Pachymeningitis associated with IgG4-related disease and ANCA positivity: Case report and review of the literature.

OBJECTIVE: Hypertrophic pachymeningitis is a rare clinical disorder involving localized or diffuse thickening of the dura mater. Considering pachymeningitis is both in the clinical spectrum of IgG4-RD and ANCA vasculitis (specifically granulomatosis with polyangiitis), an overlap syndrome is discussed. METHODS: We report a case of hypertrophic pachymeningitis revealed by headache and cranial nerve dysfunction, and coexistence of biopsy-proven IgG4-RD pachymeningitis and MPO-ANCA positivity. Furthermore, all cases previously reported in the literature of pachymeningitis with IgG4-RD and presence of ANCA were analyzed. RESULTS: Thirteen patients with pachymeningitis, IgG4-RD and ANCA were analyzed. Patients with HP-related IgG4 and ANCA are mainly male (8, 62%). Median age at diagnosis was 64 years. Main clinical manifestations at diagnosis were localized to the head and neck with headaches (10, 77%), cranial nerve dysfunction (7, 54%), hearing impairment (6, 46%) and vertigo (4, 31%). Except 1 patient with diffuse aortitis, no other systemic manifestation was observed at diagnosis and during follow-up. Serum IgG4 was often elevated (11, 85%) and ANCA was mainly with myeloperoxidase specificity (11, 85%). Seven patients had cerebrospinal fluid analyse with lymphocytic pleocytosis in 5 cases (71%), elevated proteins in 4 cases (57%), positive oligoclonal bands in 3 cases (42%) and decreased glucose in one case (14%). On the MRI, the thickening of the dura mater concerned most often the posterior fossa, in 7 cases (54%). Among 10 cases with histological findings, all showed increased IgG4-positivity of plasma cells, 50% lymphocytic infiltrate but none presented the three major histological criteria of IgG4-related disease. Three (30%) showed histological signs of vasculitis with vascular wall damage and/or giant cells. Among the 12 patients treated with steroid therapy, a clinical improvement was noted in 11 cases (92%). Relapse occurred during tapering in 4 patients (33%). An immunosuppressive drug was added in 2nd line for 7 cases (54%), with a clinical improvement in all. CONCLUSION: Pachymeningitis with IgG4 and ANCA seems a localized disease to the head and neck. Leptomeningeal biopsy commonly found IgG4 criteria and no vasculitis. All patients responded well to steroid therapy and immunosuppressive drugs, especially rituximab, with clinical and radiological improvement but relapse and/or sequelae are not uncommon.

Clustering suicidal phenotypes and genetic associations with brain-derived neurotrophic factor in patients with substance use disorders.

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

QT length during methadone maintenance treatment: gene × dose interaction.

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (rPearson  = 0.26; P = 10-3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10-4 ; pcorrected  = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (pempirical  = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

Acceptability and feasibility of HIV testing in general medicine by ELISA or rapid test from finger-stick whole blood.

OBJECTIVES: Guidelines recommend routine universal HIV testing in adults to reduce the pool of infected patients unaware of their status, without specific recommendations concerning the method. We compared acceptability and feasibility of HIV testing by ELISA tests or rapid tests from finger-stick whole blood. METHODS: Prospective randomized multi-center study comparing acceptability and feasibility of routine universal HIV testing by ELISA tests, with a charge, subsequently reimbursed by Social Security for affiliated patients, or rapid tests from finger-stick whole blood, without any charge from the patients or the general practitioner for the study. A single investigator performed all interventions. After consent, all adults (18-70 years old) consulting their general practitioner in Paris, France, unaware of their status, were enrolled. Testing was performed immediately for the patients in the rapid test arm; a prescription was given for testing in a lab for the patients in the ELISA arm. The primary endpoint was acceptability of each method. The secondary endpoint was feasibility of each method, assessed one month after the consultation. RESULTS: Two hundred and seventy patients were enrolled: 133 patients in the ELISA arm, 137 in the rapid test arm. Acceptability of the rapid test (92%) was higher than that of the ELISA (63.9%), P<0.0001. Feasibility of the rapid test (100%) was higher than that of the ELISA (50.5%), P<0.0001. A center effect was shown concerning feasibility of ELISA but not concerning feasibility of rapid tests. CONCLUSION: Rapid testing from finger-stick whole blood is more acceptable and feasible than ELISA for routine universal HIV testing. A larger use of rapid tests, ideally free of charge, by general practitioners could reduce the pool of infected patients unaware of their status.

The effect of morbid obesity on morphine glucuronidation.

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort?

An interaction of drug with food, herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John's Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient' and doctor's information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio.

Quantitative Atlas of Cytochrome P450, UDP-Glucuronosyltransferase, and Transporter Proteins in Jejunum of Morbidly Obese Subjects.

Protein expression levels of drug-metabolizing enzymes and transporters in human jejunal tissues excised from morbidly obese subjects during gastric bypass surgery were evaluated using quantitative targeted absolute proteomics. Protein expression levels of 15 cytochrome P450 (CYP) enzymes, 10 UDP-glucuronosyltransferase (UGT) enzymes, and NADPH-P450 reductase (P450R) in microsomal fractions from 28 subjects and 49 transporters in plasma membrane fractions from 24 of the same subjects were determined using liquid chromatography-tandem mass spectrometry. Based on average values, UGT1A1, UGT2B15, UGT2B17, SGLT1, and GLUT2 exhibited high expression levels (over 10 fmol/µg protein), though UGT2B15 expression was detected at a high level in only one subject. CYP2C9, CYP2D6, CYP3A5, UGT1A6, P450R, ABCG2, GLUT5, PEPT1, MCT1, 4F2 cell-surface antigen heavy chain (4F2hc), LAT2, OSTα, and OSTß showed intermediate levels (1-10 fmol/µg protein), and CYP1A1, CYP1A2, CYP1B1, CYP2C18, CYP2C19, CYP2J2, CYP3A7, CYP4A11, CYP51A1, UGT1A3, UGT1A4, UGT1A8, UGT2B4, ABCC1, ABCC4, ABCC5, ABCC6, ABCG8, TAUT, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OCTN1, CNT2, PCFT, MCT4, GLUT4, and SLC22A18 showed low levels (less than 1 fmol/µg protein). The greatest interindividual difference (364-fold) was detected for UGT2B17. However, differences in expression levels of other quantified UGTs (except UGT2B15 and UGT2B17), CYPs (except CYP1A1 and CYP3A5), and P450R, and all quantified transporters, were within 10-fold. Expression levels of CYP1A2 and GLUT4 were significantly correlated with body-mass index. The levels of 4F2hc showed significant gender differences. Smokers showed increased levels of UGT1A1 and UGT1A3. These findings provide a basis for understanding the changes in molecular mechanisms of jejunal metabolism and transport, as well as their interindividual variability, in morbidly obese patients.

Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers.

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.

Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity.

AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

Efficacy and safety of a new oral saliva equivalent in the management of xerostomia: a national, multicenter, randomized study.

OBJECTIVE AND STUDY DESIGN: The clinical efficacy, safety, and acceptability of a new oral saliva equivalent (Novasial) administered four times daily in the treatment of xerostomia in various medical conditions was compared with that of oxygenated glycerol triester oral spray (Aequasyal) and a moisturizing spray (Biotene) in a 2-week, multicenter, randomized, crossover study. Assessment included patient-based evaluation of mouth dryness score (primary endpoint) with a visual analog scale (VAS), blinded assessment of the oral tissue condition by a four-point ordinal scale, and patient-based assessment of tolerability and acceptability. RESULTS: At day 14, Novasial decreased oral mouth dryness by 19.5%, (12.5 ± 22.6 mm, P < .0001 versus baseline), versus 10% (6.6 ± 17.9 mm with Aequasyal, P < .0001 versus Baseline; and P < .0156 versus Novasial) and 13% (8.6 ± 18.9 mm) with Biotene (P < .0001 versus baseline). The 50% decrease in the primary endpoint was not achieved, and the overall efficacy of Novasial and Aequasyal were similar with respect to xerostomia. Novasial was preferred to Aequasyal and Biotene in alleviating taste alteration and chewing difficulty. Treatment compliance was higher with Novasial (P = .0014 versus Aequasyal). The treatments improved the oral condition with equal efficacy and were safe and well tolerated (VAS 72-77 mm). CONCLUSIONS: Novasial was a safe, well-tolerated, and acceptable treatment in patients with xerostomia induced by various treatments or pathologic conditions.

Effect of a Roux-en-Y gastric bypass on the pharmacokinetics of oral morphine using a population approach.

BACKGROUND AND OBJECTIVES: Obesity and opioid use for chronic pain in obese individuals are both important public health concerns. The pharmacokinetics of oral morphine after Roux-en-Y gastric bypass (RYGB) are unknown. Therefore, we aimed to study the pharmacokinetics of oral morphine in morbidly obese patients before and after RYGB surgery, to identify the effects of RYGB and the subsequent reversal of morbid obesity on the pharmacokinetic parameters of morphine. METHODS: The pharmacokinetics of oral morphine (30 mg) were studied in 30 obese patients before (Visit 1) and then 7-15 days (Visit 2) and 6 months (Visit 3) after RYGB. A population pharmacokinetic model was used to describe the time course of the plasma morphine concentration, to study the effect of RYGB on morphine pharmacokinetics and to estimate inter-patient variability. RESULTS: The oral morphine time to maximum plasma concentration (t max) was twofold lower and maximum plasma concentration (C max) was 1.7 times higher at Visit 2, and t max was 7.5 times lower and C max 3.3 times higher at Visit 3 than at Visit 1. The mean oral morphine area under the plasma concentration-time curve (AUC) increased significantly (1.55-fold) between Visits 1 and 3. Changes in body mass index (BMI) after RYGB were clearly associated with decreased apparent oral morphine clearance and apparent central and peripheral morphine volumes of distribution. None of the other anthropometric parameters explained the inter-subject variability in morphine exposure better than BMI. CONCLUSION: RYGB and the BMI reduction that followed it dramatically increased the rate of morphine absorption and slightly increased morphine exposure. The dose of immediate-release forms of morphine may be divided in obese patients after RYGB to prevent adverse events due to early and high morphine plasma peaks.

KCNH2 polymorphism and methadone dosage interact to enhance QT duration.

BACKGROUND: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. METHODS: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. RESULTS: The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001). CONCLUSION: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.

Optimizing the use of intravenous therapy in internal medicine.

BACKGROUND: We aimed to evaluate the impact of physicians' educational programs in the reduction of inappropriate intravenous lines in internal medicine. METHODS: Fifty-six French internal medicine units were enrolled in a nationwide, prospective, blinded, randomized controlled trial. Forms describing the patients with an intravenous line and internal medicine department characteristics were filled out on 2 separate days in January and April 2007. Following the first visit, all units were randomly assigned to either a specific education program on the appropriate indications of an intravenous line, during February and March 2007, or no training (control group). The Investigators' Committee then blindly evaluated the clinical relevance of the intravenous line according to pre-established criteria. The primary outcome was the percentage of inappropriate intravenous lines. RESULTS: During January 2007, intravenous lines were used in 475 (24.9%) of the 1910 hospitalized patients. Of these, 80 (16.8%) were considered inappropriate. In April 2007, 416 (22.8%) of the 1823 hospitalized patients received an intravenous line, which was considered in 10.2% (21/205) of patients managed by trained physicians, versus 16.6% (35/211) of patients in the control group (relative difference 39%; 95% confidence interval, -0.6-13.3; P = .05). Reduced intravenous administration of fluids, antibiotics, and analgesics accounted for the observed decrease. CONCLUSION: The use of a simple education program reduced the rate of inappropriate intravenous lines by almost 40% in an internal medicine setting (NCT01633307).

Sensory impairment in obese patients? Sensitivity and pain detection thresholds for electrical stimulation after surgery-induced weight loss, and comparison with a nonobese population.

INTRODUCTION: Obese patients have a high prevalence of painful musculoskeletal disorders that may decrease after massive weight loss. Pain thresholds may be different in obese participants. OBJECTIVES: To assess the sensitivity and pain detection thresholds, through the application of an electrical sensitivity, before and after massive weight loss, and to compare the thresholds obtained with those in a control population. METHODS: The sensitivity and pain detection thresholds obtained in participants subjected to electrical stimulation were determined in 31 obese individuals (age: 40.3 ± 10.5 y) before (body mass index: 45.7 ± 6.8 kg/m) and 6 months after a mean weight loss of 32 kg induced by gastric bypass. The results obtained were compared with those for 49 nonobese control participants (38.5 ± 11.2 y; body mass index: 22.6 ± 2.6 kg/m). Body composition and metabolic biomarkers, such as leptin, adiponectin, insulin, and interleukin 6, were assessed and single-nucleotide polymorphisms of the mu opioid receptor [OPRM1 (c.118A > G) and COMT (p.Val158Met)] were genotyped in obese patients. RESULTS: Sensitivity and pain detection thresholds (3.9 ± 1.1; 11.6 ± 6.0) were significantly higher in obese than in nonobese participants (3.1 ± 1.1; 6.0 ± 3.0), respectively (P < 0.0001), and were not affected by drastic weight loss (mean change: 32 kg). Pain thresholds in obese participants were not correlated with any of the clinical and biological variables studied. The obese participants in the highest quartile for both sensitivity and pain detection thresholds were significantly older than those in the lowest quartile. CONCLUSIONS: Further studies are required to explore sensory dysfunction in obese individuals and to investigate the implications of this dysfunction for pain management.

Etonorgestrel concentrations in morbidly obese women following Roux-en-Y gastric bypass surgery: three case reports.

BACKGROUND: Pregnancy should be avoided for 12 to 18 months after Roux-en-Y gastric bypass (RYGB) surgery. The etonorgestrel (ENG)-releasing implant (Implanon®) may represent a safe and effective contraceptive method in morbidly obese women who are candidates for bariatric surgery. In addition, the subcutaneous delivery of steroid is unaffected by malabsorptive surgery. METHODS: Three cases of young women with ENG-releasing implant are reported. The device was inserted 1-2 months prior to RYGB. RESULTS: Their initial weights were 130 to 176 kg, and the mean weight loss was 33.6 kg at 6 months. The concomitant serum ENG concentrations decreased currently with weight loss but remained above the minimum concentration required for effective contraceptive effect of the implant for at least 6 months following RYGB (average, 170 pg/mL). The concentrations observed before weight loss were lower than in normal-weight women, but decreases in ENG concentrations following implant insertion were similar. CONCLUSION: These unique data in morbidly obese women highlight the need for further pharmacokinetic studies of contraceptive agents in obese women during weight loss.

Prospective study of a cementless, mobile-bearing, third generation total ankle prosthesis.

BACKGROUND: The SALTO total ankle prosthesis is a noncemented mobile bearing anatomic design characterized by dual Ti-HA coating. This study reviews our results with this prosthesis. MATERIALS AND METHODS: Between 2001 and 2007, 413 consecutive SALTO prostheses were implanted in our institution in 215 women and 198 men, aged 57.1 +/- 11.9 years. At the last visit, 401 implants (47% in the left ankle) were available with a mean followup of 29 (range, 1 to 84) months. RESULTS: Based on the results of the 218 patients with at least 2 years of postoperative followup, the 5-year estimated survivorship, with the primary end-point being implant removal, was 86.6% and ranged from 85.1% in patients with post-traumatic osteoarthritis to 95.6% in those with rheumatoid arthritis. The AOFAS score increased from 50.9 +/- 16.8 points preoperatively to 82.2 +/- 14 points at followup (mean difference, 31.1 +/- 1.4, 95% confidence interval (C.I.) for the difference, 28.3 to 33.8, p < 0.001). Visual analog scale for pain decreased from 7.4 +/- 1.1 preoperatively to 2.0 +/- 2.0 postoperatively (mean difference, -5.4 +/- 0.7, 95% C.I. for the difference, -5.6 to -5.2, p < 0.001). Flexion/extension ROM increased from 25.2 +/- 14.1 degrees to 33.1 +/- 13.6 degrees at the last followup visit (mean difference, 7.9 +/- 0.5 degrees, 95% C.I. for the difference, 4.3 to 7.2, p < 0.001), while pronation/supination ROM increased from 23.8 +/- 13.7 degrees to 25.4 +/- 14.5 degrees (mean difference, 1.6 +/- 0.7 degrees, 95% C.I. for the difference, 0.9 to 2.2, p = 0.005). CONCLUSION: The SALTO prosthesis provided good clinical and functional results and we believe helps validate the concept of anatomic replacement.

Pilot study examining the frequency of several gene polymorphisms involved in morphine pharmacodynamics and pharmacokinetics in a morbidly obese population.

Morbidly obese patients are at significantly elevated risk of postsurgery complications and merit closer monitoring by health care professionals after bariatric surgery. It is now recognized that genetic factors influence individual patient's response to drug used in anesthesia and analgesia. Among the many drug administered by anesthetists, we focused in this pilot study on morphine, since morphine patient-controlled anesthesia in obese patients undergoing gastric bypass surgery is frequently prescribed. We examined the allelic frequency of three polymorphisms involved in morphine pharmacodynamics and pharmacokinetics in patients with body mass index (BMI) >40. One hundred and nine morbidly obese patients (BMI = 49.1 ± 7.7 kg/m²) were genotyped for three polymorphisms c.A118G of mu opioid receptor (OPRM1), c.C3435T of the P-glycoprotein gene (ABCB1), and p.Val158Met of catechol-O-methyltransferase gene (COMT). Allelic frequencies were 118G-0.22, C3435-0.55, and 158Met-0.5 in our whole population and 0.23, 0.5, and 0.47 in Caucasian population. Allelic frequencies did not differ according to gender. Mean BMI did no differ according to the allelic variant. OPRM1118G allele was more frequent in our population than in most previously described European populations. Since the concept of "personalized medicine" promises to individualize therapeutics and optimize medical treatment in term of efficacy and safety, especially when prescribing drugs with a narrow therapeutic index such as morphine, further clinical studies examining the clinical consequences of the OPRM1 c.A118G polymorphism in patients undergoing gastric bypass surgery are needed.

Effect of variations in the amounts of P-glycoprotein (ABCB1), BCRP (ABCG2) and CYP3A4 along the human small intestine on PBPK models for predicting intestinal first pass.

It is difficult to predict the first-pass effect in the human intestine due to a lack of scaling factors for correlating in vitro and in vivo data. We have quantified cytochrome P450/3A4 (CYP3A4) and two ABC transporters, P-glycoprotein (P-gp, ABCB1) and the breast cancer resistant protein BCRP (ABCG2), throughout the human small intestine to determine the scaling factors for predicting clearance from intestinal microsomes and develop a physiologically based pharmacokinetic (PBPK) model. CYP3A4, P-gp and BCRP proteins were quantified by Western blotting and/or enzyme activities in small intestine samples from 19 donors, and mathematical trends of these expressions with intestinal localization were established. Microsome fractions were prepared and used to calculate the amount of microsomal protein per gram of intestine (MPPGI). Our results showed a trend in CYP3A4 expression decrease from the upper to the lower small intestine while P-gp expression is increasing. In contrast, BCRP expression did not vary significantly with position, but varied greatly between individuals. The MPPGI (mg microsomal protein per centimeter intestine) remained constant along the length of the small intestine, at about 1.55 mg/cm. Moreover, intrinsic clearance measured with specific CYP3A4 substrates (midazolam and an in-house Servier drug) and intestinal microsomes was well correlated with the amount of CYP3A4 (R(2) > 0.91, p < 0.01). In vivo data were more accurately predicted using PBPK models of blood concentrations of these two substrates based on the segmental distributions of these enzymes and MPPGI determined in this study. Thus, these mathematical trends can be used to predict drug absorption at different intestinal sites and their metabolism can be predicted with the MPPGI.

Central nervous system tuberculomas in 23 patients.

Central nervous system tuberculomas are rare and severe complications of tuberculosis. We performed a retrospective study of the clinical, biological, radiological, pathological, and therapeutic features of 23 patients. Almost all patients were from countries with a high prevalence of tuberculosis (22/23). Their mean age was 37.3 y; 43.5% had laboratory-proven meningitis and 17.4% had biopsy-proven tuberculomas. For most of the patients, the duration of treatment lasted 13-18 months. The disease was controlled without relapse in 16 patients and 3 patients died. Diagnosis relies on magnetic resonance imaging and bacteriological specimens from all the involved sites. This study indicates that central nervous system tuberculomas occur in young patients from high risk countries. The anti-tuberculous drug regimen in this series was 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by at least 10 months of isoniazid and rifampin. Results did not contradict the use of a 12-month regimen as currently recommended.