Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Contribution of drug related problems to hospital admission in the elderly.

PURPOSE: To investigate the frequency and type of drug related problems (DRPs) in geriatric patients (> 65 years), and to assess their contribution to hospital admission; to explore the appropriateness of drug therapy according to the Beers' criteria. METHODS: Cross-sectional observational survey of 110 elderly patients admitted during three non-consecutive months to the geriatric ward of a university hospital. Explorative assessment of appropriateness of drug therapy prior to hospital admission based on the Beers' criteria. RESULTS: A DRP was the dominant reason for hospital admission in 14 out of the 110 patients (12.7%); for another 9 patients (8.2%), a DRP was partly contributing to hospital admission. For these 23 patients, adverse drug reactions and noncompliance were the most important types of DRPs. We found no relationship between drug related hospital admission and intake of a drug listed in the Beers criteria for inappropriate drug use in the elderly. Patients admitted for a DRP took more drugs before admission than patients admitted because of other reasons. CONCLUSIONS: DRPs are an important cause for admission on the geriatric ward of our hospital. The drugs causing DRPs in this study were not those listed in the Beers list of inappropriate drugs in the elderly.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched November 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2007), MEDLINE (1966 to November 2007), International Pharmaceutical Abstracts (IPA) (from inception to November 2007), Science Citation Index (from inception to November 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is pain caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent used to treat peripheral vascular disease. However, its clinical efficacy for IC has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for IC. SEARCH STRATEGY: We searched the specialized trials register of the Cochrane Peripheral Vascular Diseases Review Group (last searched August 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3, 2007), MEDLINE (1966 to August 2007), International Pharmaceutical Abstracts (IPA) (from inception to August 2007), Science Citation Index (from inception to August 2007). We contacted Abbott Laboratories (buflomedil distributor) for controlled clinical trial data and approached authors for additional trial information. SELECTION CRITERIA: Double-blinded, randomized controlled trials (RCTs) in patients with IC (Fontaine stage II) receiving oral buflomedil compared to placebo. Pain-free walking distance (PFWD) and maximum walking distance (MWD) were analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We included two RCTS with 127 participants. Both RCTs showed moderate improvements in PFWD for patients on buflomedil. This improvement was statistically significant for both trials (WMD 75.1 m, 95% confidence interval (CI) 20.6 to 129.6; WMD 80.6 m, 95% CI 3.0 to 158.2), the latter being a wholly diabetic population. For both RCTs, MWD gains were statistically significant with wide confidence intervals (WMD 80.7 m, 95% CI 9.4 to 152; WMD 171.4 m, 95% CI 51.3 to 291.5), respectively. AUTHORS' CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for IC. Most trials were excluded due to poor quality. The two included trials showed moderately positive results; these are undermined by publication bias since we know of at least another four unpublished, irretrievable, and inconclusive studies.Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range.

Mouse strain differences in autonomic responses to stress.

In humans, anxiety disorders are often accompanied by an overactive autonomic nervous system, reflected in increased body temperature (BT) and heart rate (HR). In rodents, comparable effects are found after exposure to stress. These autonomic parameters can give important information on stress and anxiety responses in mice. In the present experiments, stress reactivity of three frequently used mouse strains [129 Sv/Ev, Swiss Webster (SW) and C57 BL/6] was assessed using their autonomic stress responses. BT, HR and activity were telemetrically measured. Undisturbed circadian rhythms already showed clear differences between the mouse strains. Hereafter, autonomic responses to stressors with increasing intensity were measured. Strain differences were found in magnitude and duration of the stress responses, especially after high-intensity stressors. Generally, C57BL/6 mice showed the largest autonomic response, SW the lowest and the 129Sv/Ev the intermediate response. Interestingly, the observed ranking in autonomic stress response does not match the behavioral stress responsivity of these strains. Finally, sensitivity to the anxiolytic diazepam (0, 1, 2, 4 and 8 mg/kg) was tested using the stress-induced hyperthermia paradigm. Pharmacological sensitivity to diazepam differed between the strains with the 129Sv/Ev being most sensitive. These studies show that simultaneous measurement of behavioral and autonomic parameters under stressful conditions contributes considerably to a better interpretation of anxiety and stress levels in mice.

[Information about drugs from physicians and pharmacists]. / Informatie over geneesmiddelen aan artsen en apothekers.

Good quality information is essential for those who prescribe, deliver or use medications. This information should meet quality criteria: it should be evidence based, practice oriented, easy to find and topical. Pharmacists and physicians receive information from different sources and of valable quality. Initiatives should be taken to improve the quality. The authorities should stimulate these initiatives, and make sure that the information is evidence based. Medical schools and pharmacy schools should educate the students in these matters, and play a role in the continuing medical education thereabout. Opinion leaders should be aware of their responsibility. Existing initiatives should be expanded, and should be coordinated. Finally, there is the ethical obligation for health professionals to remain informed. One wonders in how far incentives (or even coercive measures) are necessary. There is a task there for the "Orders" of physicians and pharmacists, and the scientific and professional bodies.

5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms.

Generation of receptor knockout mice has offered a new approach to study processes underlying anxiety. In this paper, studies focusing on anxiety using 5-HT1A receptor knockout (1AKO) and 5-HT1B receptor knockout (1BKO) mice are reviewed. 1AKO mice on different genetic background strains have initially been described as more anxious. In 1AKO mice on the 129/Sv background strain, the initial findings could not always be replicated, although under certain conditions, mild anxiety-like responses were observed in these 1AKO mice. In 1BKO mice, some indications of reduced anxiety have been found, but these observations may be confounded partly with increased motor impulsivity of these mutants. To study whether the putative effects of the null mutations on anxiety were reflected in the autonomic nervous system, basal heart rate and body temperature of 1AKO and 1BKO mice were measured, as well as their autonomic responses to novel cage exposure and to reversal of the light-dark rhythm. 1AKO mice did not differ from wild-type mice in any parameter, neither under non-stress conditions, nor following novel cage exposure. In 1BKO mice, basal heart rate was reduced and body temperature was increased. 1BKO mice showed exaggerated autonomic responses to novel cage stress. Adaptation to the reversal of the light-dark cycle was comparable in the three genotypes. The stress-induced hyperthermia procedure showed no differential responses of the three genotypes to the stressor. Pharmacological responses to various psychotropic drugs in the stress-induced hyperthermia test were also comparable in 1AKO, 1BKO and wild-type mice. The present data illustrate the complexity of studying the behavioural and physiological consequences of deletion of genes coding for important receptors in the CNS.

Evaluation of human albumin use in a university hospital in Belgium.

UNLABELLED: In 1996-1997, a drug use evaluation (DUE) of human albumin was conducted in the Ghent University Hospital (Belgium) to determine the pattern and appropriateness of the albumin use. The DUE was followed by permanent review of the albumin consumption. This paper describes how the DUE was carried out and how the albumin use in our hospital changed over time. METHOD: The study was based on criteria for indications and end of treatment, accepted by consensus of the physicians prescribing albumin. Albumin treatment episodes were classified as appropriate or inappropriate according to these criteria. RESULTS: For 115 treatment episodes in 90 patients, the researchers found 21 (18.3%) deviations from the developed criteria. After analysis, half out of them were considered as minor. Most deviations involved starting treatment too early (n = 17). Follow-up results indicated that the overall consumption of albumin dropped by 50.1% from 1994 to 1999, while the consumption of colloid solutions during the same period remained stable. CONCLUSION: A good compliance with internally developed criteria for indications and end of treatment with human albumin was observed. Discussion with the clinicians involved led to the development of stricter criteria and a continuous decrease in albumin consumption.

Buflomedil for intermittent claudication.

BACKGROUND: Intermittent claudication is pain, caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent claimed to have beneficial effects on the microcirculation. It is used chiefly to treat peripheral vascular disease and to a lesser extent for cerebrovascular arterial disease. However, its clinical efficacy for intermittent claudication has not yet been critically examined. OBJECTIVES: To evaluate the available evidence on the efficacy of buflomedil for intermittent claudication. SEARCH STRATEGY: We searched Medline, International Pharmaceutical Abstracts (IPA) and the Cochrane Controlled Trials Register. Abbott Laboratories, the distributor of buflomedil, was asked to provide reports of controlled clinical trials. Reference lists of retrieved articles were checked, and enquiries sent to authors of known trials, to identify additional trials. Finally, we conducted a Science Citation Index search. SELECTION CRITERIA: Trial reports had to be double-blinded, randomized, and conformed to our PIO-criteria (Patients, Intervention, Outcome) to be considered for inclusion. Patients were required to have proven intermittent claudication (Fontaine stage II); the intervention was to be oral administration of buflomedil compared to placebo; and outcomes had to include pain-free walking distance (PFWD) and maximum walking distance (MWD) analysed by standardized exercise test. DATA COLLECTION AND ANALYSIS: Searches of bibliographic databases yielded three eligible randomized controlled trials (RCTs) and a meta-analysis referring to nine eligible trials. Two of these nine trials had already been identified; two had been published in journals not referenced in traditional bibliographic indexes; and five were unpublished. Despite multiple requests, only one of the five unpublished trials was provided by the author of the meta-analysis, the other four could not be retrieved. Four of the six eligible trials retrieved were subsequently excluded after quality evaluation. Data on walking distances were extracted from the two remaining trials. Differences in incremental gain between active and placebo groups for PFWD and MWD with their confidence intervals were calculated. MAIN RESULTS: Both RCTs showed moderate improvements in PFWD for patients on buflomedil. In one trial this improvement (75 m, 95% CI 37-114) was statistically significant, but in the other, with a wholly diabetic population, it was non-significant (81m, 95% CI -9-170) compared to placebo. For both RCTs the gains in MWD were statistically significant, but with wide confidence intervals (81 m, 95% CI 30-131; and 171 m, 95% CI 27-316 respectively). Pooling of the data was not attempted. REVIEWER'S CONCLUSIONS: There is little evidence available to evaluate the efficacy of buflomedil for intermittent claudication. Most available trials are of poor quality and were excluded. The two trials included showed moderately positive results but these are undermined by publication bias since we know of another four unpublished, irretrievable, and inconclusive studies. There is a lack evidence for the efficacy of buflomedil in intermittent claudication.

Oral vasoactive medication in intermittent claudication: utile or futile?

OBJECTIVE: To evaluate the role of orally administered vasoactive medication in the management of intermittent claudication. SETTING: We limited our study to the products on the market in Belgium: cinnarizine, cyclandelate, isoxsuprine, naftidrofuryl, pentoxifylline, xanthinol nicotinate and buflomedil. DATA SOURCES: We conducted a systematic literature search involving Medline, International Pharmaceutical Abstracts, the Cochrane Library, direct contact with marketing companies and key authors, snowballing and Science Citation Index search. We looked for randomised placebo-controlled trials (RCTs) in patients with Fontaine stage II, in which pain-free and/or maximal walking distance were measured using a standardised exercise test. For isoxsuprine and xanthinol nicotinate, no trials conforming to these criteria were found. Thirty-six trials on cinnarizine, cyclandelate, buflomedil, naftidrofuryl and pentoxifylline met our inclusion criteria. STUDY SELECTION: After quality assessment, 26 trials were excluded, mainly because of short trial duration (less than 12 weeks), small sample size (less than 30 patients) and/or failure to report details on variability (standard deviation or confidence limits). For cinnarizine and cyclandelate, none of the three selected RCTs was included. DATA EXTRACTION: For buflomedil, of six published RCTs, two were included after quality assessment, each showing a marginally positive effect of buflomedil versus placebo. For naftidrofuryl, nine RCTs were selected; six were included of which five showed a significant positive result. The likelihood of publication bias and the heterogeneity of the results within and between trials precluded a meta-analysis. For pentoxifylline, of the 18 selected RCTs, only two could be included, both with inconclusive results. CONCLUSION: A national consensus conference, based on this review, concluded that health resources should be allocated to prevention and rehabilitation of intermittent claudication rather than to reimbursement of these products with doubtful efficacy.

Use of laxatives in institutions for the mentally retarded.

OBJECTIVE: To study, in institutionalized mentally retarded patients, the prevalence of regular laxative use, and to identify its correlates. METHODS: Twenty-one of the 22 institutions for the mentally retarded in Flanders (Belgium) provided the setting for the study, which included a population of 3712 residents with an IQ of < 50. This was a descriptive cross-sectional study of a random sample of 20 patients per institution, consisting of a structured interview of the personnel responsible for daily care of the selected patients. The study population consisted of 420 mentally retarded patients. Their median age was 29 years (range 2-72 years). Twenty-six percent of patients had an IQ of 35-49, 40% an IQ of 20-34 and 34% an IQ of <20. Sixteen percent of the patients were non-ambulant. RESULTS: Regular laxative use was found in 26.4% (111/420) of the residents. In addition, occasional laxative use was found in 2% (10/420) of the residents. Oral laxatives were used daily by 13% (56/420) and oral laxatives daily in combination with enemas were used by 9% (39/420). Enemas but no oral laxatives were used by 3% (11/420); manual evacuation in combination with oral laxatives and enemas was used by 1% (5/420). Seventy-eight percent (78/100) of the oral laxative users used them for more than 1 year. Seventy-one percent (71/100) used one laxative, 23% two and 6% three. Thirty different brands of oral laxatives were used. Sixty-seven percent (67/100) used osmotic laxatives alone or in combination, 30% used stimulant laxatives, 19% used bulk forming laxatives and 19% mineral oil. Oral laxatives were always prescribed by attending physicians, while enemas were also initiated by nurses in 35% (18/52). Laxative use was positively and independently correlated with female gender, with being non-ambulant, with oral motor dysfunction and with the use of medication other than laxatives. It did not correlate with age. Within the institutions, laxative use varied from one to 15 users out of the 20 randomly selected patients (median 4/20). CONCLUSION: Laxative use is frequent in institutions for the mentally retarded, with a large inter-institution variation, indicating that constipation is an important problem and underlining the need for research into cost-effective treatment.

Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients.

OBJECTIVE: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability of the disposition of morphine administered by subcutaneous infusion in cancer patients. METHODS: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60-3000 mg per day) via chronic (8-160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible, on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and its degradation products in the solutions. RESULTS: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng.ml(-1).mg(-1) to 0.8 ng.ml(-1).mg(-1) for morphine, from 1.0 ng.ml(-1).mg(-1) to 3.1 ng.ml(-1).mg(-1) for morphine-6-glucuronide and from 6.8 ng.ml(-1).mg(-1) to 24.3 ng.ml(-1).mg(-1) for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. CONCLUSION: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition which could be of clinical relevance.

[Drug policy 1996]. / Geneesmiddelenbeleid 1996.

The task of the authorities with regard to medications starts with formulating the appropriate rules concerning clinical studies, mainly for drugs that are not yet registered, and also includes registration and reimbursement. There is, however, an important task for the authorities with regard to post-marketing activities, e.g. pharmacovigilance and drug use studies, in order to define better the value of a product, with implications for the future fate and reimbursement of a product. The authorities have also an important role in providing information to those who prescribe, deliver or use medications. Also in order to improve prescribing, the prescriber should be aware of his/her prescribing pattern. Ever more emphasis is put upon the "rational use of drugs" (use only drugs for which validated studies exist, use them in an appropriate manner and with consideration for the financial aspects) and upon "Evidence-Based Medicine" and "Evidence-Based Pharmacotherapy". For rational prescribing and use of medications based on evidence, a long term policy is needed and Belgium has in this regard still much to do.

Development and validation of alternative metabolic systems for mutagenicity testing in short-term assays.

We present here the results obtained within the framework of an EU funded project aimed to develop and validate alternative metabolic activating systems to be used in short-term mutagenicity assays, in order to reduce the use of laboratory animals for toxicology testing. The activating systems studied were established cell lines (Hep G2, CHEL), genetically engineered V79 cell lines expressing specific rat cytochromes P450, erythrocyte-derived systems, CYP-mimetic chemical systems and plant homogenates. The metabolically competent cell lines were used as indicator cells for genotoxic effects as well as for the preparation of external activating systems using other indicator cells. The following endpoints were used: micronuclei, chromosomal aberrations and sister chromatid exchanges, mutations at the hprt locus, gene mutations in bacteria (Ames test), unscheduled DNA synthesis and DNA breaks detected in the comet assay. All metabolic systems employed activated some promutagens. With some of them, promutagens belonging to many different classes of chemicals were activated to genotoxicants, including carcinogens negative in liver S9-mediated assays. In other cases, the use of the new activating systems allowed the detection of mutagens at much lower substrate concentrations than in liver S9-mediated assays. Therefore, the alternative metabolizing systems, which do not require the use of laboratory animals, have a substantial potential in in vitro toxicology, in the basic genotoxicity testing as well as in the elucidation of activation mechanisms. However, since the data basis is much smaller for the new systems than for the activating systems produced from subcellular liver preparations, the overlapping use of both systems is recommended for the present and near future. For example, liver S9 preparations may be used with some indicator systems (e.g., bacterial mutagenicity), and metabolically competent mammalian cell lines may be used with other indicator systems (e.g., a cytogenetic endpoint) in a battery of basic tests.

Attitude of physicians toward patient package inserts for medication information in Belgium.

In Belgium, the distribution of medications to outpatients in community pharmacies is almost exclusively by branded unit-of-use packages, with a package insert inside every package. At the time of the study (spring 1990), the implementation of legislation that mandated a shift from highly technical documents to patient package inserts (PPIs), understandable by the lay person, had begun. This study explores the attitude of practising physicians toward written medication information for patients. A mail questionnaire was sent to 1500 (8% random sample) Belgian general practitioners and to 500 (22% random sample) internal medicine specialists. A total of 543 usable questionnaires were returned (27.5% return rate). Ninety-two percent of the physicians stated that their patients seldom or never requested additional information on drug efficacy or side effects, during routine consultation; 30% estimated that more than half of their patients read the PPI; 75% expect that a patient would experience side effects after reading about them in the PPI; 59% agreed that the PPI could help the patient react more adequately in unforeseen situations. It was possible to cluster the respondents in a stable segmentation of three clusters: moderately positive physicians (20%), ambiguous to neutral physicians (44%), physicians overtly negative to written drug information (36%). The low response rate to this extensive postal questionnaire limits the conclusions to a qualitative description of relevant clusters of respondents. In contrast with the opinion of physicians about patient readership, results from other studies indicate that the vast majority of patients read the package inserts.