Suicide attempt following sickness absence and disability pension due to common mental disorders: a prospective Swedish twin study.

PURPOSE: The aim of this study was to investigate if sickness absence and disability pension (SA/DP) in general and due to specific common mental disorders (CMDs) are associated with subsequent suicide attempt among women and men by taking familial factors (genetics and shared environment) into consideration. METHODS: This register-based cohort study includes 4871 twin pairs 18-65 years of age discordant for SA/DP due to CMDs 2005-2010. Twins were followed up for suicide attempt from inpatient and specialised outpatient care until December 2012. Conditional Cox proportional hazards regression models, adjusting for familial factors, were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: SA/DP due to CMDs was associated with a higher risk of suicide attempt (HR 3.14, CI 2.51-3.93). The risk of suicide attempt was five times higher among men and three times higher among women, compared to the SA/DP unaffected co-twins. In the diagnosis-specific analysis, SA/DP due to anxiety disorders resulted in the highest HR (4.09, CI 2.37-7.06) for suicide attempt, followed by depressive disorders (HR 3.70, CI 2.66-5.14) and stress-related disorders (HR 1.96, CI 1.35-2.84). The stratified analysis on zygosity indicates that there seems to be a genetic influence on the associations between SA/DP due to CMDs and suicide attempt, particularly among women and among those with SA/DP due to depressive disorders. CONCLUSIONS: SA/DP due to CMDs was a risk factor for suicide attempt among women and men. Genetic factors might explain part of the associations for women and for those with SA/DP due to depressive disorders.

On Dr Dick Climie and Dr Jack Thomas, and the genesis of chemical-clinical pharmacology in Australian anaesthesia research.

Pharmacokinetic and pharmacodynamic research is regularly reported in most contemporary anaesthesia-oriented journals. This sub-specialty area of pharmacology grew rapidly from the 1960s as various essential concepts and tools-laboratory analysis of drug/metabolite concentrations in biofluids, physiological signal collection, and methods for analysing/presenting relevant pharmacokinetic and pharmacodynamic data-started coming together. For Australia, such research began in Sydney in the mid-1960s with collaboration between anaesthetist Dr C.R. Climie (1923-2013) at the Royal Hospital for Women and medicinal chemist Dr J. Thomas OAM (1928-2017), and was achieved through a succession of postgraduate research student projects in the Department of Pharmacy of The University of Sydney, initially supervised by Dr Thomas. These consisted of studies concerned with the systemic absorption and placental transmission of drugs being used in parturients. By the late 1960s, Sydney anaesthetists Drs G.J. Long and C.A. Shanks (1936-1998) were also participating, and the projects were becoming more complex, including studies of the metabolism of local anaesthetics and other drugs by mothers and neonates. Between the mid-1970s and early-1980s, with additional anaesthetists, postgraduate research students and their academic supervisors participating, the projects focussed mainly on the pharmacokinetics and pharmacodynamics of neuromuscular blocking agents. This form of chemical-clinical-pharmacologically-based anaesthesia-oriented research that started in Sydney with the collaboration of Drs Climie and Thomas led to many challenging higher degree projects for pharmaceutical scientists, and access to unprecedented research capabilities for anaesthetists. Most significantly, it established a permanent place for multidisciplinary pharmacokinetic- and pharmacodynamic-based research within Australian academic departments of anaesthesia.

Dr Snow killed a bird: The genesis of pharmacokinetics and pharmacodynamics in anaesthesia.

This essay presents a pharmacologist's perspective of what would be now called 'preclinical research' and 'uncontrolled clinical trials' surrounding the first public demonstration by William Thomas Green Morton of painless surgery achieved by the inhalation of ether in a patient at the Massachusetts General Hospital on 16 October 1846. Of the many people who made history in those earliest days of surgical anaesthesia in both the United States and Great Britain, John Snow stands out for his personal research that spanned basic science and clinical medicine. Primarily, Snow used the relationship between the vapour pressure of a volatile liquid and temperature to design a vaporiser. This allowed control of the inspired concentration of the volatile liquid epitomised by diethyl ether, and thus the time-course and depth of anaesthesia. In an era when developments in anaesthesia were almost exclusively based on empirical modifications to apparatus and technique, Snow, and to a lesser extent his contemporary Andrew Buchanan, stood out from all others in advancing the quantitative basis of anaesthesia. Both described the physiological basis of control over gas uptake whereby they related that gas moved across concentration gradients in the body: alveolar to arterial to tissue to venous gas tensions, and Snow devised a progressional semi-quantitative scale of five 'stages' of ether anaesthesia. They thereby introduced the elements of what would be referred to 'pharmacokinetics' and 'pharmacodynamics', a century later. This essay attempts to place them and their scientific insights into context with contemporaneous principal personae and knowledge.

Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH) monotherapy and paclitaxel used alone or in combination with a platinum-based compound for the second-line or subsequent treatment of advanced ovarian cancer. DATA SOURCES: Electronic databases covering publication years 2000-4. Company submissions. REVIEW METHODS: Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of PLDH, topotecan and paclitaxel and economic evaluations of the cost-effectiveness of PLDH, topotecan and paclitaxel. Selected studies were quality assessed and data extracted, as were the three company submissions. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results. RESULTS: Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five, three included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes of participants were PLDH versus topotecan, topotecan versus paclitaxel and PLDH versus paclitaxel. In the further two trials that included participants with the subtype of platinum-sensitive disease, the comparators that were assessed were single-agent paclitaxel versus a combination of cyclophosphamide, doxorubicin and cisplatin (CAP) and paclitaxel plus platinum-based chemotherapy versus conventional platinum-based therapy alone. A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were oxaliplatin versus paclitaxel, paclitaxel given weekly versus every 3 weeks, paclitaxel at two different dose levels and oral versus intravenous topotecan. Four studies met the inclusion criteria for the cost-effectiveness review. The review of the economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of PLDH, topotecan and paclitaxel. Analysis 1 assessed the cost-effectiveness of PLDH, topotecan and paclitaxel administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data and alternative assumptions regarding treatment and monitoring costs. In the base-case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, topotecan was dominated by PLDH. Hence the options considered in the estimation of the ICERs were paclitaxel and PLDH. The ICER for PLDH compared with paclitaxel was pound 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive, -refractory and -resistant patients). The ICER was more favourable in the platinum-sensitive group ( pound 5777 per QALY) and less favourable in the platinum-refractory/resistant group ( pound 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of the additional trial data resulted in less favourable estimates for the ICER for PLDH versus paclitaxel compared with the base-case results. The ICER of PLDH compared with paclitaxel was pound 20,620 per QALY in the overall patient population, pound 16,183 per QALY in the platinum-sensitive population and pound 26,867 per QALY in the platinum-resistant and -refractory population. The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model comprised PLDH, topotecan, paclitaxel-monotherapy, CAP, paclitaxel/platinum combination therapy and platinum monotherapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum monotherapy, CAP and paclitaxel-platinum combination therapy. Of these three alternatives, platinum monotherapy was the least costly and least effective. The ICER for CAP compared with platinum monotherapy was pound 16,421 per QALY. The ICER for paclitaxel-platinum combination therapy compared with CAP was pound 20,950 per QALY. CONCLUSIONS: For participants with platinum-resistant disease there was a low probability of response to treatment with PLDH, topotecan or paclitaxel. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three comparators differed significantly in terms of their toxicity profiles, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs. For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that PLDH is more effective than topotecan. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three comparators did, however, differ significantly in terms of their toxicity profiles across the trials. Although treatment with PLDH may therefore be more beneficial than that with topotecan, patient and physician choice as to the potential toxicities associated with each of the comparators and the patient's ability and willingness to tolerate these are of importance. Assuming the NHS is willing to pay up to pound 20,000-40,000 per additional QALY, PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of additional trial data gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. On the strength of the evidence reviewed here, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs. To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.

Stereochemistry in anaesthetic and analgetic drugs.

Isomers are molecules that have the same number of the same kind of atoms arranged in different ways. There are two major categories of isomers: constitutional (or structural) isomers and stereoisomers. Stereoisomers have identical sets of atoms that are configured in the same positions but are arranged differently spatially. Enantiomers are stereoisomers bearing a mirror image relationship. The pharmacological complication caused by drug racemates is that their component enantiomers usually have different pharmacodynamic effects and different pharmacokinetic properties. Enantioselective pharmacology can occur at any site in the body where a drug interacts with an endogenous chiral centre. The purpose of this presentation is to give some examples where drug chirality is pharmacologically significant to potency, uptake, distribution and elimination. The chosen examples were the anesthetic drugs, thiopentone and bupivacaine.

Cannabinoid pharmacotherapy: past, present and future.

Cannabinoids are medically interesting, but the available data are still weak scientifically and overwhelming anecdotally. In the management of pain, cannabinoids have been shown to have antinociceptive properties in animal models of pain, with non-opiate mechanisms appearing to predominate. A widely cited meta-analysis suggested that cannabinoids offer moderate pain relief, similar to codeine, and limited by side effects. Further research, particularly into modes of delivery, to assess their therapeutic potential are needed. Any successful future clinical development of cannabinoid pharmacotherapy depends upon a dosage form that is reliable, rapidly titratable to effect, non-smoked, and preferably parenteral to avoid hepatic first pass metabolism.

Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions.

AIMS: Previous isobolographic analysis revealed that coadministration of morphine and oxycodone produces synergistic antinociception in laboratory rodents. As both opioids can produce ventilatory depression, this study was designed to determine whether their ventilatory effects were synergistic when coadministered to healthy human subjects. METHODS: A placebo-controlled, randomized, crossover study was performed in 12 male volunteers. Ventilatory responses to hypoxaemia and hypercapnia were determined from 1-h intravenous infusions of saline ('placebo'), 15 mg morphine sulphate (M), 15 mg oxycodone hydrochloride (O), and their combination in the dose ratios of 1:2, 1:1, 2:1. Drug and metabolite concentrations in serial peripheral venous blood samples were measured by high-performance liquid chromatography-MS/MS. RESULTS: 'Placebo' treatment was without significant ventilatory effects. There were no systematic differences between active drug treatments on either the slopes or intercepts of the hypoxaemic and hypercapnia ventilation responses. During drug treatment, the mean minute ventilation at PetCO(2) = 55 mmHg (V(E55)) decreased to 74% of the subjects' before treatment values (95% confidence interval 62, 87), 68% (57, 80), 69% (59, 79), 68% (63, 73), and 61% (52, 69) for M15, M10/O5, M7.5/O7.5, M5/O10 and O15, respectively. Recovery was more prolonged with increasing oxycodone doses, corresponding to its greater potency and lower clearance compared with morphine. CONCLUSIONS: Although adverse ventilatory effects of these drugs were found as expected, no unexpected or disproportionate effects of any of the morphine and oxycodone treatments were found that might impede their use in combination for pain management.

Plasma levobupivacaine concentrations following scalp block in patients undergoing awake craniotomy.

BACKGROUND: Levobupivacaine is an effective local anaesthetic agent for nerve blockade with less systemic toxicity than racemic bupivacaine. The safety and efficacy of levobupivacaine for scalp blockade during awake craniotomy have not been addressed previously. METHODS: Serial arterial plasma levobupivacaine concentrations following scalp blockade were measured to 2 h in 10 patients booked for awake craniotomy for epilepsy or tumour surgery. Bilateral scalp blockade providing surgical anaesthesia was achieved with a mean dose of 177 mg (2.5 mg kg(-1), range 1.6-3.2 mg kg(-1)) of levobupivacaine (0.5%, 5 mg ml(-1)) with epinephrine (5 microg ml(-1)) added immediately before the block insertion. RESULTS: The maximum measured plasma levobupivacaine concentration was 1.58 (0.44) microg ml(-1) [mean (SD)] with a mean time to peak plasma concentration of 12 (4) min. There were no episodes in any of the 10 patients of symptoms or signs suggestive of either CNS or CVS toxicity. CONCLUSIONS: This study demonstrated a relatively rapid rise of plasma levobupivacaine concentration without evidence of cardiovascular or central nervous system sequelae in a sample population of patients who may be particularly prone to perioperative seizures.

A systematic review of the clinical effectiveness of orlistat used for the management of obesity.

The aim of this paper is to assess the clinical effectiveness of orlistat used for the management of obesity. Nineteen electronic databases were searched for randomized controlled trials evaluating the effectiveness of orlistat for weight loss or maintenance of weight loss in overweight or obese patients. Each included trial was assessed for methodological quality. Statistical pooling was performed when trials were considered to be sufficiently similar. Twenty-three trials were eligible for inclusion. Placebo-controlled trials recruiting patients with uncomplicated obesity reported statistically significant differences in favour of orlistat for weight loss and changes in obesity-related risk factors at all time points. Trials in obese patients with defined risk factors at baseline showed similar results, however, smaller effect sizes were observed in patients with type 2 diabetes. The effectiveness of orlistat relative to other anti-obesity drugs is currently unclear. When orlistat was added to simvastatin, this proved to be more effective for weight loss than either drug used individually. Orlistat use is associated with a higher incidence of gastrointestinal adverse events compared with placebo. In conclusion, orlistat is more effective than placebo in promoting weight loss, maintenance of weight loss, and improving cardiovascular risk factor profiles. Baseline parameters of patients seen in clinical practice should be taken into account when considering treatment.

Stereochemistry in clinical medicine: a neurological perspective.

Stereoisomers are compounds that have identical sets of atoms configured in the same positions but are arranged differently spatially. Approximately 25% of contemporary drugs are marketed and used as racemates (i.e., as equimolar mixtures of stereoisomers). This may have major clinical implications, as stereoisomers may possess qualitative and/or quantitative differences in pharmacological effects, plasma protein and tissue binding, metabolic and renal clearance. There are many examples of racemic drugs manufactured and used as single stereoisomers in the field of neurology including the anti-Parkinsonian drugs levodopa, selegiline, apomorphine and entacapone, the antiepileptic drugs tiagabine and levetiracetam, the secondary stroke prevention agent clopidogrel and the acetylcholinesterase inhibitor rivastigmine. The role of drug stereochemistry in the re-evaluation of established drugs and the production of new agents is becoming increasingly important as pharmaceutical companies endeavour to show proof of "no penalty" for the introduction of a racemic new drug over one or other of its single stereoisomers.

Concurrent ketamine and alfentanil administration: pharmacokinetic considerations.

BACKGROUND: A ketamine-alfentanil combination has been suggested for total i.v. anaesthesia. We determined the pharmacokinetics of ketamine and alfentanil, alone and together, in three groups of adult male rats, to assess any pharmacokinetic interaction. METHODS: Group 1 animals were infused with i.v. ketamine for 5 min; in group 2, constant low plasma concentrations of alfentanil were maintained by computer-controlled infusion; in group 3, the treatments were combined. Serial plasma and terminal tissue concentrations were measured by high performance liquid chromatography or gas chromatography-mass spectrometry. RESULTS: In the presence of alfentanil, the mean plasma ketamine concentration-time area under the curve (AUC) value was significantly lower (by 13%, P<0.05), while clearance (CIT) and volume of distribution (Vss) were significantly higher (by 16 and 28%, respectively, both P<0.05). Tissue:plasma distribution coefficients for ketamine in the presence of alfentanil were significantly higher in forebrain (by 128%, P<0.005), hindbrain (by 207%, P<0.01), gut (by 254%, P<0.005), and fat (by 344%, P<0.0001). Mean AUC values for alfentanil did not differ significantly in the presence of ketamine, but alfentanil tissue concentrations were significantly lower in forebrain (by 77%, P<0.0001), hindbrain (by 28%, P<0.01), heart (by 33%, P<0.01), lung (30%, P<0.05), and gut (by 21%, P<0.05). Corresponding tissue:plasma distribution coefficients were significantly lower for forebrain (by 69%, P<0.0001) alone. CONCLUSIONS: The finding that the distribution of ketamine into the brain was increased by low plasma concentrations of alfentanil could have important clinical applications for pain management.

Anatomical-physiological approaches in pharmacokinetics and pharmacodynamics.

Use of an anatomical-physiological approach allows an investigator an alternative to regarding the whole body as a 'black box' producing biofluid specimens for drug assay, and then blindly applying a formula-driven mathematical approach to determine the pharmacokinetics and pharmacodynamics of the drug of interest. Instead, it means the investigator can consider that the body is the sum of interacting parts or regions connected anatomically by blood flow carrying the drug of interest, that the regions as well as the carrier blood are not homogeneous because each has a physiological role, and that the parts or regions are connected neurally and humorally so that the response in any region or part of the system may be modified by and/or modulate effects at another region or part. Such an approach is difficult to institute experimentally because a complicated (and often expensive) preparation is usually required in animal studies, and is rarely possible in research with humans because of ethical constraints. Despite these restrictions, there are many examples of the use of an anatomical-physiological approach allowing greater insight into pharmacological problems than would have been possible with a conventional 'whole body' approach alone. This paper takes a number of examples from the discipline of anaesthesia and pain management and groups them to illustrate the principles of the approach regarding drug arterio-venous equality and tissue distribution, multiple sites of clearance and multiple sites of action.

Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion.

Ketamine, used clinically as an intravenous analgetic and dissociative anaesthetic agent, is a racemate with both pharmacokinetic and pharmacodynamic enantioselectivity. S-ketamine has been found have a higher clearance and greater potency than R-ketamine as well as a greater therapeutic index. We performed a study in rats with two complementary paradigms: (i) constant rate "washin" infusion until fatal, (ii) brief infusion then "washout". These, respectively, allowed examination of ketamine and norketamine serial plasma enantiomer concentrations and tissue distribution at maximal and minimal drug effects. Both paradigms found plasma concentrations of R-ketamine>S-ketamine; however, tissue distribution coefficients for S-ketamine>R-ketamine. For paradigm (i), plasma concentrations of R-norketamine>S-norketamine; for paradigm (ii), R-norketamine>>S-norketamine initially, but S-norketamine>>R-norketamine later. Comparison of distribution coefficients of ketamine and norketamine enantiomers for the two paradigms provided indirect evidence for metabolic inversion. During washin, when circulating concentrations of ketamine enantiomers were high, uptake and metabolism occurred predominantly in the kidney and to a lesser extent in liver, lung and gut, with formation of R-norketamine by a (presumed) first-order process predominating. However, following washout, when circulating concentrations of ketamine enantiomers were low, uptake and metabolism was dominated by the kidney and gut. Under these conditions inversion of R- to S-ketamine appeared to predominate with subsequent metabolism to S-norketamine by (presumed) zero-order processes. In summary, different profiles for the uptake and metabolism of ketamine enantiomers were apparent following constant rate washin, and brief infusion washout, paradigms with i.v. rac-ketamine. Uptake into most tissues, and metabolism in some tissues, was enantioselective.

Prolonged thiopentone infusion for neurosurgical emergencies: usefulness of therapeutic drug monitoring.

Serial serum thiopentone concentrations were measured during and following completion of an intravenous infusion of thiopentone in 20 patients with neurosurgical emergencies. The concentration data from a further 55 patients who had had some such measurements were reviewed retrospectively. The patients received an infusion for longer than 24 hours at a rate adjusted to maintain EEG burst suppression. The data were interpreted in terms of thiopentone pharmacokinetics and used to produce statistical models relating to clinical outcomes. In these patients, the one-month mortality rate following commencement of thiopentone treatment was 20%; the mean durations of pupillary and motor unresponsiveness following cessation of an infusion were 22 and 91 hours, respectively. Predictors of a prolonged duration of motor unresponsiveness included a prolonged duration of pupillary unresponsiveness, a low thiopentone clearance and a high maximum serum concentration of thiopentone. From pooled logistic regression, median effective serum thiopentone concentrations (EC50) were found to be 50 mg x l(-1) for recovery of pupillary responsiveness and 12 mg x l(-1) for the recovery of motor responsiveness. Because prolonged high-dose thiopentone leads to prolonged residual serum concentrations, it is difficult to distinguish the residual pharmacological effects of thiopentone from the clinical condition. This study suggests that, based on EC50 values for responses, monitoring of post-infusion serum thiopentone concentrations may help determine whether a patient's clinical state is due to residual thiopentone pharmacological effects.