome in non-neoplastic drug resistant epilepsy (DRE). TIW were divided into three groups (respectively,<1 year, 1-<2 years, and ≥2 years). The seizure outcome at the different time points after starting AED withdrawal were compared among three groups. Other factors that related to seizure recurrence and TIW were included into the multiple analysis to investigate the predictors of seizure-free. Altogether, 205 patients were involved in the study. 102 individuals (50%) had seizure recurrence and 127 (62%) had seizure-free at the final follow up. 115 of them have attempted AED reduction and had not seizure recurrence before AED reduction. The rate of seizure-free had no significant difference among people with different TIW. Multiple analysis indicated that temporal surgery is a favorable predictor of seizure-free at the first year after starting AED withdrawal, and preoperative secondary generalized seizures is an unfavorable predictor of seizure-free at the final follow up. In patients with non-neoplastic DRE, TIW is not the mainly influence factor on seizure outcome, however, preoperative secondary generalized seizures and extra-temporal surgery are negatively associated with seizure-free.
Surgery is an effective treatment for patients with drug resistant epilepsy (DRE), and previous studies indicated that among people with poorly controlled epilepsy, patients who underwent surgery often had better control of seizure than those with medical therapy1,2,3,4. In these studies, surgery was proved to be of great benefit to patients with DRE either seizure freedom or quality of life.
In order to reduce the risk of seizure recurrence, patient with DRE frequently were recommended to continue to take AED until seizure free for two years after surgery5. However, the ideal outcome of surgery for epilepsy is to discontinue antiepileptic drugs (AED) without any seizure attack6. As early AED withdrawal at no cost of seizure outcome not only reduce the financial burden of patients but also is beneficial to neurodevelopment7,8, some other researchers put forward to start AED reduction before 2 years after surgery with completed seizure control9. Nevertheless, as for optimum timing to taper AED after surgery, survey of epileptologists showed that the duration for AED treatment after surgery were wildly different, ranging from less than one year to more than two years and no standardized guidelines exist10,11,12. How to find the suitable time point of AED withdrawal is difficult and controversial.
In previous studies, results about the time of AED withdrawal and seizure outcome are conflict. Some studies indicated that early reduction of AED increase the risk of relapse and is associated to lower rate of seizure free13,14, however, other studies showed that early AED withdrawal was not associated with seizure recurrence and had no affection on long-term seizure outcome15,16,17. Therefore, time point of withdrawing AED is a controversial but meaningful issue. However, most of previous studies included individuals with various pathological result, including tumor, which often had poorer outcome than those with non-tumor-associated epilepsy18, and few study specially focused on non-neoplastic DRE. This study aimed to assess the association between different time point of starting AED withdrawal and seizure outcome after epilepsy surgery in patients with non-neoplastic DRE.[…]
Continue —> Postoperative seizure outcome and timing interval to start antiepileptic drug withdrawal: A retrospective observational study of non-neoplastic drug resistant epilepsy | Scientific Reports
[REPORT] Progress report on new antiepileptic drugs: A summary of the Eleventh Eilat Conference (EILAT XI) – Full Text HTML
The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012.
About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included “Indications overlapping with epilepsy” and “Securing the successful development of an investigational antiepileptic drug in the current environment”.
Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089.
Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.