Generation of Toxicological Data on Chemicals in the U.S.A.

The paper reviews the current trends of toxicological testing of chemicals in the U.S.A. and the methods of data generation for risk assessment and regulatory purposes. The recent survey conducted by NAS/NRC revealed that only a small fraction of widely used chemicals have been tested toxicologically. In spite of developments in short-term toxicological tests, using non-mammalian test species continue to be indispensable.In evaluating carcinogenicity tests, the current approach is generally based on the assumption that there is not threshold.Under the regulation of the Toxic Substances Act 1977 (U.S.A.) the responsibility of providing toxicological data lies with the manufacturer. The National Toxicology Programme emerged as a new governmental agency for toxicological evaluation since 1978 integrating a number of pre-existing testing activities in U.S.A. A number of private testing laboratories which can provide test data on contract basis also have come into existence in U.S.A. The guidelines published for risk assessment by the Environmental Protection Agency is expected to provide standards for the conduct of toxicological tests used for regulatory purposes. The newly formed Board on Environmental Studies and Toxicology reviews and evaluates the toxicological issues

The allergic scholar

Allergic diseases are on the increase globally. There has been a doubling in the number of scholars suffering from allergy-related disease in the past two decades. This article describes the predisposing factors which contribute to an increased incidence of allergies within the population. These factors include a genetic  predisposition, allergen exposure, abnormalities in the bowel flora and infection exposure. Some of these  relate to the hygiene hypothesis and the microflora hypothesis, which are discussed in this article. Treatment options for those suffering from allergic disease are also discussed, with an emphasis on asthma, anaphylaxis, allergic rhinitis and atopic dermatitis.Keywords: atopy, allergy, scholars, corticosteroids, antihistamine

Pharmacokinetic-pharmacodynamic modelling of the cardiovascular effects of drugs – method development and application to magnesium in sheep

BACKGROUND: There have been few reports of pharmacokinetic models that have been linked to models of the cardiovascular system. Such models could predict the cardiovascular effects of a drug under a variety of circumstances. Limiting factors may be the lack of a suitably simple cardiovascular model, the difficulty in managing extensive cardiovascular data sets, and the lack of physiologically based pharmacokinetic models that can account for blood flow changes that may be caused by a drug. An approach for addressing these limitations is proposed, and illustrated using data on the cardiovascular effects of magnesium given intravenously to sheep. The cardiovascular model was based on compartments for venous and arterial blood. Blood flowed from arterial to venous compartments via a passive flow through a systemic vascular resistance. Blood flowed from venous to arterial via a pump (the heart-lung system), the pumping rate was governed by the venous pressure (Frank-Starling mechanism). Heart rate was controlled via the difference between arterial blood pressure and a set point (Baroreceptor control). Constraints were made to pressure-volume relationships, pressure-stroke volume relationships, and physical limits were imposed to produce plausible cardiac function curves and baseline cardiovascular variables. "Cardiovascular radar plots" were developed for concisely displaying the cardiovascular status. A recirculatory kinetic model of magnesium was developed that could account for the large changes in cardiac output caused by this drug. Arterial concentrations predicted by the kinetic model were linked to the systemic vascular resistance and venous compliance terms of the cardiovascular model. The kinetic-dynamic model based on a training data set (30 mmol over 2 min) was used to predict the results for a separate validation data set (30 mmol over 5 min). RESULTS: The kinetic-dynamic model was able to describe the training data set. A recirculatory kinetic model was a good description of the acute kinetics of magnesium in sheep. The volume of distribution of magnesium in the lungs was 0.89 L, and in the body was 4.02 L. A permeability term (0.59 L min(-1)) described the distribution of magnesium into a deeper (probably intracellular) compartment. The final kinetic-dynamic model was able to predict the validation data set. The mean prediction error for the arterial magnesium concentrations, cardiac output and mean arterial blood pressure for the validation data set were 0.02, 3.0 and 6.1%, respectively. CONCLUSION: The combination of a recirculatory model and a simple two-compartment cardiovascular model was able to describe and predict the kinetics and cardiovascular effects of magnesium in sheep

Normalized Affymetrix expression data are biased by G-quadruplex formation

Probes with runs of four or more guanines (G-stacks) in their sequences can exhibit a level of hybridization that is unrelated to the expression levels of the mRNA that they are intended to measure. This is most likely caused by the formation of G-quadruplexes, where inter-probe guanines form Hoogsteen hydrogen bonds, which probes with G-stacks are capable of forming. We demonstrate that for a specific microarray data set using the Human HG-U133A Affymetrix GeneChip and RMA normalization there is significant bias in the expression levels, the fold change and the correlations between expression levels. These effects grow more pronounced as the number of G-stack probes in a probe set increases. Approximately 14 of the probe sets are directly affected. The analysis was repeated for a number of other normalization pipelines and two, FARMS and PLIER, minimized the bias to some extent. We estimate that ∼15 of the data sets deposited in the GEO database are susceptible to the effect. The inclusion of G-stack probes in the affected data sets can bias key parameters used in the selection and clustering of genes. The elimination of these probes from any analysis in such affected data sets outweighs the increase of noise in the signal. © 2011 The Author(s)

Is penicillin allergy de-labelling about to find its place in UK antimicrobial stewardship strategy?

Penicillin allergy records are common, often incorrect, limit antibiotic treatment options and associated with patient and health system harm. The large numbers of patients with penicillin allergy records and the paucity of allergists have led researchers to explore non-allergist delivered assessment of penicillin allergy records and removal of those inconsistent with allergy (called de-labelling). A recent systematic review and meta-analysis of the literature concludes non-allergist delivery of penicillin allergy de-labelling to be safe and effective. Several countries outside Europe have endorsed non-allergist de-labelling and produced national guidelines and toolkits for de-labelling, but until recently the UK lacked such guidance. In September 2022 the British Society of Allergy and Clinical Immunology (BSACI) produced their guidelines endorsing non-allergist delivered penicillin allergy de-labelling. These BSACI guidelines, coupled with the ongoing NIHR funded penicillin allergy de-labelling studies, will enable this important patient safety and antimicrobial stewardship intervention to become standard of care for NHS patients

Measuring degree-degree association in networks

The Pearson correlation coefficient is commonly used for quantifying the global level of degree-degree association in complex networks. Here, we use a probabilistic representation of the underlying network structure for assessing the applicability of different association measures to heavy-tailed degree distributions. Theoretical arguments together with our numerical study indicate that Pearson's coefficient often depends on the size of networks with equal association structure, impeding a systematic comparison of real-world networks. In contrast, Kendall-Gibbons' $\tau_{b}$ is a considerably more robust measure of the degree-degree association

Reflection on remote teaching and learning of a final-year BPharm clinical training module during a pandemic

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Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria

Background The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Patients and methods Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. Results A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). Conclusions This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/