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Blood May 2014This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
Topics: Adult; Aged; Aged, 80 and over; Alopecia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Fatigue; Female; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nausea; Nitrogen Mustard Compounds; Paresthesia; Peripheral Nervous System Diseases; Prednisone; Rituximab; Treatment Outcome; Vincristine; Vomiting
PubMed: 24591201
DOI: 10.1182/blood-2013-11-531327 -
Medicina (Kaunas, Lithuania) Jun 2020Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms...
BACKGROUND AND OBJECTIVE
Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration.
METHODS
A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans.
RESULTS
The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration.
CONCLUSIONS
Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.
Topics: Administration, Oral; Dronabinol; Drug Compounding; Humans; Nitrogen Mustard Compounds
PubMed: 32585912
DOI: 10.3390/medicina56060309 -
Toxicology Letters Feb 2020Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to... (Review)
Review
Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.
Topics: Alkylating Agents; Animals; Chemical Warfare Agents; Humans; Lung; Lung Injury; Mustard Compounds; Pulmonary Fibrosis; Respiratory Tract Diseases
PubMed: 31698045
DOI: 10.1016/j.toxlet.2019.10.026 -
Cleveland Clinic Journal of Medicine Oct 2013
Topics: Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Dexamethasone; Humans; Lymphoma, Non-Hodgkin; Male; Nail Diseases; Nitrogen Mustard Compounds; Oral Ulcer; Paraneoplastic Syndromes; Pemphigus; Rituximab; Weight Loss
PubMed: 24085808
DOI: 10.3949/ccjm.80a.12160 -
Cancer Chemotherapy and Pharmacology Jun 2015Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin's lymphoma.... (Review)
Review
PURPOSE
Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin's lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug-drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies.
METHODS
A literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion.
RESULTS
Bendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (~40 min) as the effective t 1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m(2) is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure-efficacy response relationship has been observed.
CONCLUSIONS
Altogether, the findings support dosing based on body surface area for most patient populations.
Topics: Area Under Curve; Bendamustine Hydrochloride; Cytochrome P-450 CYP1A2; Drug Interactions; Hematologic Neoplasms; Humans; Nitrogen Mustard Compounds
PubMed: 25829094
DOI: 10.1007/s00280-015-2727-6 -
Oncology Reports Jun 2022Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany... (Review)
Review
Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of chronic lymphocytic leukemia and indolent B‑cell non‑Hodgkin lymphoma. Considering its beneficial properties in the therapy of relapsed or refractory hematological malignancies, synergistic effects with other antineoplastic agents and increasing recent reports on its immunomodulatory effects, bendamustine has once again gained its justified attention. The uniqueness of bendamustine‑mediated effects should be observed keeping in mind its distinctive structure with structural similarities to both alkylating agents and purine analogs. In the present review, the current knowledge on the use of bendamustine in oncology, its pharmacokinetics, mechanism of action and toxicity was summarized. In addition, its immune‑modulating effects that have not been fully elucidated so far are emphasized, hoping to encourage further investigations of this unique drug.
Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Nitrogen Mustard Compounds
PubMed: 35506458
DOI: 10.3892/or.2022.8325 -
Chinese Journal of Cancer Feb 2014Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain... (Review)
Review
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Cell Hypoxia; Humans; Indolequinones; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Nitrogen Mustard Compounds; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Tirapazamine; Triazines
PubMed: 23845143
DOI: 10.5732/cjc.012.10285 -
Annals of Oncology : Official Journal... Oct 2010Follicular lymphoma is an indolent and usually incurable disease. It has been therefore traditionally approached either by watch and wait or with single-agent... (Review)
Review
Follicular lymphoma is an indolent and usually incurable disease. It has been therefore traditionally approached either by watch and wait or with single-agent treatments. The purpose was to maintain a good quality of life for a prolonged time. More aggressive regimens, including polychemotherapy, high-dose chemotherapy with stem-cell rescue and the emergence of new cytotoxic drugs have significantly improved the remission duration but could never demonstrate an impact on overall survival. In the past decade, through the addition of drugs acting on the immune system such as interferon or rituximab, the survival of follicular lymphoma patients could be improved by the range of several years. As a consequence several clinicians believe that we are near to a cure for follicular lymphoma so that the first-line treatment should be more aggressive to reach this goal. Nevertheless, at present, none of the new strategies can be shown to cure. We believe that even in the presence of many possible treatment options, watch and wait remains a good option for many patients with follicular lymphoma. When treatment is needed, chemotherapy with rituximab is the standard even though none of the chemotherapy regimens can be shown to be superior. As quality of life remains an issue, the combination of rituximab and bendamustine, a drug with high efficacy and a favourable toxicity profile, is a good new option for patients.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Humans; Lymphoma, Follicular; Neoadjuvant Therapy; Nitrogen Mustard Compounds; Rituximab; Watchful Waiting
PubMed: 20943608
DOI: 10.1093/annonc/mdq287 -
Expert Opinion on Pharmacotherapy Jul 2012Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than... (Review)
Review
INTRODUCTION
Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.
AREAS COVERED
This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL.
EXPERT OPINION
Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.
Topics: Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrogen Mustard Compounds
PubMed: 22663160
DOI: 10.1517/14656566.2012.693163 -
Medical Oncology (Northwood, London,... May 2014Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line... (Review)
Review
Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line therapy in indolent lymphoma, a growing body of evidence suggests its efficacy and safety in first-line use. The results of randomised and observational studies with bendamustine as front-line therapy in non-Hodgkin lymphoma (NHL) with emphasis on efficacy and toxicity are presented. Furthermore, completed and ongoing clinical trials evaluating upfront bendamustine effectiveness in combination with other agents are discussed. The review refers mainly to indolent lymphoma, mantle cell lymphoma and aggressive lymphoma, as the most commonly diagnosed NHL types. Finally, we elaborated on the safety profile of bendamustine and the perspectives of using the drug as a first-line therapy.
Topics: Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Humans; Lymphoma, Non-Hodgkin; Nitrogen Mustard Compounds; Prognosis
PubMed: 24752517
DOI: 10.1007/s12032-014-0944-1