A comprehensive approach for drug safety assessment

A comprehensive, multidisciplinary approach is proposed here for the development of a drug with an acceptable safety profile. Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (1) Pharmacology: Possible toxicity due to drug-target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (2) Chemistry: Chemical scaffolding and side-chains with safety concerns. (3) Toxicology: Toxicity in animals in vivo, and in relevant animal and human cells in culture. (4) Drug metabolism and pharmacokinetics: Safety concerns due to toxification or detoxification, organ distribution, clearance and pharmacokinetic drug-drug interactions. (5) Risk factors: Physiological, environmental and genetic factors that may enhance a patient's susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development.     

An alginate bead technique for determining the safety of microwave cooking

A simple method for determining the microbiological safety of microwave cooking is described. It involves the use of a micro-organism with known heat sensitivity immobilized in alginate beads which can be placed throughout a food prior to microwaving. The reduction in numbers of viable organisms is related not only to the temperature the bead has been exposed to but also to the duration of heating. The method is capable of achieving multi-point measurements of the effects of lethal temperatures during microwave cooking.     

Observational evidence that diversity may increase productivity in Mediterranean shrublands

This paper reports field observational evidence on the diversity-biomass production relationship from eastern Mediterranean shrublands dominated by Cistus salviifolius. The main results are: (1) plant diversity and ecosystem primary production are positively correlated in the Cistus shrublands, which are multigrowth form systems; (2) the taxonomic and growth form diversity in Cistus shrublands suggests that there is strong differentiation along the structural niche axis, and thus functional redundancy is weak; (3) the performance of the dominant Cistus in terms of biomass production did not affect the overall diversity-biomass production of the studied communities. Received: 18 October 1999 / Accepted: 13 April 2000     

Observational evidence of risk-sensitive reproductive allocation in a long-lived mammal

Organisms should adopt a risk-sensitive reproductive allocation when summer reproductive allocation competes with survival in the coming winter. This trade off is shown through autumn female body mass, which acts as an insurance against unpredictable winter environmental conditions. We tested this hypothesis on female reindeer in a population that has experienced a time period of dramatic increase in abundance. Environmental conditions during winter were fairly stable (with the exception of 1 year). We conclude that increased population abundance (perhaps in interaction with winter environmental conditions) could have represented a worsening of winter environmental conditions as both autumn offspring and spring female body mass decreased during the course of the study. Moreover, we found that the cost of reproduction was related to environmental conditions as: (1) autumn body mass was larger for barren than for lactating females, and this difference was temporally highly variable; (2) lactating females produced smaller offspring than barren ones in the following year; and (3) reproductive output (offspring size) decreased over time. We also found evidence of quality effects as lactating females had a higher reproductive success in the following year. In sum, a worsening of winter conditions lead to: (1) decreased reproductive output; (2) lowered autumn body mass for lactating females; and (3) increased body mass for barren females. Since females reduce their reproductive allocation as winter conditions becomes more severe, we conclude that reindeer have adopted a risk-sensitive reproductive allocation.     

Computer support for determining drug dose: systematic review and meta-analysis

ObjectiveTo review the effectiveness of computer support for determining optimum drug dose.DesignSystematic review of comparative studies where computers gave advice to clinicians on the most appropriate drug dose. Search methods used were standard for the Cochrane Collaboration on Effective Professional Practice.SubjectsComparative studies conducted worldwide and published between 1966 and 1996.ResultsEighteen studies met the inclusion criteria. The drugs studied were theophylline, warfarin, heparin, aminoglycosides, nitroprusside, lignocaine, oxytocin, fentanyl, and midazolam. The computer programs used individualised pharmacokinetic models to calculate the most appropriate dose. Meta-analysis of data from 671 patients showed higher blood concentrations of drug with computer support (effect size 0.69, 95% confidence interval 0.36 to 1.02) and reduced time to achieve therapeutic control (0.44, 0.17 to 0.71). The total dose of drug used was unchanged, and there were fewer unwanted effects of treatment. Five of six studies measuring outcomes of care showed benefit from computer assistance.ConclusionsThis review suggests that using computers to determine the correct dose of certain drugs in acute hospital settings is beneficial. Computers may give doctors the confidence to use higher doses when necessary, adjusting the drug dose more accurately to individual patients. Further research is necessary to evaluate the benefits in general use.

Key messages

• This systematic review of studies examining computer support for determining optimum drug dose showed benefits from computer use
• Computer support led to patients having increased blood concentrations of drug, reduced time to achieve therapeutic benefits, and fewer unwanted effects of treatment
• Computer support helps doctors to tailor drug doses more closely to the needs of individual patients
• All the studies took place in hospitals, and further research is needed to determine the risks and benefits of widespread use of computer support, particularly in general practice, where most prescribing takes place

     

DNA microarrays--perspective of application for drug effectivity and safety evaluation

Microarray technology provides a unique tool for the determination of gene expression at the level of messenger RNA (mRNA). Microarray has been successfully applied to the high throughput simultaneous expression of many thousands of genes in a single experiment. One important application of DNA microarray technology, within the context of drugs effectiveness and safety evaluation studies, is its use as a screening tool for the identification of biochemical pathways, potential targets for novel molecular therapeutics, for the identification of molecular mechanisms of toxicity and to understand and predict individual drug sensitivity and resistance. The purpose of this review is presentation of the utility of DNA microarray technology in all phases of the drug discovery process.     

Molecular basis for determining the sensitivity of eucaryotes to the antimitotic drug rhizoxin

Summary Rhizoxin, an antibiotic, exhibits potent anti-mitotic activity against most eucaryotic cells including those of higher vertebrates, plants and fungi by binding to -tubulin. ThebenA gene of three independently isolated rhizoxin-resistant (Rhi^r) mutants ofAspergillus nidulans was cloned, sequenced and compared with that of the wild-type, rhizoxin-sensitive (Rhi^s) strain. In all three Rhi^r mutants, the AAC codon for Asn-100 of thebenA -tubulin gene was altered to ATC, coding for Ile. Sequence displacement experiments confirmed that the substitution of Ile for Asn-100 confers resistance to rhizoxin in this organism. The amino acid sequences of -tubulin surrounding the 100th amino acid residue from the N-terminus including Asn-100 are highly conserved with a few exceptions. The fission yeastSchizosaccharomyces pombe and the budding yeastSaccharomyces cerevisiae are naturally occurring Rhi^r organisms whose -tubulin genes encode Ile and Val respectively at the 100th amino acid residue. The Ile-100 ofS. pombe and the Val-100 ofS. cerevisiae were altered to Asn using site-directed mutagenesis and gene displacement techniques. The resultant haploid strains of these two yeasts uniquely expressing -tubulin (Asn-100) instead of -tubulin (Ile-100 or Val-100) were found to be Rhi^s. Haploid yeast expressing -tubulin (Asn-100) is normal except for its sensitivity to rhizoxin. These results suggest that rhizoxin resistance has a common basis in both naturally occurring species and experimentally selected mutants in the substitution of Ile or Val for Asn-100 in -tubulin.