Ezogabine: An Evaluation of Its Efficacy and Safety as Adjunctive Therapy for Partial-Onset Seizures in Adults

2012 ◽  
Vol 46 (10) ◽  
pp. 1358-1367 ◽  
Author(s):  
Mikiko Yamada ◽  
Timothy E Welty
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
English Language ◽  
De Novo ◽  
Phase 1 ◽  
Published Data ◽  
Partial Seizures ◽  
Phase 3 ◽  
Safety And Efficacy

Objective: To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamic properties, and clinical application of ezogabine (retigabine. INN), an antiepileptic drug approved in 2011. Data Sources: Published data from in vitro, animal, and clinical studies were obtained from PubMed and CINAHL searches, from January 1980 to March 31, 2012. Other relevant data regarding the safety and efficacy of ezogabine were obtained from the Food and Drug Administration and the European Medication Agency Web sites. Study Selection and Data Extraction: Selected articles were prospective in vitro, animal, and controlled clinical studies of ezogabine. Non-English-language articles were excluded. Data Synthesis: In vitro and animal studies show that ezogabine activates voltage-gated potassium channels, leading to reduction of seizure frequency by inhibiting hyperexcitability activity in the central nervous system. Additionally, ezogabine enhances γ-aminobutyric acid (GABA) activity and de novo GABA synthesis. Eight clinical studies of ezogabine have been published, 5 being Phase 1 clinical trials in healthy subjects and 3 being Phase 3 clinical trials in patients with pharmacoresistant partial-onset seizures. Phase 3 clinical trials demonstrated the safety and efficacy of ezogabine in patients with partial-onset seizures. Conclusions: Clinical trials have shown that ezogabine is efficacious as an adjunctive agent in patients with pharmacoresistant partial seizures. Careful monitoring of drug interactions and adverse reactions is necessary. While ezogabine is efficacious (or partial seizures, its precise role in the management of patients with epilepsy is yet to be determined.

Levoleucovorin as Replacement for Leucovorin in Cancer Treatment

2012 ◽  
Vol 46 (10) ◽  
pp. 1349-1357 ◽  
Author(s):  
Victor Tuan Giam Chuang ◽  
Manabu Suno
Keyword(s):  
Clinical Trials ◽  
Cancer Treatment ◽  
Clinical Studies ◽  
English Language ◽  
Antitumor Agents ◽  
Data Extraction ◽  
Phase 1 ◽  
Phase 3 ◽  
Medline Search ◽  
Reasonable Alternative

Objective: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. Data Sources: A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms I-LV. levoleucovorin, d,I-LV, leucovorin, folinic acid, tolinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. Study Selection and Data Extraction: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. Data Synthesis: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. Conclusions: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.

Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis

2008 ◽  
Vol 42 (10) ◽  
pp. 1458-1465 ◽  
Author(s):  
Anne R Korenke ◽  
Michael P Rivey ◽  
Douglas R Allington
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Adverse Events ◽  
Sustained Release ◽  
English Language ◽  
Walking Speed ◽  
Data Extraction ◽  
Walking Ability ◽  
Phase 3 ◽  
Safety And Efficacy

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of sustained-release (SR) fampridine in patients with multiple sclerosis (MS). Data Sources: An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms fampridine-SR, 4-aminopyridine. and multiple sclerosis. References of selected articles and information from the drug developer were used to further identify pertinent trials. Study Selection and Data Extraction: Article selection was based primarily on studies that evaluated the pharmacokinetics, safety, and efficacy of fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis. Data Synthesis: Fampridine-SR is a sustained-release, orally administered potassium-channel blocker acting in the central nervous system to enhance conduction in demyelinated axons Several small trials have evaluated the safety and efficacy of fampridine-SR in patients with MS to improve their walking ability. Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with fampridine-SR compared with 9.3% of those who received placebo (p < 0.001), Treatment-related adverse events associated with the use of fampridine-SR include dizziness, insomnia, nausea, and paresthesia. More severe adverse events, such as seizure, have occurred in patients receiving doses higher than those currently recommended. Conclusions: Positive results from 2 Phase 3 clinical trials have put fampridine-SR on the path toward approval as a medication for improving walking speed and tower extremity strength in patients with MS.

scholarly journals COVID-19: A need for new rather than repurposed antiviral drugs

2021 ◽  
Author(s):  
Dory Kovacs ◽  
Chris Davis ◽  
Paul Cannon ◽  
Melanie McFarlane ◽  
Stephanie M Rainey ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Antiviral Drugs ◽  
New Drugs ◽  
Added Value ◽  
Wild Type Virus ◽  
Published Data ◽  
Antiviral Compounds ◽  
The Uk

AbstractBackgroundSARS-CoV-2 infection, the causative agent of COVID-19, has resulted in over 2,500,000 deaths to date1. Although vaccines are becoming available, treatment options remain limited. Repurposing of compounds could reduce the time, cost, and risks associated with the development of new drugs and has been the focus of many clinical studies.Here, we summarise available evidence on 29 FDA-approved compounds, from in vitro results to clinical trials, focussing on remdesivir, galidesivir and favipiravir, and test 29 antiviral compounds’ activity in vitro.MethodsA comprehensive search strategy was used to retrieve trials and publications related to antiviral compounds with potential efficacy to treat coronaviruses. These data were used to prioritise testing of a panel of antiviral drugs in vitro against patient isolates of SARS-CoV-2. An in vitro screen was carried out to determine the activity of 29 FDA-approved compounds.Results625 clinical trials investigated 16 repurposed antiviral candidate compounds for the treatment of COVID-19. In vitro studies identified ten drug candidates with demonstrable anti-SARS-CoV-2 activity, including favipiravir, remdesivir, and galidesivir. To validate these findings, a drug screen was conducted using two cell lines and wildtype isolates of SARS-CoV-2 isolated from patients in the UK. While eight drugs with anti-SARS-CoV-2 activity were identified in vitro, activity in clinical trials has, as yet failed to demonstrate a strong effect on mortality.ConclusionsSo far, no repurposed antiviral has shown a strong effect on mortality in clinical studies. The urgent need for novel antivirals in this pandemic is clear, despite the costs and time associated with their development.Research in ContextEvidence before this studyRepurposing of existing compounds for the treatment of COVID-19 has been the focus of many in vitro studies and clinical trials, saving time, costs and risks associated with the research and development of new compounds.Added value of this studyWe reviewed the literature for 29 FDA-approved compounds with previously reported (or suspected) anti-SARS-CoV-2 activity and found 625 clinical trials that have been undertaken on 16 different drugs. We determined if repurposed antivirals are suitable for clinical trials based on previously published data, and conducted an additional in vitro screen using locally circulating strains in the UK (PHE2 and GLA1). We report the difference in IC50 from published data using Wuhan1/Wash1 strains with PHE2 and GLA1, including IC50 values below 100μM for galidesivir in wild-type virus. Given the limited success of repurposed compounds in the treatment of COVID-19, we comment on the urgent need for new antivirals specifically targeting SARS-CoV-2.Implications of all the available evidenceOur data show that most prospective compounds for repurposing show no anti-SARS-CoV-2 activity, and antiviral activity in vitro does not always translate to clinical benefit. So far, no repurposed compound has shown a strong effect on mortality in clinical studies. Drugs, including monoclonal antibody therapies, that have been developed to target SARS-CoV-2 virus itself have shown most promise.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Debora Rubio-Aparicio ◽  
Thomas G. Nolan ◽  
Jonathan Parkinson ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Hollow Fiber ◽  
Phase 1 ◽  
Phase 3 ◽  
Fiber Model ◽  
Content Type ◽  
Development Of Resistance ◽  
Carbapenem Resistant ◽  
Dosage Regimens

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

scholarly journals Efficacy and Safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three doses combination

2021 ◽  
Author(s):  
Maria Eugenia Toledo-Romani ◽  
Mayra Garcia-Carmenate ◽  
Carmen Valenzuela Silva ◽  
Waldemar Baldoquin-Rodriguez ◽  
Marisel Martinez Perez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Placebo Group ◽  
Conjugate Vaccine ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Dose Schedule ◽  
T Cell Response ◽  
Group 14 ◽  
Phase 3 ◽  
Double Blinded

Background: SOBERANA 02 is a COVID19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phase 1 and 2 clinical trials demonstrated its high immunogenicity, promoting neutralizing IgG together with specific T-cell response. A third dose of SOBERANA Plus (SARS-CoV-2 RBD-dimer) further increased the specific anti-RBD neutralizing antibodies. Methods: In a randomized, double-blinded, placebo-controlled, phase 3 trial we randomly assigned 44 031 participants, aged 19-80 years to three groups in a 1:1:1 ratio to receive 28 days apart either a) two doses of 25 microg SOBERANA 02, or b) two doses of 25 microg SOBERANA 02 followed by a third dose of 50 microg SOBERANA Plus, or c) two doses of placebo. Reported study endpoints are vaccine efficacy (VE) evaluated through laboratory-confirmed symptomatic COVID-19 cases and safety. During the trial, the SARS CoV-2 isolates in Havana were predominantly (beta 74.0 %) and shift gradually to delta (100%). Results: Two doses of SOBERANA 02 protects against symptomatic COVID-19: 43 cases in the two-dose group (14 371) vs. 155 in the placebo group (14 403), VE 71.0%, adjusted (CI 95%58.9-79.1). The heterologous three dose combination with SOBERANA Plus protected against symptomatic COVID-19: 15 cases in the vaccine groups (13 833) vs. 155 in the placebo group (14 303), VE 92.4%, adjusted (CI 95% 86.9-95.6%). For two-dose schedule VE against severe COVID-19 was 63.0% and for death 59.0%; for heterologous three-dose schedule, 100% in both cases. Conclusions: This is the first phase 3 study of a three-dose, heterologous vaccine combination against SARS-CoV-2. Two doses of the conjugate vaccine SOBERANA 02 was safe and attained efficacy of 71.0% in adults population 19-80 y/o; incorporating SOBERANA Plus after two doses of SOBERANA 02, increased efficacy from 71.0 % to 92.4% (Clinical Trials IFV/COR/09 number, RPCEC00000354.)

Safety and efficacy of combined essential oils for the skin barrier properties: in vitro , ex vivo and clinical studies

2022 ◽  
Author(s):  
VHP Infante ◽  
PMBG Maia Campos ◽  
LR Gaspar¹ ◽  
ME Darvin ◽  
J Schleusener ◽  
...  
Keyword(s):  
Essential Oils ◽  
Clinical Studies ◽  
Ex Vivo ◽  
Skin Barrier ◽  
Barrier Properties ◽  
Safety And Efficacy

scholarly journals Remdesivir: Critical Clinical Appraisal for COVID 19 Treatment

Drug Research ◽  
2020 ◽  
Author(s):  
Saptarshi Chatterjee
Keyword(s):  
Clinical Trials ◽  
Clinical Research ◽  
Clinical Studies ◽  
Promising Result ◽  
Drug Repurposing ◽  
In Vitro Studies ◽  
Therapeutic Molecules ◽  
Regulatory Aspect ◽  
Plausible Mechanism

AbstractRemdesivir is presently been considered as ‘molecule of hope’ to curb the menace of COVID19. Non-availability of any USFDA approved drug has led to several attempt of drug-repurposing and development of new therapeutic molecules. However, Remdesivir has been found to be effective against a broad range of virus including SARS, MERS and COVID 19 through in-vitro studies. Several clinical research attempt are presently being conducted showing promising result yet not conclusive. This review summarized all such clinical trials to critically appraise the usage of Remdesivir against COVID 19 along with the publications related to the results of the clinical studies. The present regulatory aspect i. e. Emergency Use Authorization (EYA) and information of molecule and plausible mechanism is also dealt.

scholarly journals Implementing Curcumin in Translational Oncology Research

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5240
Author(s):  
Koraljka Gall Trošelj ◽  
Ivana Samaržija ◽  
Marko Tomljanović ◽  
Renata Novak Kujundžić ◽  
Nikola Đaković ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
Metabolic Reprogramming ◽  
Current Status ◽  
Strong Indication ◽  
Experimental Animals ◽  
Oncology Research ◽  
Modifying Effect ◽  
Detailed Presentation

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.

Relapsed Multiple Myeloma

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 303-309 ◽  
Author(s):  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Great Promise ◽  
New Agents ◽  
Ongoing Work ◽  
The Many

Abstract Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

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