A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the ...commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.
The use of triple drug combinations has resulted in significant progress in the treatment of HIV infections. However, problems related to development of resistance, drug incompatibilities, and ...patient intolerance emphasize the need for new AIDS therapies. In the present study, two essential steps of the HIV life cycle have been targeted for the development of new therapeutic agents. The alkenyldiarylmethanes (ADAMs), a recently reported class of non-nucleoside inhibitors (NNRTIs), was further developed to improve the antiviral potency with the design and synthesis of a new set of compounds. Two analogs, termed ADAM II-Cl and ADAM II-Br, displayed excellent anti-HIV-1 potency and therapeutic index. Results obtained from different mechanisms of action assays and resistance mutation studies confirmed the mode of action of these compounds. The use of these ADAMS as new leads for the design of more potent analogs and the potential clinical utility of this class of NNRTIs against AZT resistant strains of HIV-1 are suggested based on the results derived from this work. Interference with the entry of HIV to the cell was targeted in the second part of this study with the design and synthesis of two series of cosalane analogs. Cosalane is a novel anti-HIV agent that acts primarily by inhibition of viral attachment and fusion. In the first set of compounds, the linker chain of cosalane was altered by incorporating amido or amino groups. Only certain compounds possessing an amido moiety displayed anti-HIV activity. The incorporation of an amino group gave inactive derivatives. In the second set of congeners, two units of the cosalane pharmacophore were attached to the steroid ring with appropriate linker chains. The position of the pharmacophore groups and the length and composition of the linker were varied. The most potent compound of this series, which showed an approximate four-fold increase in anti-HIV-1 potency over the lead, had the pharmacophore units attached at C-3 and C-17 of the steroid with a linker chain length equal to that present in cosalane. It was thus demonstrated that having additional pharmacophore units is an attractive approach for increasing the anti-HIV potency in the cosalane series.
Abstract
Background and Aims
The population with chronic kidney disease (CKD) presents an increased risk of infection by hepatitis B virus (HBV). Usually, the protective immunological response rate ...(considering HBV titer > 10 mIU/mL) is 90–95% after the 4th dose of vaccine; In CKD the immune response is lower and correlates with the degree of CKD. In dialysis, this response is variable, less than 50% with three-dose regimens and higher with four doses. Cardiovascular risk factors have been implicated in the response rate to vaccination.
The objective of this work is to analyze the efficacy of the HBV vaccine in hemodialysis patients and to identify cardiovascular factors as predictors of response.
Method
Retrospective observational study. We evaluated the response to a 4-dose vaccination protocol (0-1-2-6 months), determining the levels of HBVA 3 months after the last dose. Demographic variables (age, sex), associated comorbidity, etiology of CKD, among others, were collected. Statistical analysis with SPSS 25.0. Categorical variables are expressed as percentages and have been compared using the Chi2 test. The quantitative variables are expressed as mean +/- standard deviation and the T-student was used to compare them. Statistical significance for a value of p <0.05.
Results
89 patients were included; 68.5% are male, with an average age of 65 years. 85.4% had arterial hypertension, and 39.3 were diabetic, the most frequent cause of CKD being renal vascular disease (20.8%), diabetic nephropathy (26.4%) and interstitial (9%). The immune response to HBV vaccination was 79.2%. When making statistical comparisons between the qualitative variables, we have not observed differences between serological response and DM or sex; We did find a trend towards significance when comparing the serological response with the variable HT and etiology of CKD (polycystic kidney disease), pNS. The comparison of means between quantitative variables when performing the Student's T-test did not show differences for any of the study variables.
Conclusion
In our center, HBV vaccination on dialysis achieves a response rate of 79.2%. HT may condition the immune response to vaccination in HD patients, although significance was not reached. Hereditary pathology has been the one that has shown the best serological response with respect to the rest of etiologies, perhaps associated with greater residual renal function.
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