Nonsteroidal anti-inflammatory drugs may elevate blood pressure and antagonize the blood pressure-lowering effect of antihypertensive medication to an extent that may potentially increase hypertension-related morbidity. Although certain NSAIDs and antihypertensive agents could be more likely to produce these effects, the underlying mechanisms require further study.

No abstract

The exposure postoperatively of patients who have undergone spinal surgery to increased amounts of natural sunlight during their hospital recovery period may result in decreased stress, pain, analgesic medication use, and pain medication costs.

1 This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). 2 A mean of 63 + 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There was no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. 3 It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. 4 The data have demonstrated that the pharmacokinetics of ibuprofen and other amethylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.

No abstract

Gold(I) salts and selenite, which have diverse therapeutic and biological effects, are noted for their reactivity with thiols. Since the binding of Jun-Jun and Jun-Fos dimers to the AP-1 DNA binding site is regulated in vitro by a redox process involving conserved cysteine residues, we hypothesized that some of the biological actions of gold and selenium are mediated via these residues. In electrophoretic mobilityshift analyses, AP-1 DNA binding was inhibited by gold(I) thiolates and selenite, with 50% inhibition occurring at approximately 5 ,M and 1 uiM, respectively. Thiomalic acid had no effect in the absence of gold(I), and other metal ions inhibited at higher concentrations, in a rank order correlating with their thiol binding affinities. Cysteine-to-serine mutants demonstrated that these effects of gold(I) and selenite require Cys272 and Cys154 in the DNA-binding domains ofJun and Fos, respectively. Gold(I) thiolates and selenite did not inhibit nonspecific protein binding to the AP-1 site and were at least an order of magnitude less potent as inhibitors of sequencespecific binding to the AP-2, TFIID, or NF1 sites compared with the AP-1 site. In addition, 10 ,IM gold(I) or 10 j,M selenite inhibited expression of an AP-1-dependent reporter gene, but not an AP-2-dependent reporter gene. These data suggest a mechanism regulating transcription factor activity by inorganic ions which may contribute to the known antiarthritic action of gold and cancer chemoprevention by selenium.

Many important drugs exhibit substantial variability in pharmacokinetics and pharmacodynamics leading to a loss of the desired clinical outcomes or significant adverse effects. Forecasting drug exposures using pharmacometric models can improve individual target attainment when compared with conventional therapeutic drug monitoring (TDM). However, selecting the 'correct' model for this model-informed precision dosing (MIPD) is challenging. We derived and evaluated a model selection algorithm (MSA) and a model averaging algorithm (MAA), which automates model selection and finds the best model or combination of models for each patient using vancomycin as a case study, and implemented both algorithms in the MIPD software 'TDMx'. The predictive performance (based on accuracy and precision) of the two algorithms was assessed in (i) a simulation study of six distinct populations and (ii) a clinical dataset of 180 patients undergoing TDM during vancomycin treatment and compared with the performance obtained using a single model. Throughout the six virtual populations the MSA and MAA (imprecision: 9.9-24.2%, inaccuracy: less than ±8.2%) displayed more accurate predictions than the single models (imprecision: 8.9-51.1%; inaccuracy: up to 28.9%).In the clinical dataset the predictive performance of the single models applying at least one plasma concentration varied substantially (imprecision: 28-62%, inaccuracy:-16-25%), while the MSA or MAA utilizing these models simultaneously, resulted in unbiased and precise predictions (imprecision: 29% and 30%, inaccuracy:-5% and 0%, respectively). MSA and MAA approaches implemented in 'TDMx' might thereby lower the burden of fit-for-purpose validation of individual models and streamline MIPD.

Many clinicians are confronted by the use of illicit drugs on a daily basis. The unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and nicotine is a major cause of morbidity and mortality. Multiple factors have inhibited the scientific study of these agents including prohibition, public denial and lack of commercial interests. In dealing with problems related to these drugs, clinicians need a scientific understanding of their pharmacology, quantifiable effects and potential adverse effects. Illicit drug users select drugs with particular pharmacokinetic parameters and pharmacodynamic properties. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution and high free drug clearance are pharmacokinetic characteristics which predict a high potential for harmful use because these factors increase positive reinforcement. Drug users adapt the method and route of drug administration to optimise the delivery of the drug to the brain while attempting to maximise the bioavailability of the drug. Inhalation and smoking are the routes of administration which allow the most rapid delivery of drug to the brain, while intravenous injection maximises the bioavailability of an administered drug. Each route of administration results in attendant complications related to mucosal damage, carcinogenesis and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long half-life, low free drug clearance and sufficient drug exposure to allow development of tolerance. The preventive or reductive pharmacotherapeutics of illicit drug use makes use of several subsets of agents: those which act on the same receptor or system as the illicit drug (such as methadone), those which produce an adverse reaction on consumption of the illicit drug (such as disulfiram) and those which symptomatically attenuate illicit drug withdrawal symptoms (such as clonidine). Many new agents are being trialled as potential preventive or reductive agents. It is important to consider pharmacotherapy as only one potential part of the treatment of illicit drug users. The complications of illicit drug use present many therapeutic challenges. As with all patients consuming multiple drugs, illicit drug users are prone to developing drug interactions. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the additive effects of different drugs on the central nervous system. However, alcohol, cocaine, disulfiram, methadone and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme stimulating drugs in diminishing the efficacy of methadone are the most commonly encountered.