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.

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.

Leukotriene-Receptor Antagonists and 5-Lipoxygenase Inhibitors in Asthma

1993 ◽  
Vol 27 (7-8) ◽  
pp. 898-903 ◽  
Author(s):  
Julie S. Larsen ◽  
Edward P. Acosta
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Data Extraction ◽  
Background Information ◽  
Receptor Antagonists ◽  
Lipoxygenase Inhibitors ◽  
Medline Search ◽  
Leukotriene Receptor Antagonists ◽  
Patient Tolerance ◽  
Leukotriene Receptor

OBJECTIVE: To familiarize readers with a potentially new class of compounds for treating asthma. Background information on leukotrienes is provided in addition to an indepth review of pertinent clinical trials. DATA SOURCES: Information was obtained from controlled clinical trials, abstracts, and review articles identified through a MEDLINE search of English-language articles. STUDY SELECTION: Emphasis was placed on early clinical trials that showed some benefit with these compounds as well as more recent studies using newer agents that produced more promising results. DATA EXTRACTION: Information regarding leukotriene biochemistry was extracted from basic science research and data from human studies were evaluated by the authors according to patient selection, study design, methodology, and therapeutic response. DATA SYNTHESIS: Leukotrienes have a pathophysiologic role in asthma. Two distinct but pharmacologically similar classes of leukotriene inhibitors are currently being clinically evaluated. These are leukotriene receptor antagonists and 5-lipoxygenase inhibitors. Early clinical trials with these agents yielded unfavorable results primarily because of lack of drug potency and selectivity, poor patient tolerance, and possibly the route of administration. Subsequent studies with more potent and selective agents have further implicated leukotrienes as biochemical mediators in asthma and, consequently, have shown promising clinical outcomes with respect to pulmonary function testing and patient tolerance. CONCLUSIONS: Advancements in the pathogenesis of asthma are beginning to define a role for the leukotrienes. Although more studies are needed to assess the efficacy of leukotriene inhibitors, recent clinical trials using leukotriene-receptor antagonists and 5-lipoxygenase inhibitors indicate a potential for the expansion of therapeutic regimens currently used in the treatment of asthma.

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.

Calcium-Channel Antagonists for Prevention of Atherosclerosis

1993 ◽  
Vol 27 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Shawn M. Borcherding ◽  
Suzanne G. Meeves ◽  
Neil E. Klutman ◽  
Patricia A. Howard
Keyword(s):  
Clinical Trials ◽  
Calcium Channel ◽  
Calcium Antagonists ◽  
Clinical Studies ◽  
Animal Studies ◽  
English Language ◽  
Data Extraction ◽  
Calcium Channel Antagonists ◽  
Trial Duration

OBJECTIVE: To critically evaluate the current literature regarding the role of calcium-channel antagonists in preventing atherosclerosis. DATA SOURCES: English language clinical studies, abstracts, conference proceedings, and review articles pertaining to calcium-channel antagonists and atherosclerosis. STUDY SELECTION: Relevant animal and human studies examining the role of calcium-channel antagonists in atherosclerosis prevention and treatment. DATA EXTRACTION: Potential mechanisms for the development of atherosclerosis and the use of calcium antagonists for preventing and treating coronary artery disease are discussed. Animal studies are summarized; next, significant data from human clinical studies are presented. DATA SYNTHESIS: Available studies are described and discussed. CONCLUSIONS: Results from animal and clinical trials in humans suggest that calcium antagonists may retard the development and progression of atherosclerosis. However, most clinical trials to date have been conducted in patients with proven atherosclerotic plaques. Further studies examining the role of calcium-channel antagonists in preventing and treating atherosclerosis are needed, but may be difficult to conduct because of the large numbers of patients required, long trial duration, and associated costs.

Zolpidem: Distinct from Triazolam?

1997 ◽  
Vol 31 (5) ◽  
pp. 625-632 ◽  
Author(s):  
Bob L Lobo ◽  
William L Greene
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Memory Impairment ◽  
English Language ◽  
Data Extraction ◽  
Residual Effects ◽  
Data Synthesis ◽  
Medline Search ◽  
Study Selection ◽  
Pertinent Information

OBJECTIVE: TO review the literature that compares Zolpidem with triazolam, with an emphasis on efficacy and safety in humans. DATA SOURCES: Information was retrieved from a MEDLINE search (1983–1996) of the English-language literature using the terms triazolam and zolpidem. STUDY SELECTION: Reports of clinical trials comparing the safety and efficacy of zolpidem and triazolam were included in this review. DATA EXTRACTION: Data were evaluated according to study design, efficacy, and adverse effects. Pertinent information was selected and the data synthesized into a review format. DATA SYNTHESIS: Zolpidem and triazolam have similar pharmacokinetic and pharmacodynamic effects in humans. Clinical trials have shown that usually recommended, equipotent dosages of zolpidem and triazolam do not differ with respect to pharmacokinetics, efficacy, tolerability, residual effects, memory impairment, rebound insomnia, abuse potential, or other adverse effects. CONCLUSIONS: Zolpidem offers no distinct therapeutic advantage over triazolam for the treatment of insomnia.

Role of Acetyl-L-Carnitine in the Treatment of Diabetic Peripheral Neuropathy

2008 ◽  
Vol 42 (11) ◽  
pp. 1686-1691 ◽  
Author(s):  
Jeffery D Evans ◽  
Tibb F Jacobs ◽  
Emily W Evans
Keyword(s):  
Clinical Trials ◽  
Peripheral Neuropathy ◽  
Diabetic Peripheral Neuropathy ◽  
English Language ◽  
Data Extraction ◽  
Disease Process ◽  
Medline Search ◽  
Treatment And Prevention ◽  
Meta Analyses

Objective: To examine the role of acetyl-L-carnitine (ALC) in the treatment of diabetic peripheral neuropathy (DPN). Data Sources: A MEDLINE search (1966–April 2008) of the English-language literature was performed using the search terms carnitine, diabetes, nerve, and neuropathy. Studies identified were then cross-referenced for their citations. Study Selection and Data Extraction: The search was limited to clinical trials, meta-analyses, and reviews addressing the use of ALC for the treatment of DPN. Studies that included other disease states that could cause peripheral neuropathy were excluded. Two large clinical studies that used ALC for the treatment of DPN were identified. No case studies were identified. Data Synthesis: The results from 2 published clinical trials Involving 1679 subjects were included. Subjects who received at least 2 g daily of ALC showed decreases in pain scores. One study showed improvements in electrophysiologic factors such as nerve conduction velocities, while the other did not. Patients who had neuropathic pain reported reductions in pain using a visual analog scale. Nerve regeneration was documented in one trial. The supplement was well tolerated, A proprietary form of ALC was used in both studies. Conclusions: Data on treatment of DPN with ALC support its use. It should be recommended to patients early in the disease process to provide maximal benefit. Further studies should be conducted to determine the effectiveness of ALC in the treatment and prevention of the worsening symptoms of DPN.

Acute Management of Cancer-Related Hypercalcemia

1996 ◽  
Vol 30 (5) ◽  
pp. 507-513 ◽  
Author(s):  
Marie A Chisholm ◽  
Anthony L Mulloy ◽  
A Thomas Taylor
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Data Extraction ◽  
Symptomatic Relief ◽  
Gallium Nitrate ◽  
Medline Search ◽  
Patients With Cancer ◽  
Study Selection ◽  
Life Threatening ◽  
Acute Hypercalcemia

OBJECTIVE: TO review the pathogenesis and pharmacologic treatment of acute hypercalcemia associated with malignancy. DATA SOURCES: A MEDLINE search (1966 to 1995) of the English-language literature pertaining to acute hypercalcemia was performed. Additional literature was obtained from reference lists of articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles discussing the etiology and medical management of cancer-related acute hypercalcemia were considered in the review. Clinical trials reporting efficacy and safety of antihypercalcemic agents were also included. Information selected in the review was based on the discretion of the authors. DATA SYNTHESIS: Hypercalcemia is a life-threatening disorder associated with malignancy. It occurs in approximately 10–20% of patients with cancer. A variety of medications have been used in the management of hypercalcemia including bisphosphonates, calcitonin, furosemide, gallium nitrate, glucocorticoids, NaCl 0.9%, and plicamycin. Each of these agents has been reviewed with consideration of pharmacologic mechanism of action, evaluation of clinical trials, recommended dosages, efficacy, safety, cost, and role in treating cancer-related acute hypercalcemia. CONCLUSIONS: Immediate management of cancer-related acute hypercalcemia to prevent death and provide symptomatic relief is warranted. Severity determined by symptoms, calcium concentrations, and the overall status of the patient are important considerations in selecting appropriate therapy. Although the specific role of individual agents may vary, hydration remains the cornerstone of therapy. NaCl 0.9%, calcitonin, and Pamidronate disodium have established roles as dominant first-line agents for the management of acute hypercalcemia associated with malignancy.

Ezetimibe for Management of Hypercholesterolemia

2003 ◽  
Vol 37 (6) ◽  
pp. 839-848 ◽  
Author(s):  
Vincent F Mauro ◽  
Chad E Tuckerman
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Data Extraction ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Outcome Data ◽  
Lipoprotein Cholesterol ◽  
Intestinal Cell ◽  
Medline Search ◽  
Concurrent Use

OBJECTIVE: To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. DATA SOURCES: A MEDLINE search (1966–December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. DATA SYNTHESIS: Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C–lowering effect of statin medications by an additional 15–20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. CONCLUSIONS: Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.

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?

Treatment Options for Rheumatoid Arthritis: Celecoxib, Leflunomide, Etanercept, and Infliximab

2000 ◽  
Vol 34 (6) ◽  
pp. 743-760 ◽  
Author(s):  
Brigitte T Luong ◽  
Barbara S Chong ◽  
Dionne M Lowder
Keyword(s):  
Rheumatoid Arthritis ◽  
English Language ◽  
Data Extraction ◽  
Treatment Options ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Safety And Efficacy ◽  
Medline Search ◽  
Pertinent Data

OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966–January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

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