An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT.

BACKGROUND: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). METHODS: The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. RESULTS: Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). CONCLUSIONS: The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

An examination of the steric effects of 5-tert-butylproline on the conformation of polyproline and the cooperative nature of type II to type I helical interconversion.

The influence of steric effects on the helical geometry and the interconversion of type II to type I polyproline in water was examined by the synthesis and analysis of proline dimers and hexamers containing up to three (2S,5R)-5-tert-butylproline residues. In the dimers, the bulky 5-tert-butyl substituent was found to exert a significant influence on the local prolyl amide geometry such that the predominant trans-isomer in N-(acetyl)prolyl-prolinamide (1) was converted to 63% cis isomer in N-(acetyl)prolyl-5-tert-butylprolinamide (2) as measured by (1)H-nmr spectroscopy. Similarly, the presence of a 5-tert-butyl group on the C-terminal residue in the polyproline hexamer Ac-Pro(5)-t-BuPro-NH(2) (4) produced a local 5-tert-butylprolyl amide population containing 61% cis isomer in water. In spite of the presence of a local prolyl cis amide geometry, the downstream prolyl amides in 4 remained in the trans isomer as determined by NOESY spectroscopy. Conformational analysis by (13)C-nmr and CD spectroscopy indicated that Ac-Pro(6)-NH(2) (3) adopted the all-trans amide polyproline type II helix in water. As the amount of 5-tert-butylproline increased from one to three residues in hexamers 4-6, a gradual destabilization of the polyproline type II helical geometry was observed by CD spectroscopy in water; however, no spectrum was obtained, indicative of a complete conversion to a polyproline type I helix. The implications of these results are discussed with respect to the previously proposed theoretical mechanisms for the helical interconversion of polyproline, which has been suggested to occur by either a cooperative C- to N-terminal isomerization of the prolyl amide bonds or via a conformational intermediate composed of dispersed sequences of prolyl amide cis and trans isomers.

A review of present antimalaria activities in Africa.

In the WHO African Region, malaria still remains a public health problem that constitutes a serious obstacle to development. This is due to the high intensity of transmission and the lack of sufficient resources to apply effective methods of control. However, the recent adoption of the primary health care delivery system offers a new basis for antimalaria strategies, and this has led to renewed hope of (1) reducing mortality and morbidity, (2) minimizing harmful effects on socioeconomic development, (3) achieving ultimate eradication, and (4) protecting the status of areas freed from malaria.Primary health care systems make it possible to ensure the ready availability of antimalarial drugs for treatment and for chemoprophylactic schemes to protect young children and pregnant women. However, with the presence of chloroquine resistance in several countries, a critical review of the use of drugs is required.In the countries of southern Africa where malaria is unstable and liable to be epidemic, control is achieved mainly by the seasonal use of residual insecticides and chemotherapy.So far, eradication has been achieved only in Réunion, but it is also likely to be achieved soon in the islands of Sao Tome and Principe. Considerable reduction of transmission has been achieved in Ethiopia.

Antibodies against poliomyelitis and measles viruses in immunized and unimmunized children, Ghana 1976-78.

The serological response of children to two doses of live oral poliomyelitis vaccine (the first at age 3-8 months and the second at age 9-14 months) and to one dose of measles vaccine (at age 9-14 months) was determined in two regions of Ghana. The seroconversion rates after two doses of poliomyelitis vaccine were lower than expected-24% for poliovirus type 1, 60% for type 2, and 52% for type 3; 23% of the subjects were triple negative. A third dose of the vaccine increased the seroconversion rates to 36%, 73%, and 61% for poliovirus types 1, 2, and 3, respectively; the rate for triple negatives fell to 8%. In the course of the study it was found that there was an intensive circulation of wild polioviruses and that a high proportion of 3-8 month-old infants had maternal antibodies.The seroconversion rate following one dose of measles vaccine was about 90%, a response similar to that obtained in temperate climates. The two main conclusions drawn from the study were: (1) two doses of poliomyelitis vaccine are inadequate to provide protection against poliomyelitis in developing countries; and (2) in developing countries measles vaccine should be given as soon as possible after the age of 8 months.