Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides

BACKGROUND: Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP), a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. METHODS: The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring β-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP), the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. RESULTS: The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate), cellulose sulfate, carrageenan, CAP (in soluble form) and polystyrene sulfonate, respectively, was considerably (range ≈ 4 to ≈ 73-fold) diminished in the presence of SP (33.3%). Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. CONCLUSION: The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP) or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors

Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implications

Owing to their chemical reactivity, radicals have cytocidal properties. Destruction of cells by irradiation-induced radical formation is one of the most frequent interventions in cancer therapy. An alternative to irradiation-induced radical formation is in principle drug-induced formation of radicals, and the formation of toxic metabolites by enzyme catalysed reactions. Although these developments are currently still in their infancy, they nevertheless deserve consideration. There are now numerous examples known of conventional anti-cancer drugs that may at least in part exert cytotoxicity by induction of radical formation. Some drugs, such as arsenic trioxide and 2-methoxy-estradiol, were shown to induce programmed cell death due to radical formation. Enzyme-catalysed radical formation has the advantage that cytotoxic products are produced continuously over an extended period of time in the vicinity of tumour cells. Up to now the enzymatic formation of toxic metabolites has nearly exclusively been investigated using bovine serum amine oxidase (BSAO), and spermine as substrate. The metabolites of this reaction, hydrogen peroxide and aldehydes are cytotoxic. The combination of BSAO and spermine is not only able to prevent tumour cell growth, but prevents also tumour growth, particularly well if the enzyme has been conjugated with a biocompatible gel. Since the tumour cells release substrates of BSAO, the administration of spermine is not required. Combination with cytotoxic drugs, and elevation of temperature improves the cytocidal effect of spermine metabolites. The fact that multidrug resistant cells are more sensitive to spermine metabolites than their wild type counterparts makes this new approach especially attractive, since the development of multidrug resistance is one of the major problems of conventional cancer therapy

Improving clinical outcomes for hospital patients initiated on warfarin

Background: Studies have demonstrated that the risk of warfarin-related complications is highest in the first 90 days of treatment, while quality audits suggest that warfarin initiation protocols are not always adhered to. Aim: To improve the quality of anticoagulation for hospital patients initiated on warfarin. Method: A warfarin drug chart, incorporating the hospital’s warfarin initiation protocol, was implemented on four target medical and cardiothoracic wards. The chart was used to record international normalised ratios (INRs) and prescribe warfarin, and was faxed to the patient’s GP on discharge. Warfarin initiations on the target wards immediately postintroduction of the warfarin drug chart were reviewed and compared to the pre-intervention data collected over a 17- month period. Results: The pre-intervention and post-intervention groups included 271 and 183 patients initiated on warfarin, respectively. The intervention was associated with fewer warfarin-related complications (thromboembolism, major bleeding) occurring within a 90-day follow-up period (2.1% vs 11%; adjusted OR 0.24; 95%CI 0.07–0.85; p = 0.03), largely driven by a reduction in the incidence of major bleeding (0.7% vs 7.1%; adjusted OR 0.17; 95%CI 0.02–1.45; p = 0.05). Adherence to the warfarin initiation protocol improved significantly from 36% to 71% (p 4 and the proportion of patients who required a warfarin dose to be withheld was reduced from 8.5% and 13%, to 3.8% (p < 0.05) and 6.6% (p = 0.02), respectively. Conclusion: Adherence to an age and disease based warfarin initiation protocol, and improving the quality of discharge information for patients initiated on warfarin, significantly improved patient outcomes

Cytotoxicity of polyamines to Amoeba proteus: Role of polyamine oxidase

SCOPUS: ar.jinfo:eu-repo/semantics/publishe