Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.

BACKGROUND: Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability. METHODS: Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®). RESULTS: A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs' pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients. CONCLUSION: The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.

Les combinaisons fixes de medicaments antihypertenseurs. [Fixed antihypertensive drug combinations]

Arterial hypertension is a highly heterogeneous condition. It is therefore not surprising that blood pressure lowering agents acting via a given mechanism allow a normalization of blood pressure in a fraction of hypertensive subjects only. The combination of drugs with different mechanisms of action on the cardiovascular system results in a considerably higher antihypertensive efficacy, not only with regard to the absolute blood pressure reduction but also in the number of responders. This effect is not achieved at the expenses of tolerance, because usually lower doses of the combined agents are sufficient to achieve the target blood pressure. The administration of antihypertensive agents in fixed combination has the advantage of its simplicity for both the physician as well as the patient. This aspect also explains the increasing popularity of fixed combinations as a valuable option in the initial treatment of the hypertensive patient.

Adolescent substance-use assessment: methodological issues in the use of the ADAD (Adolescent Drug Abuse Diagnosis).

During the past twenty years, various instruments have been developed for the assessment of substance use in adolescents, mainly in the United States. However, few of them have been adapted to, and validated in, French-speaking populations. Consequently, although increasing alcohol and drug use among teenagers has become a major concern, the various health and social programs developed in response to this specific problem have received little attention with regard to follow-up and outcome assessment. A standardized multidimensional assessment instrument adapted for adolescents is needed to assess the individual needs of adolescents and assign them to the most appropriate treatment setting, to provide a single measurement within and across health and social systems, and to conduct treatment outcome evaluations. Moreover, having an available instrument makes it possible to develop longitudinal and trans-cultural research studies. For this reason, a French version of the Adolescent Drug Abuse Diagnosis (ADAD) was developed and validated at the University Child and Adolescent Psychiatric Clinic in Lausanne, Switzerland. This paper aims to discuss the methodological issues that we faced when using the ADAD instrument in a 4-year longitudinal study including adolescent substance users. Methodological aspects relating to the content and format of the instrument, the assessment administration and the statistical analyses are discussed.

Being old-for-grade and drug use: not such a clear connection.

AIM: To assess whether repeating a grade was associated with drug use among adolescents after controlling for personal, family and school-related variables, and whether there were differences between students in mandatory and post-mandatory school. METHODS: Data were drawn from the Catalonia Adolescent Health Survey, a cross-sectional study of in-school adolescents aged 14-19 y. The index group included 366 subjects who were repeating a grade at the time the survey was carried out (old-for-grade, OFG). A control group matched by gender, school and being one grade ahead was randomly chosen among all the subjects who had never repeated a grade. All statistically significant variables in the bivariate analysis were included in a multivariate analysis. In a second step, all analyses were repeated for students in mandatory (14-16 y) and post-mandatory (17-19 y) school. RESULTS: After controlling for background variables, subjects in the index group were more likely to perceive that most of their peers were using synthetic drugs and to have ever used them, to have bad grades and a worse relationship with their teachers. OFG students in mandatory school were more likely to have divorced parents, bad grades and have ever used synthetic drugs, whereas they were less likely to be regular drinkers. OFG students in post-mandatory school were more likely to have below average grades, to be regular smokers and to perceive that most of their peers used synthetic drugs. CONCLUSIONS: When background variables are taken into consideration, the relationship between repeating a grade and drug use is not so clear. By increasing the familial and academic support of adolescents with academic underachievement, we could reduce their drug consumption.

Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.

The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.

Prevalence of HIV type 1 drug resistance mutations in treatment-naïve and experienced patients from resource-limited settings with universal access to antiretroviral therapy: a survey in two small Brazilian cities

Concerns have been raised that universal availability of antiretroviral agents in resource-limited settings might lead to the emergence and spread of resistant strains. We present the largest survey on human immunodeficiency virus type 1 (HIV-1) resistance among treatment-naïve and experienced patients followed in small, relatively underprivileged cities in Brazil with universal availability to standard of care antiretroviral combinations. Samples were collected between 2004 and 2006 from 95 patients followed in the cities of Saquarema and Santo Antonio de Pádua, state of Rio de Janeiro. A proviral fragment encompassing protease and reverse transcriptase (RT) regions was generated and drug susceptibility level was inferred. Among 50 strains from drug-naïve subjects, one (2%) had intermediate-level resistance to RT inhibitors. Among 38 patients on therapy as of sampling, 28 (73.7%) had plasma viral load (PVL) below detection limit (26 of whom without evidence of resistance mutations) and 11 (28.9%) harbored strains with reduced susceptibility. Only two strains harbored both protease and RT inhibitor mutations. Among seven patients who were off-treatment as of sampling, two (28.5%) harbored strains with reduced susceptibility to RT inhibitors. The relatively high frequency of undetectable PVL among patients on treatment and the overall low prevalence of resistance-associated mutations are reassuring. Continued surveillance, however, is necessary.

Sublingual sugar for hypoglycaemia in children with severe malaria: a pilot clinical study.

BACKGROUND: Hypoglycaemia is a poor prognostic indicator in severe malaria. Intravenous infusions are rarely feasible in rural areas. The efficacy of sublingual sugar (SLS) was assessed in a pilot randomized controlled trial among hypoglycaemic children with severe malaria in Mali. METHODS: Of 151 patients with presumed severe malaria, 23 children with blood glucose concentrations < 60 mg/dl (< 3.3 mmol/l) were assigned randomly to receive either intravenous 10% glucose (IVG; n = 9) or sublingual sugar (SLS; n = 14). In SLS, a teaspoon of sugar, moistened with a few drops of water, was gently placed under the tongue every 20 minutes. The child was put in the recovery position. Blood glucose concentration (BGC) was measured every 5-10 minutes for the first hour. All children were treated for malaria with intramuscular artemether. The primary outcome measure was treatment response, defined as reaching a BGC of >or= 3.3 mmol/l (60 mg/dl) within 40 minutes after admission. Secondary outcome measures were early treatment response at 20 minutes, relapse (early and late), maximal BGC gain (CGmax), and treatment delay. RESULTS: There was no significant difference between the groups in the primary outcome measure. Treatment response occurred in 71% and 67% for SLS and IVG, respectively. Among the responders, relapses occurred in 30% on SLS at 40 minutes and in 17% on IVG at 20 minutes. There was one fatality in each group. Treatment failures in the SLS group were related to children with clenched teeth or swallowing the sugar, whereas in the IVG group, they were due to unavoidable delays in beginning an infusion (median time 17.5 min (range 3-40).Among SLS, the BGC increase was rapid among the nine patients who really kept the sugar sublingually. All but one increased their BGC by 10 minutes with a mean gain of 44 mg/dl (95%CI: 20.5-63.4). CONCLUSION: Sublingual sugar appears to be a child-friendly, well-tolerated and effective promising method of raising blood glucose in severely ill children. More frequent repeated doses are needed to prevent relapse. Children should be monitored for early swallowing which leads to delayed absorption, and in this case another dose of sugar should be given. Sublingual sugar could be proposed as an immediate "first aid" measure while awaiting intravenous glucose. In many cases it may avert the need for intravenous glucose.

Changes in the transcriptional profile of transporters in the intestine along the anterior-posterior and crypt-villus axes.

BACKGROUND: The purpose of this work was to characterize the expression of drug and nutrient carriers along the anterior-posterior and crypt-villus axes of the intestinal epithelium and to study the validity of utilizing whole gut tissue rather than purified epithelial cells to examine regional variations in gene expression. RESULTS: We have characterized the mRNA expression profiles of 76 % of all currently known transporters along the anterior-posterior axis of the gut. This is the first study to describe the expression profiles of the majority of all known transporters in the intestine. The expression profiles of transporters, as defined according to the Gene Ontology consortium, were measured in whole tissue of the murine duodenum, jejunum, ileum and colon using high-density microarrays. For nine transporters (Abca1, Abcc1, Abcc3, Abcg8, Slc10a2, Slc28a2, Slc2a1, Slc34a2 and Slc5a8), the mRNA profiles were further measured by RT-PCR in laser micro-dissected crypt and villus epithelial cells corresponding to the aforementioned intestinal regions. With respect to differentially regulated transporters, the colon had a distinct expression profile from small intestinal segments. The majority (59 % for p cutoff < or = 0.05) of transporter mRNA levels were constant across the intestinal sections studied. For the transporter subclass "carrier activity", which contains the majority of known carriers for biologically active compounds, a significant change (p < or = 0.05) along the anterior-posterior axis was observed. CONCLUSION: All nine transporters examined in laser-dissected material demonstrated good replication of the region-specific profiles revealed by microarray. Furthermore, we suggest that the distribution characteristics of Slc5a8 along the intestinal tract render it a suitable candidate carrier for monocarboxylate drugs in the posterior portion of the intestine. Our findings also predict that there is a significant difference in the absorption of carrier-mediated compounds in the different intestinal segments. The most pronounced differences can be expected between the adjoining segments ileum and colon, but the differences between the other adjoining segments are not negligible. Finally, for the examined genes, profiles measured in whole intestinal tissue extracts are representative of epithelial cell-only gene expression.

Species differences in the response of liver drug-metabolizing enzymes to (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949) in vivo and in vitro.

Induction of drug-metabolizing enzymes (DMEs) is highly species-specific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species specificity of the antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPARalpha target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPARalpha agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPARalpha agonists in monkeys and humans.

Prevalence of antiretroviral drug resistance among treatment-naive and treated HIV-infected patients in Venezuela

An in-house, low-cost method was developed to determine the genotypic resistance of immunodeficiency virus type 1 (HIV-1) isolates. All 179 Venezuelan isolates analysed belonged to subtype B. Primary drug resistance mutations were found in 11% of 63 treatment-naïve patients. The prevalence of resistance in isolates from 116 HIV-positive patients under antiretroviral treatment was 47% to protease inhibitors, 65% to nucleoside inhibitors and 38% to non-nucleoside inhibitors, respectively. Around 50% of patients in the study harboured viruses with highly reduced susceptibility to the three classical types of drugs after only five years from their initial diagnoses.

The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53-Independent Manner in Colon and Breast Cancer Cells

The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR)as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNalpha treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner,inducing phosphorylation of the protein synthesis translation initiation factor eIF-2alpha and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNalpha combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug.

Prevalence of hepatitis C virus infection and associated factors among male illicit drug users in Cuiabá, Mato Grosso, Brazil

Intravenous drug injection has been reported as the main risk factor for hepatitis C virus (HCV) infection. The aim of the present study was to describe the prevalence and the epidemiological profile of HCV infection among abusers of illegal injected and non-injected drugs in Cuiabá, state of Mato Grosso, Central Brazil. A cross-sectional study including 314 male drug users from eight detoxification centres was performed. Out of 314 subjects studied, 48 (15.2%) were intravenous drug users. Participants were interviewed and had blood samples taken and tested for the presence of anti-HCV antibodies. Positive samples were tested for the presence of HCV RNA. Genotyping was performed on HCV RNA-positive samples. The overall prevalence of anti-HCV antibodies was 6.4% (n = 20). Out of 20 anti-HCV antibody-positive subjects, 16 (80%) were also HCV RNA-positive. Genotype 1 predominated (75%), followed by 3a (25%). Subtype 1a was more common than 1b. HCV infection was more prevalent among intravenous drug users (33%) than non-injecting users (1.5%). Logistic regression analyses showed independent associations between HCV infection and intravenous drug use, imprisonment and increasing age. In the present study, injecting drug use was the factor most strongly associated to HCV infection and inhaling or sniffing did not represent an increased susceptibility to infection.

Appropriate drug treatment for status epilepticus does not influence its prognosis

Objective: Status epilepticus (SE) prognosis, is mostly related to non-modifiable factors (especially age, etiology), but the specific role of treatment appropriateness (TA) has not been investigated. Methods: In a prospective cohort with incident SE (excluding postanoxic), TA was defined, after recent European recommendations, in terms of drug dosage (630% deviation) and sequence. Outcome at hospital discharge was categorized into mortality, new handicap, or return to baseline. Results: Among 225 adults, treatment was inappropriate in 37%. In univariate analyses, age, etiology, SE severity and comorbidity, but not TA, were significantly related to outcome. Etiology (95% CI 4.3-82.8) and SE severity (95% CI 1.2-2.4) were independent predictors of mortality, and of lack of return to baseline conditions (etiology: 95% CI 3.9-14.0; SE severity: 95% CI 1.4-2.2). Moreover, TA did not improve outcome prediction in the corresponding ROC curves. Conclusions: This large analysis suggests that TA plays a negligible prognostic role in SE, probably reflecting the outstanding importance of the biological background. Awaiting treatment trials in SE, it appears questionable to apply further resources in refining treatment protocols involving existing compounds; rather, new therapeutic approaches should be identified and tested.

Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection.

OBJECTIVE: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation. METHODS: The population pharmacokinetic analysis was performed by use of NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution was examined. The average drug exposure during 1 dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample. RESULTS: Data from 235 patients with a total of 719 efavirenz concentrations were collected. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L, and the absorption rate constant was 0.3 h(-1). Neither the demographic covariates evaluated nor the comedications showed a clinically significant influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (coefficient of variation, 54.6%), whereas the intrapatient variability was small (coefficient of variation, 26%). An inverse correlation between average drug exposure and viral load and a trend with central nervous system toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target from 1000 to 4000 microg/L to optimize viral load suppression and to minimize central nervous system toxicity. CONCLUSIONS: The high interpatient and low intrapatient variability values, as well as the potential relationship with markers of efficacy and toxicity, support the therapeutic drug monitoring of efavirenz. However, further evaluation is needed before individualization of an efavirenz dosage regimen based on routine drug level monitoring should be recommended for optimal patient management.