Influence of N-Hexane Inhalation on the Enantioselective Pharmacokinetics and Metabolism of Verapamil in Rats

Verapamil (VER) is commercialized as a racemic mixture of the (+)-(R)-VER and (-)-(S)-VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP-dependent pathways. N-hexane is a solvent that can alter the metabolism of CYP-dependent drugs. The present study investigated the influence of n-hexane (nose-only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m(3)) on the kinetic disposition of the (+)-(R)-VER, (-)-(S)-VER, (R)-NOR and (S)-NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC-MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak (R) AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (-)-(S)-VER eutomer (AUC(0-infinity) = 250.8 vs. 120.4 ng/ml/h; P <= 0.05, Wilcoxon test). The (S)-NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC(0-infinity) ratio of 1.5. The pharmacokinetic parameters AUC(0-infinity), Cl/F, Vd/F, and t(1/2) obtained for VER and NOR enantiomers were not altered by nose-only exposure to n-hexane at concentrations of 88, 176, or 352 mg/m(3) (P > 0.05, Kruskal-Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n-hexane at concentrations equal to or higher than the TLV-TWA. This finding is relevant considering that the (-)-(S)-VER eutomer is 10-20 times more potent than R-(+)-VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans. Chirality 22:29-34, 2010. (C) 2009 Wiley-Liss, Inc.

Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients

Purpose This study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally. Methods Thirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol. Results The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the beta-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the alpha-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women. Conclusions The approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the alpha-blocking activity of this isomer.

Determination of mitragynine in rat plasma by LC-MS/MS: Application to pharmacokinetics

This study used for the first time LC-MS/MS for the analysis of mitragynine (MIT), a mu-opioid agonist with antinociceptive and antitussive properties, in rat plasma. Mitragynine and the internal standard (amitriptyline) were extracted from plasma with hexane-isoamyl alcohol and resolved on a Lichrospher (R) RP-SelectB column (9.80 and 12.90 min, respectively). The quantification limit was 0.2 ng/mL within a linear range of 0.2-1000 ng/mL The method was applied to quantify mitragynine in plasma samples of rats (n = 8 per sampling time) treated with a single oral dose of 20 mg/kg. The following pharmacokinetic parameters were obtained (mean): maximum plasma concentration: 424 ng/mL; time to reach maximum plasma concentration: 1.26 h; elimination half-life: 3.85 h, apparent total clearance: 6.35 L/h/kg, and apparent volume of distribution: 37.90 L/kg. (C) 2009 Elsevier B.V. All rights reserved.

Disposition of MDMA and Metabolites in Human Sweat Following Controlled MDMA Administration

BACKGROUND: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. METHODS: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek (R) sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. RESULTS: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. CONCLUSIONS: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results. (C) 2008 American Association for Clinical Chemistry

Depression in women living with HIV: clinical and psychosocial correlates

The number of Brazilian women living with HIV has increased significantly in past years, rendering studies of their particular care demands including psychiatric issues. This study measures the prevalence of major depression, using the Structured Clinical Interview for DSM-IV Axis I Disorders, in a sample of 120 women living with HIV in treatment at a reference centre in So Paulo. Socio-demographic variables, HIV-related clinical and laboratory data, including CD4+ cell counts and HIV plasma viral loads, as well as psychosocial features (intimate relationships, disclosure of HIV serostatus, partner`s serostatus and patient`s emotional and financial support) were investigated as factors potentially associated with depression. The prevalence of major depression at the time of evaluation was 25.8% (95% CI 18.2-33.4%). Clinical status (p = 0.002), lack of emotional support (p = 0.02), use of antidepressants (p = 0.028) and length of time since HIV diagnosis (p = 0.05) were associated with major depression in univariate analysis. In multivariate multiple-regression model, HIV clinical status, lack of emotional support and higher plasma viral loads were associated with depression. Sixty per cent of the women have a major depression diagnosis during lifetime. We conclude that major depression is highly prevalent among women living with HIV, but it is still underdiagnosed and undertreated.

Eating Disorders in Patients with Obsessive-Compulsive Disorder: Prevalence and Clinical Correlates

Objective: The objective is to evaluate the prevalence and associated clinical characteristics of eating disorders (ED) in patients with obsessive compulsive disorder (OCD). Method: This is a cross-sectional study comparing 815 patients with OCD. Participants were assessed with structured interviews and scales: SCID-I, Y-BOCS, Dimensional Y-BOCS, BABS, Beck Depression and Anxiety Inventories. Results: Ninety-two patients (11.3%) presented the following EDs: binge-eating disorders [= 59 (7.2%)], bulimia nervosa [= 16 (2.0%)], or anorexia nervosa [= 17 (2.1%)]. Compared to OCD patients without ED (OCD-Non-ED), OCD-ED patients were more likely to be women with previous psychiatric treatment. Mean total scores in Y-BOCS, Dimensional Y-BOCS, and BABS were similar within groups. However, OCD-ED patients showed higher lifetime prevalence of comorbid conditions, higher anxiety and depression scores, and higher frequency of suicide attempts than did the OCD-Non-ED group. Primarily diagnosed OCD patients with comorbid ED may be associated with higher clinical severity. Discussion: Future longitudinal studies should investigate dimensional correlations between OCD and ED. (C) 2009 by Wiley Periodicals, Inc.

Myocardial scintigraphy and clinical stratification as predictors of events in renal transplant candidates

Background: We tested the hypothesis that the universal application of myocardial scanning with single-photon emission computed tomography (SPECT) would result in better risk stratification in renal transplant candidates (RTC) compared with SPECT being restricted to patients who, in addition to renal disease, had other clinical risk factors. Methods: RTCs (n=363) underwent SPECT and clinical risk stratification according to the American Society of Transplantation (AST) algorithm and were followed up until a major adverse cardiovascular event (MACE) or death. Results: Of the 363 patients, 79 patients (22%) had an abnormal SPECT scan and 270 (74%) were classified as high risk. Both methods correctly identified patients with increased probability of MACE. However, clinical stratification performed better (sensitivity and negative predictive value 99% and 99% vs. 25% and 87%, respectively). High-risk patients with an abnormal SPECT scan had a modest increased risk of events (log-rank = 0.03; hazard ratio [HR] = 1.37; 95% confidence interval [95% CI], 1.02-1.82). Eighty-six patients underwent coronary angiography, and coronary artery disease (CAD) was found in 60%. High-risk patients with CAD had an increased incidence of events (log-rank = 0.008; HR=3.85; 95% CI, 1.46-13.22), but in those with an abnormal SPECT scan, the incidence of events was not influenced by CAD (log-rank = 0.23). Forty-six patients died. Clinical stratification, but not SPECT, correlated with the probability of death (log-rank = 0.02; HR=3.25; 95% CI, 1.31-10.82). Conclusion: SPECT should be restricted to high-risk patients. Moreover, in contrast to SPECT, the AST algorithm was also useful for predicting death by any cause in RTCs and for selecting patients for invasive coronary testing.

EEG-based Brain-Computer Interfaces: An Overview of Basic Concepts and Clinical Applications in Neurorehabilitation

Some patients are no longer able to communicate effectively or even interact with the outside world in ways that most of us take for granted. In the most severe cases, tetraplegic or post-stroke patients are literally `locked in` their bodies, unable to exert any motor control after, for example, a spinal cord injury or a brainstem stroke, requiring alternative methods of communication and control. But we suggest that, in the near future, their brains may offer them a way out. Non-invasive electroencephalogram (EEG)-based brain-computer interfaces (BCD can be characterized by the technique used to measure brain activity and by the way that different brain signals are translated into commands that control an effector (e.g., controlling a computer cursor for word processing and accessing the internet). This review focuses on the basic concepts of EEG-based BC!, the main advances in communication, motor control restoration and the down-regulation of cortical activity, and the mirror neuron system (MNS) in the context of BCI. The latter appears to be relevant for clinical applications in the coming years, particularly for severely limited patients. Hypothetically, MNS could provide a robust way to map neural activity to behavior, representing the high-level information about goals and intentions of these patients. Non-invasive EEG-based BCIs allow brain-derived communication in patients with amyotrophic lateral sclerosis and motor control restoration in patients after spinal cord injury and stroke. Epilepsy and attention deficit and hyperactive disorder patients were able to down-regulate their cortical activity. Given the rapid progression of EEG-based BCI research over the last few years and the swift ascent of computer processing speeds and signal analysis techniques, we suggest that emerging ideas (e.g., MNS in the context of BC!) related to clinical neuro-rehabilitation of severely limited patients will generate viable clinical applications in the near future.

Clinical changes of cervical dystonia pattern in long-term botulinum toxin treated patients

Cervical dystonia (CD) is a complex disorder but the response to long-term botulinum toxin (BTX) therapy is satisfactory in most cases. Bad results are attributed by some authors to changes in muscle activation. Our purpose is to verify if the change in head deviation affects negatively the response to BTX therapy it) a long-term follow-up, and if there are any differences in clinical parameters of these patients in comparison to those with stable pattern. From a total of 88 patients evaluated at the Movement Disorders Clinics of Hospital das Clinicas - University of Sao Paulo School of Medicine between January 1993 and December 2005, 67 were included. In 24 (35.8%) change in pattern of CID was observed, in a medium follow-up period of 80 months. The time between onset of dystonia and the diagnosis of pattern change was 9.7 years. Comparing with patients with no changes in CD pattern, there were no significant statistical differences. Improvement of symptoms around 60% was reported in both groups. In conclusion, the change in head deviation observed in CD was not responsible for bad response to therapy with BTX and there were no significant differences between both groups. (C) 2009 Elsevier Ltd. All rights reserved.

Home blood pressure monitoring in blood pressure control among haemodialysis patients: an open randomized clinical trial

Background. It is not known if the adjustment of antihypertensive therapy based on home blood pressure monitoring (HBPM) can improve blood pressure (BP) control among haemodialysis patients. Methods. This is an open randomized clinical trial. Hypertensive patients on haemodialysis were randomized to have the antihypertensive therapy adjusted based on predialysis BP measurements or HBPM. Before and after 6 months of follow-up, patients were submitted to ambulatory blood pressure monitoring (ABPM) for 24 h, HBPM during 1 week and echocardiogram. Results. A total of 34 and 31 patients completed the study in the HBPM and predialysis BP groups, respectively. At the end of study, the systolic (SBP) and diastolic (DBP) blood pressure during the interdialytic period measured by ABPM were significantly lower in the HBPM group in relation to the predialysis BP group (mean 24-h BP: 135 +/- 12 mmHg/76 +/- 7 mmHg versus 147 +/- 15 mmHg/79 +/- 8 mmHg; P < 0.05). In the HBPM analysis, the HBPM group showed a significant reduction only in SBP compared to the predialysis BP group (weekly mean: 144 +/- 21 mmHg versus 154 +/- 22 mmHg; P < 0.05). There were no differences between the HBPM and predialysis BP groups in relation to the left ventricular mass index at the end of the study (108 +/- 35 g/m(2) versus 110 +/- 33 g/m(2); P > 0.05). Conclusions. Decision making based on HBPM among haemodialysis patients has led to a better BP control during the interdialytic period in comparison with predialysis BP measurements. HBPM may be a useful adjuvant instrument for blood pressure control among haemodialysis patients.

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

DNA-hsp65, a DNA vaccine encoding the 65-kDa heat-shock protein of Mycobacterium leprae (Hsp65) is capable of inducing the reduction of established tumors in mouse models. We conducted a phase I clinical trial of DNA-hsp65 in patients with advanced head and neck carcinoma. In this article, we report on the vaccine`s potential to induce immune responses to Hsp65 and to its human homologue, Hsp60, in these patients. Twenty-one patients with unresectable squamous cell carcinoma of the head and neck received three doses of 150, 400 or 600 mu g naked DNA-hsp65 plasmid by ultrasound-guided intratumoral injection. Vaccination did not increase levels of circulating anti-hsp65 IgG or IgM antibody, or lead to detectable Hsp65-specific cell proliferation or interferon-gamma (IFN-gamma) production by blood mononuclear cells. Frequency of antigen-induced IL-10-producing cells increased after vaccination in 4 of 13 patients analyzed. Five patients showed disease stability or regression following immunization; however, we were unable to detect significant differences between these patients and those with disease progression using these parameters. There was also no increase in antibody or IFN-gamma responses to human Hsp60 in these patients. Our results suggest that although DNA-hsp65 was able to induce some degree of immunostimulation with no evidence of pathological autoimmunity, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured. Future studies should focus on characterizing more reliable correlations between immune response parameters and clinical outcome that may be used as predictors of vaccine success in immunosuppressed individuals. Cancer Gene Therapy (2009) 16, 598-608; doi:10.1038/cgt.2009.9; published online 6 February 2009

CLINICAL TUMOR DIMENSIONS MAY BE USEFUL TO PREVENT GEOGRAPHIC MISS IN CONVENTIONAL RADIOTHERAPY OF UTERINE CERVIX CANCER-A MAGNETIC RESONANCE IMAGING-BASED STUDY

Purpose: To evaluate the risk of geographic miss associated with the classic four-field ""box"" irradiation technique and to define the variables that predict this risk. Materials and Methods: The study population consisted of 80 patients with uterine cervix cancer seen between 2001 and 2006. Median age was 55 years (23-82 years), and 72 (90%) presented with squamous cell carcinoma. Most patients (68.7%) presented with locally advanced disease (IIb or more). Magnetic resonance imaging findings from before treatment were compared with findings from simulation of the conventional four-field ""box"" technique done with rectal contrast. Study variables included tumor volume; involvement of vagina, parametrium, bladder, or rectum; posterior displacement of the anterior rectal wall; and tumor anteroposterior diameter (APD). Margins were considered adequate when the target volume (primary tumor extension, whole uterine body, and parametrium) was included within the field limits and were at least 1 cm in width. Results: Field limits were inadequate in 45 (56%) patients: 29 (36%) patients at the anterior and 28 (35%) at the posterior border of the lateral fields. Of these, 12 patients had both anterior and posterior miss, and this risk was observed in all stages of the disease (p = 0.076). Posterior displacement of the anterior rectal wall beyond S2-S3 was significantly correlated with the risk of geographic miss (p = 0.043). Larger tumors (APD 6 cm or above and volume above 50 cm(3)) were also significantly correlated with this risk (p = 0.004 and p = 0.046, respectively). Conclusions: Posterior displacement of the anterior rectal wall, tumor APD, and volume can be used as guidance in evaluating the risk of geographic miss. (C) 2009 Elsevier Inc.

Can we start to think about consensus-oriented clinical practices?

Pulmonary Vascular Research Institute

Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury

Purpose: The aim of this study is to evaluate the relationship between timing of renal replacement therapy (RRT) in severe acute kidney injury and clinical outcomes. Methods: This was a prospective multicenter observational study conducted at 54 intensive care units (ICUs) in 23 countries enrolling 1238 patients. Results: Timing of RRT was stratified into ""early"" and ""late"" by median urea and creatinine at the time RRT was started. Timing was also categorized temporally from ICU admission into early (<2 days), delayed (2-5 days), and late (>5 days). Renal replacement therapy timing by serum urea showed no significant difference in crude (63.4% for urea <= 24.2 mmol/L vs 61.4% for urea >24.2 mmol/L; odds ratio [OR], 0.92; 95% confidence interval [CI], 0.73-1.15; P = .48) or covariate-adjusted mortality (OR, 1.25; 95% CI, 0.91-1.70; P = .16). When stratified by creatinine, late RRT was associated with lower crude (53.4% for creatinine >309 mu mol/L vs 71.4% for creatinine <= 309 mu mol/L; OR, 0.46; 95% CI, 0.36-0.58; P < .0001) and covariate-adjusted mortality (OR, 0.51; 95% CI, 0.37-0.69; P < .001).However, for timing relative to ICU admission, late RRT was associated with greater crude (72.8% vs 62.3% vs 59%, P < .001) and covariate-adjusted mortality (OR, 1.95; 95% CI, 1.30-2.92; P = .001). Overall, late RRT was associated with a longer duration of RRT and stay in hospital and greater dialysis dependence. Conclusion: Timing of RRT, a potentially modifiable factor, might exert an important influence on patient survival. However, this largely depended on its definition. Late RRT (days from admission) was associated with a longer duration of RRT, longer hospital stay, and higher dialysis dependence. (C) 2009 Elsevier Inc. All rights reserved.

Combined Laser and Intravitreal Triamcinolone for Proliferative Diabetic Retinopathy and Macular Edema: One-year Results of a Randomized Clinical Trial

PURPOSE: To evaluate laser combined with intravitreal triamcinolone acetonide (IVTA) for the management of patients with proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME). DESIGN: Randomized clinical trial. METHODS: SETTINGS: Single center. STUDY POPULATION: Twenty-two patients with bilateral treatment,naive moderate PDR and CSME. INTERVENTION: Laser (panretinal and macular) photocoagulation was performed in each eye, followed by IVTA in one randomly assigned eye. Best,corrected visual acuity (BCVA), fundus photography, and optical coherence tomography were performed at baseline and at months 1, 3, 6, 9, and 12. MAIN OUTCOME MEASURES:. Changes in BCVA, central macular thickness (CMT), and total macular volume (TMV). RESULTS: The mean logarithm of the minimal angle of resolution (logMAR) BCVA improved significantly, and mean CMT and TMV were significantly reduced in the IVTA group compared with the laser,only group (controls) at all study follow-up visits (P < .001). The mean logMAR BCVA (Snellen equivalent) was 0.44 (20/50(-2)) for the IVTA group and 0.38 (20/50(+1)) for the controls at baseline, and 0.12 (20/25(-1)) for the IVTA group and 0.32 (20/40(-1)) for the controls at 12 months (P < .001.). The mean CMT and TMV were, respectively, 360 mu m and 8.59 mm(3) for the IVTA group and 331 mu m and 8.44 mm(3) for the controls at baseline, and 236 mu m and 7.32 mm(3) for the IVTA group and 266 mu m and 7.78 mm(3) for the controls at 12 months (P < .001). CONCLUSIONS: The combination of laser photocoagulation with IVTA was associated with improved BCVA and decreased CMT and TMV when compared with laser photocoagulation alone for the treatment of moderate PDR with CSME. (Am J Ophthalmol 2009;147:291-297. (C) 2009 by Elsevier Inc. All rights reserved.)