Drug-specific Properties Research Articles

A review of the angiotensin-converting enzyme inhibitor, zofenopril, in the treatment of cardiovascular diseases

Based on preclinical and clinical findings, zofenopril appears to be an angiotensin-converting enzyme (ACE) inhibitor with high potency, significant tissue selectivity and a long duration of action. Its ancillary properties, such as antioxidant activity and cardiovascular (CV) protection, make this drug potentially suitable for the treatment, and possibly prevention, of several CV diseases. There is a large body of evidence that support a complex interaction between ACE inhibitors and CV disease. A review of the preclinical profile of zofenopril clearly suggest that such interaction can be even more complex and could involve some drug-specific properties directly involved in the definition of the overall clinical profile of zofenopril as emerged from randomised clinical trials. In particular, zofenopril combines the feature of an effective ACE inhibitor, with plasma and tissue activity, along with that of an antioxidant compound, and both these characteristics can contribute to its capacity of controlling hypertension and improving the prognosis of patients with coronary artery disease. The results of The Survival of Myocardial Infarction Long term Evaluation (SMILE) trials have demonstrated that the early administration of zofenopril to patients with acute myocardial infarction is associated with a significant reduction in the 6-week occurrence of major CV events (death and congestive heart failure) in high-risk patients with anterior non-thrombolysed myocardial infarction, and this effect is enhanced in some higher-risk subgroups of patients, such as those with a history of diabetes or arterial hypertension.

Analysis of drug pharmacology towards predicting drug behavior by expression profiling using high-density oligonucleotide arrays.

An important aspect of the drug development process is prediction of efficacious and toxic side effects. Profiling of mRNA expression is a powerful approach to analyze the molecular phenotype of cells under various conditions, for example, in response to stimulation by compounds. We attempt to explore the approach of using expression profiling to identify patterns or fingerprints that are correlated with specific drug properties or behaviors. Identification of such expression patterns may also lead to revelation of the potential action mechanism of drugs and fingerprints indicative of certain drug efficacy or side effects. We describe here a strategy that was used to identify a set of genes whose differential expression pattern correlates with activation mode and target specificity of a specific group of drug compounds.

Markedly increased clearance of vancomycin during hemodialysis using polysulfone dialyzers

Clearance of a drug during hemodialysis is affected by drug specific, membrane specific and dialysis specific factors [1, 2]. Drug specific properties determining dialysability include its volume of distribution (Vd), protein binding and molecular weight. Dialyzer membrane specific factors include surface area, permeability and adherence of the drug to the membrane. Finally, blood flow and dialysate flow also influence drug clearance. Vancomycin is commonly used in patients for the treatment of gram + infections. More than 90% of the drug is excreted by the kidneys; however, in the presence of renal failure significant dosage adjustments are required. The half life of vancomycin is quite prolonged in ESRD (200 hours) as compared to those with normal renal function (6 to 8 hours) [3–9]. Typically, vancomycin is not appreciably removed by the cuprophane or cellulose acetate membranes used in conventional hemodialysis. However, with the introduction of the newer, more permeable membranes, such as the polysulfone dialyzers, the pharmacokinetics of vancomycin removal during hemodialysis may be increased since vancomycin has a small Vd (0.47 to 0.84 liter/kg), minimal protein binding [3, 5, 9] and a relatively low molecular weight (1500 daltons) [3]. The purpose of the present study was therefore, to determine whether polysulfone membranes increased the clearance of vancomycin.

In-vitro techniques: can they replace animal testing?

In-vitro tests for the long-term safety evaluation of drugs offer certain advantages. Specific properties of drugs can be identified including mutagenic and carcinogenic effects. The mechanisms leading to toxicity can be assessed. Tissue from several species, including man, can be examined. These tests should reduce the number of animal tests required for screening new drugs.