Posts Tagged Pharmacology
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.
Physicians in neurorehabilitation often deal with pharmacological problems, marshalling antihypertensive, anticonvulsive and anticoagulation treatments. In addition, there is growing interest in positive or negative effects of medication on brain recovery. Of great importance is the concept of so-called “detrimental drugs” known to negatively influence processes of brain reorganization and recovery. To this group belong anti-convulsive agents such as phenytoin and barbiturates as well as benzodiazepines, butyrophynones and the antihypertensives clonidine and prazosine. Whenever possible these drugs should be avoided in the course of brain recovery after a cerebral lesion.
For only two substances (the SSRI fluoxetine and cerebrolysin, a mixture of pleotropic neuropeptides and amino acids) large randomized controlled trials showed a positive influence on facilitating motor recovery after the stroke. Both substances probably work through pleotropic multiple molecular mechanisms and not as a one-to-one agonist on the receptor. In general the use of antidepressive agents especially SSRI after the stroke can also be recommended for non-depressed stroke patients.
Also dopaminergic drugs have been shown in smaller studies to positively influence functional recovery. Considering their low side-effect profile, the tentative use of 100 mg of L-Dopa per day in the subacute phase of the stroke can be recommended. In MS patients the use of antidepressive agents is also recommend to improve life quality.
In patients with diminished states of consciousness amantadine is the only substance which a randomized controlled study proved to have at least some transient effect. The use of amantadine can be recommended for the improvement of the level of consciousness in these patients.
Physicians engaged in neurological rehabilitation constantly have to deal with aspects of primary pharmacological treatment of patients, including control of high blood pressure, anticonvulsive therapies and suitable anticoagulation treatment to reduce risk factors and secondary problems. Furthermore, neurological rehabilitation must also take into account pharmacological issues relating to restoration of brain function. This concerns the avoidance of pharmaceuticals that may interfere with brain recovery as well as the use of drugs that may have a positive affect on brain function. This overview aims to provide a critical summary of the options available to the clinician in the pharmacological treatment of patients after acute neurological events as part of the process of the rehabilitation of brain organization and restoration of brain function, as well as discuss the avoidance of potentially negative effects of pharmacological interventions. […]
The University of Utah College of Pharmacy’s Anticonvulsant Drug Development (ADD) Program has been awarded a five-year $19.5 million contract renewal with the National Institutes of Health (NIH) to test drugs to treat epilepsy, and the major focus of the project is to address needs that affect millions of people worldwide -identify novel investigational compounds to prevent the development of epilepsy or to treat refractory, or drug-resistant, epilepsy.
The ADD program began in 1975 and since then has tested the vast majority of drugs used to control seizures in patients with epilepsy, helping millions of people worldwide. Unfortunately, almost one-third of the estimated 50 million people with the disorder has refractory, or unresponsive, epilepsy that isn’t adequately controlled by medications currently available. The contract renewal, awarded through the National Institute of Neurological Disorders and Stroke (NINDS) to the U Department of Pharmacology and Toxicology, represents a shift in the mission to identify new therapies, according to ADD Director Karen S. Wilcox, Ph.D., professor and chair of pharmacology and toxicology and principal investigator of the contract.
“We’re proud that over the past 41 years, the ADD program has played a key role in identifying and characterizing many of the drugs now available to treat patients with epilepsy and to control their seizures,” Wilcox says. “Now, we’re looking for drugs that can modify or prevent the disease, particularly in those patients either with refractory epilepsy or at risk for developing epilepsy following a brain injury.”
Epilepsy is a group of neurological disorders characterized by a tendency for repeated seizures over time. It occurs when permanent changes in the brain result in abnormal or excessive neuronal activity in the brain. An estimated 2.9 million people in the United States and 50 million people worldwide have active epilepsy, according the Centers for Disease Control and World Health Organization. There is no cure for epilepsy and the mainstay of treatment is anti-seizure medications.
ADD is a long-standing program dedicated to testing drugs to treat epilepsy. It has received continuous funding from NINDS’ Epilepsy Therapy Screening Program (ETSP) (formerly known as the Anticonvulsant Screening Program) since its founding in 1974. In collaboration, the ETSP and the ADD Program have evaluated more than 32,000 compounds. ADD received the contract in a competitive bidding process. The renewal of the contractual relationship between the NINDS and the University of Utah reflects the ongoing commitment of the NIH and the ETSP to finding and developing novel therapies for epilepsy and represents a unique partnership between government, industry, and academia.
“The NIH-NINDS ETSP is pleased to continue the productive relationship with the University of Utah,” says Dr. John Kehne, a Program Director at NINDS and head of the ETSP. “These and other efforts supported by the NINDS will help to discover new pharmacotherapies to address the unmet medical needs of people living with epilepsy.”
In addition to its focus on evaluating potential candidate drugs for the treatment of therapy-resistant epilepsy, the mission of the ADD Program includes efforts to identify novel therapies for different types of epilepsy. The program also serves as a base for innovative basic research that sheds new light on the pathophysiology of epilepsy and provides a unique training environment for students, research fellows, and visiting scientists. Currently, the ADD program employ18 researchers, technicians, and staff. Cameron S. Metcalf, Ph.D is associate director and a co-Investigator of the contract and Peter J. West, Ph.D., and Misty D. Smith, Ph.D, research assistant professors of pharmacology and toxicology, are also co-investigators on the contract renewal.
Although there currently is no cure for epilepsy, Wilcox, who previously served as a co-Investigator of ADD before taking over as PI in 2016, believes that can be changed.
“The brain has remarkable plasticity throughout a person’s life,” she says. “If we learn enough about neuroscience and the details of how the brain works, it’s very possible to find a cure.”
[Abstract] Pharmacokinetics and pharmacodynamics of incobotulinumtoxin A influencing the clinical efficacy in post-stroke spasticity – Expert Opinion on Drug Metabolism & Toxicology –
[ARTICLE] Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward: Report of the Department of Defense Neurotrauma Pharmacology Workgroup – Full Text HTML
Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of disability and mortality in both developed and developing societies.
The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI.
To inform this plan, the Workgroup
- assessed the current state of the science and ongoing research and
- identified research gaps to inform future development of research priorities for the neurotrauma research portfolio.
The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI.
[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.