Search

Background: Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin. However, nebulized colistin can cause bronchoconstriction in CF patients. Therefore, in the progress of developing a dry powder formula, the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects. To investigate the side effects, a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF-patients. Methods: Nine CF-patients chronically infected with P. aeruginosa participated in a double blind, randomized cross over study. On two visits to the outpatient clinic, patients were submitted to either nebulized colistin sulphate or colistin sulphomethate solution. Lung function tests were performed immediately before and 15 and 30 min after nebulization. Results: Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate. A significant decrease in mean changes (SD) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of −7.3% (8.6%), −5.7% (7.3%) and −8.4% (7.5%) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate (P

Hypothesis / aims of study Alpha-blockers are the cornerstone for the medical treatment of male LUTS [1]. Despite the positive recommendation in all relevant guidelines, the efficacy of these drugs has been debated [2]. The Dutch general practitioners guideline Male LUTS recommends the discontinuation of α-blockers after a successful period of treatment for 3 to 6 months [3]. No evidence is provided to support that recommendation. The 2015 EAU guideline Treatment of Non-neurogenic Male LUTS recommends that the discontinuation of the α1-blocker after six months might be considered in men with moderate LUTS, who are treated with combination therapy [1]. This reommendation is based on one randomised controlled trial and one open label study. In this study, we systematically reviewed the literature for studies evaluating the effect of discontinuation of α-blockers in uncomplicated male LUTS. We were particularly interested in the effect of discontinuation on symptom severity and urinary flow rates. Study design, materials and methods A systematic review of the literature was conducted according to PRISMA guidelines. The review protocol was registered at the PROSPERO database (number blinded to allow anonymous review of abstract). On January 15th 2016, The PUBMED, EMBASE and COCHRANE databases were searched without limitations on study design or time limits. The following search terms were used: Adrenergic alpha blockers [MeSH] AND (LUTS OR BPH OR lower urinary tract symptoms OR benign prostate hypertrophy OR benign prostate enlargement) AND (discontinu∗ OR interrup∗ OR cessa∗ OR stop∗ OR withdra∗ OR intermit∗). We included all studies in which the discontinuation of α-blocker treatment in men with LUTS was assessed with at least one of the following outcomes: symptom score (International Prostate Symptom Score [IPSS], or other), quality of life outcomes, uroflowmetric assessment, post voided residual urine volume (PVR). Two reviewers independently selected the studies and extracted all data; in case of disagreement consensus was found. Risk of bias was assessed using the Cochrane Collaborations tool for assessing risk of bias. Results We included 16 studies out of 876 potential publications. Nine studies (with 1,440 patients) reported on α-blocker monotherapy discontinuation (2 double-blind RCTs, 3 open label RCTs and 4 cohort studies). Seven other studies (with 1,148 participants) reported on discontinuation of an α-blocker following combination of α-blocker and 5- α-reductase inhibitors therapy (1 blinded RCT, 4 open label RCTs and 2 cohort studies). All studies were performed in secondary or tertiary care centres. The 10 RCTs are further discussed. The quality of the 10 RCTs was generally poor, with high risk of selection bias, performance bias and detection bias (Figure 1). Pooling of data was possible for IPSS outcomes and urinary flow rates (Qmax) at 3 and 6 months after discontinuation. At 3 months, men who continued α-blocker treatment had lower IPSS scores than those who discontinued (3 studies, 157 participants): mean difference (CI95%) -3.65 (-5.04, -2.25). At 6 months (4 studies, 226 participants) this difference was -3.25 (-5.74, -0.76). At 3 months (3 studies, 157 participants), Qmax did not differ between discontinuation and continuation groups 1.20 ml/sec (- 1.10, 3.50). At 6 months, in men who were on combination therapy, discontinuation of α-blocker therapy did not result in a change in Qmax, when compared to men who continued therapy (See Figure 2). Interpretation of results Only a small number of studies were found on the effect of (dis)continuation of α-blocker use, and only short-term outcomes are reported. The methodological quality of these studies was generally poor, especially with respect to selection, randomisation and blinding. Mean difference in symptom scores was 3.65 and 3.25 at 3 and 6 months, respectively. This difference is around the effect that patients may note as 'slight change'. Differences in Qmax were noted in men who discontinued α-blocker monotherapy, but not in those on combination therapy. Concluding message Discontinuation of α-blocker therapy results in a slight symptom deterioration, when compared to continuation of treatment. This supports both the Dutch GP guideline Male LUTS [3], as well as the EAU guideline Treatment of Non-neurogenic Male LUTS [1]. We believe, however, that strong conclusions cannot be drawn, because only a few studies of generally poor methodological quality were available, reporting on short-term outcomes only. (Level of Evidence 1a). (Table Presented).

This study compared the efficacy and safety of the cyclooxygenase-2 specific inhibitor celecoxib with the conventional non-steroidal anti-inflammatory drug diclofenac in the symptomatic treatment of viral pharyngitis. Adult patients from 27 study centers in Latin America were treated with oral doses of celecoxib 200 mg once daily or 200 mg twice daily, or diclofenac 75 mg twice daily for 5 days in a double-blind, randomized study. The primary efficacy assessment was ‘Throat Pain on Swallowing’ on day 3. In addition, secondary quality-of-life assessments were performed on days 3 and 5. All adverse events and treatment-emergent signs and symptoms were recorded. Data from 313 patients were evaluable for efficacy (105 celecoxib 200 mg once daily, 107 celecoxib 200 mg twice daily, 101 diclofenac 75 mg twice daily). The upper 95% confidence limits for the visual analog scale of ‘Throat Pain on Swallowing’ on day 3 for celecoxib 200 mg once daily relative to diclofenac 75 mg twice daily, and celecoxib 200 mg twice daily relative to diclofenac 75 mg twice daily were 9.26 and 7.83, respectively. All secondary efficacy and quality-of-life measures were clinically similar for the three treatment groups, and no statistically significant differences were detected. The incidences of treatment-emergent adverse events and withdrawals due to adverse events were similar for all groups, but numerically higher among patients taking diclofenac than celecoxib. More patients in the diclofenac group reported gastrointestinal complaints (7.3%) compared with those in the celecoxib groups (4.3% in the celecoxib 200 mg once-daily group and 3.4% in the celecoxib 200 mg twice-daily group). In conclusion, 5 days of treatment with celecoxib 200 mg once daily is as effective as diclofenac 75 mg twice daily in the symptomatic treatment of viral pharyngitis. Celecoxib 200 mg once daily is also as effective as celecoxib 200 mg twice daily in this condition.

Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.

Background: Current influenza vaccines mainly induce immune responses against viral membrane glycoproteins, which undergo continuous mutations through antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy is inconvenient and cost-inefficient. Moreover, poor protective effectiveness is observed when there is antigenic mismatch between vaccine strains and actual epidemic strains. This is especially of concern during a pandemic outbreak, when large populations are affected by the newly re-assorted viral strain derived from antigenic shift. Objectives: To design phase IIb studies to evaluate the safety, immunogenicity and cross-seasonal clinical efficacy of two universal influenza vaccines (Flu-v and M-001) targeting different conserved epitopes of influenza viruses. The tested epitopes are identified from the viral surface glycoproteins as well as the viral internal (structural) proteins. Moreover, these epitopes are consistently expressed on both influenza A and B viruses. Methods: In two separate trials, a total of 1500 healthy adults will be recruited from multiple centers in Europe and randomized to receive placebo or the tested influenza vaccines at low or high antigen doses through a double-blind procedure. Two parenteral administrations will be given with a 21 day interval. In one trial, additional administrations of pandemic influenza vaccine will be given 21 and 42 days after the second administration. Clinical symptom scores and adverse events (AEs) will be collected from AE diary card. Humoral and cellular immune correlates of protection will be assessed. The (severity of) incident RT-PCR-confirmed influenza infection will be recorded over two subsequent influenza seasons. Conclusions: Universal influenza vaccines are urgently needed to increase protection among vulnerable groups. Vaccine trial design needs to incorporate safety, correlates of protection and clinical efficacy.

In the present double-blind, randomised, parallel intervention study, the effects of the intake of galacto-oligosaccharides (GOS) on the gut microbiota of twelve healthy adult subjects (aged 18-45 years with a normal BMI (18-25 kg/m2)) receiving amoxicillin (AMX) treatment were determined. All the subjects were treated with AMX (375 mg; three times per d) for 5 d and given either GOS (n 6) or placebo (maltodextrin, n 6) (2·5 g; three times per d) during and 7 d after AMX treatment. Faecal samples were collected twice before starting the treatment and on days 2, 5, 8, 12, 19 and 26. Due to AMX treatment, a decrease in the abundance of Bifidobacterium spp., an overgrowth of Enterobacteriaceae, and a disruption of the metabolic activity of the microbiota (increase in succinate, monosaccharide and oligosaccharide levels in the faecal samples) were observed in both groups (P< 0·05). Positive effects of GOS intake were observed on the levels of bifidobacteria, although not found to be significant. Data revealed that the levels of bifidobacteria were higher upon GOS intake than upon placebo intake, especially after AMX treatment. The activity of bifidobacteria and subsequent cross-feeding activity of the microbiota upon GOS intake compared with those upon placebo intake were reflected by the significant increase in butyrate levels (P< 0·05) in the faecal samples after AMX treatment. Despite the small number of subjects, our findings confirm previous results obtained in vitro, namely that GOS intake supports the recovery of the beneficial bifidobacteria and, indirectly, the production of butyrate after AMX treatment. © 2014 The Authors. Chemicals/CAS: amoxicillin, 26787-78-0, 34642-77-8, 61336-70-7; maltodextrin, 9050-36-6; succinic acid, 110-15-6

Objective: Postoperative cognitive dysfunction (POCD) is a decrease on mental and memorial process that provides individual information and solving the problems. We aimed to review the effect of intraoperative mean blood pressure (MBP) on development of in geriatric patients diagnosed with hypertension. Material and Metod: Patients older than 65 years old, diagnosed with an American Society of Anesthesiologist (ASA) physical condition II-III and underwent elective surgery that continued at least one hour were included this prospective, randomized and double blinded study conducted between March 2012-October 2012. The patients were divided into two groups (Group H, diagnosed as hypertension; Group K, normotension). 1.5-2 mg kg-1 propofol and 0.08-0.1 mg kg-1 vecuronium were applied at anesthesia induction and desflurane and 0.1 mcg kg-1 min-1 remifentanil at anesthesia maintain. Intraoperative MBP was stabilized at limits ±20% of control measure and was recorded on minute 5, 15, 30, 45, 60, 90 and 120. Neuropsychological tests were applied preoperatively and repeated at postoperative day 1 and month 1. Results: 90 patients were included in the study but 81 of them (40 in Group H; 41 in Group K) completed. Preoperative MBPs were higher in Group H (110±15 vs 104±13, p0.05) at postoperative day 1 and as 15% in Group H and 19.5% Group K (6/40 vs 8/41, p>0.05). No correlation was found between POCD and values of MBPs. Conclusion: We conclude that intraoperative MBP is not a risk factor for development of POCD at short and intermediate period in non-cardiac geriatric surgical patients, when it was maintained within±20% compared to to preoperative control values. © 2015, Nobelmedicus. All Rights Reserved.

In the present double-blind, randomised, parallel intervention study, the effects of the intake of galacto-oligosaccharides (GOS) on the gut microbiota of twelve healthy adult subjects (aged 18–45 years with a normal BMI (18–25 kg/m2)) receiving amoxicillin (AMX) treatment were determined. All the subjects were treated with AMX (375 mg; three times per d) for 5 d and given either GOS (n 6) or placebo (maltodextrin, n 6) (2·5 g; three times per d) during and 7 d after AMX treatment. Faecal samples were collected twice before starting the treatment and on days 2, 5, 8, 12, 19 and 26. Due to AMX treatment, a decrease in the abundance of Bifidobacterium spp., an overgrowth of Enterobacteriaceae, and a disruption of the metabolic activity of the microbiota (increase in succinate, monosaccharide and oligosaccharide levels in the faecal samples) were observed in both groups (PPin vitro, namely that GOS intake supports the recovery of the beneficial bifidobacteria and, indirectly, the production of butyrate after AMX treatment.

BACKGROUND Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P

Purpose: To investigate the efficacy of bupivacaine-soaked spongostan in cesarean section wound for postoperative anxiety level, satisfaction and early postpartum depression rate. Methods: A total of 121 women, American Society of Anesthesiologists physical status I-II, scheduled to undergo general anesthesia and elective cesarean section were recruited and randomized into a study group (n = 61) or a control group (n = 60). In the spongostan group, bupivacaine-soaked spongostan was placed in the cesarean section wound. The control group did not receive spongostan, but only general postoperative care. Maternal health was assessed using a visual analog scale for satisfaction, a visual analog scale for anxiety and the Edinburgh Postpartum Depression Scale for postpartum depression. Also, first breast-feeding time, first mobilization time and opioid consumption were recorded and compared. Results: The anxiety level of the spongostan group was lower than that of the control group and the difference was statistically significant at all time intervals (1, 6, 12, 18, 24, 30, 36 and 48 h, p < 0.001, respectively). Postpartum depression rate again was significantly lower in the spongostan group both on postoperative day 2 and day 9 (p ≤ 0.01). All satisfaction scores were significantly higher in the spongostan group than in the control group (p < 0.001). Additionally, first breast-feeding and first mobilization times were significantly shorter and opioid consumption was lower in the spongostan group (p < 0.001). Conclusion: Placement of bupivacaine-soaked spongostan into the cesarean section wound resulted in decreased postoperative anxiety level and postpartum depression rate and increased satisfaction. © 2014 Springer-Verlag.

Objective: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled-release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain.Methods: In a double-blind, randomised, two-way crossover trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSG, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration-time curve (AUC)(0-12) (h), peak plasma concentration (C-max), time to reach C-max (t(max)), and C0 and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0-10 scale, while side effects and rescue medication were recorded.Results: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC(0-12 h), t(max) and C-max of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC(0-12 h) and C-max of M6G, and AUC(0-12 h), C-max, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the t(max) of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P = 0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed.Conclusion: The newly developed controled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain.

Purpose The efficacy and adverse effects of 0.25% apraclonidine on intraocular pressure (IOP) after Nd: YAG laser posterior capsulotomy were investigated, and the results were compared with placebo, 0.50% timolol maleate and 1% apraclonidine. Methods Eighty eyes were randomly assigned to four groups of 20 eyes. In a double-masked design, the groups were treated with placebo (group I), 0.50% timolol maleate (group 2), 1% apraclonidine (group 3), 0.25% apraclonidine (group 4) one hour before and five minutes after Nd:YAG laser posterior capsulotomy. IOP was measured by applanation tonometry 1 hour before (baseline IOP) and 1,3, 24 hours after capsulotomy. Results The average baseline IOP increased respectively 3.90 ± 5.35, 5.95 ± 5.32, 1.15 ± 3.20 mmHg in the first group 1, 3 and 24 hours post-treatment. There were significant differences between baseline IOP and 1 and 3 hours but not at 24 hours (p=0.004, p=0.001, p=0.13). IOP increased 0.40 ± 4.08, 0.75 ± 5.33, 0.80 ± 6.03 mmHg in the second group at the same times. The differences between the average baseline IOP and the 1, 3 and 24h measurement were not significant (p=0.83, p=0.65, p=0.93). In the third group, IOP decreased 3.70 ± 2.40, 3.30 ± 2.47, 2.65 ± 1.56 mmHg at the measurement times, with significant differences between the average baseline IOP and the 1, 3 and 24 hour measurements (p=0.001, p=0.0001, p=0.01). In the fourth group IOP increased 0.35 ± 3.32 mmHg at 1 hour, but decreased 1.25 ± 3.41, 0.90 ± 2.07 mmHg at 3 and 24 hours. The differences were not significant (p=0.94, p=0.16, p=0.08). When the 0.25% and 1% apraclonidine groups were compared, there were significant differences between the average IOP at 1 hour in both groups but not at 3 and 24 hours (p=0.01, p=0.17, p=0.21). Similarly, there were no significant differences between the average IOP at the same times when the 0.25% apraclonidine group was compared with the timolol group (p=0.30, p=0.08, p=0.16). Some systemic and local side effects were seen in the timolol and 1% apraclonidine groups, but none with 0.25% apraclonidine. Conclusions It was concluded that 0.25% apraclonidine is effective in preventing the early elevation of IOP after Nd:YAG laser posterior capsulotomy and may offer an alternative to 0.50% timolol maleate and 1% apraclonidine.

In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic postmenopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17β-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (−6%, P =.04), LDL cholesterol (−16%, P =.0001), and apoB (−11%, P =.001) levels decreased and HDL cholesterol (20%, P =.0001) and apoA-I (14%, P =.0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (−3%, P =.03), the cholesterol content of the LDL particles decreased (−5%, P =.006), triglyceride content increased (16%, P =.01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17β-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.

Objectives: To examine and compare the effects of massage and matrix rhythm therapy in young women on the peripheral blood circulation. Design: Randomized, double-blind, controlled trial. Setting: Pamukkale University in Denizli, Turkey. Patients: Fifteen healthy women age 19-23 years. Intervention: Matrix rhythm therapy was applied to the left lower extremity for a single 30-minute session. At least 1 week later, massage was applied to the left lower extremity for 30 minutes in a single session. The same physiotherapist applied both sessions. Outcome measures: The blood velocity (cm/s), artery diameter (mm), and blood flow (ml/min) of the popliteal and the posterior tibial arteries were measured with color Doppler ultrasonography. All images were evaluated by the same radiologist. Results: After matrix rhythm therapy and massage application, blood velocity, artery diameter, and blood flow in arteries increased. However, matrix rhythm therapy caused a more prominent increase in the amount of blood flow in the popliteal and in the posterior tibial artery than did massage. After matrix rhythm therapy application, the average increases in the blood flow rates in the popliteal and the posterior tibial arteries were 25.29%±16.55% and 34.33%±15.66%, respectively; after the massage, the increases were 17.84%±17.23% and 16.07%±10.28%, respectively. Conclusion: Matrix rhythm therapy and massage increased peripheral blood flow in young women. Matrix rhythm therapy method resulted in more prominent increases. © Mary Ann Liebert, Inc.

This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin (“paromomycin alone”) and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was 2,180 ± 2,621 ng · h/ml (mean ± standard deviation [SD]) for the paromomycin-alone group and 975.6 ± 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC 0–24 and maximum concentration of drug ( C max ) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC 0–24 was 8,575 ± 7,268 ng · h/ml and the C max was 1,000 ± 750 ng/ml, compared with 6,037 ± 3,956 ng · h/ml and 660 ± 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences ( P ≥ 0.05) in the AUC 0–24 or C max were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% ± 6.26% and 9.68% ± 6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.)

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:28:36Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:32:19Z : No. of bitstreams: 1 2-s2.0-84875843214.pdf: 1017479 bytes, checksum: 49dd5f844839e41ddb848ef72062cf93 (MD5) Made available in DSpace on 2014-05-27T11:28:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-03-01 The authors report a case of bilateral Tinea nigra plantaris treated through a double-blind study with the topical antifungal agents Isoconazole and Terbinafine. The objective of the study was to clinically compare the efficacy of these two topical antifungal agents on days 10, 20 and 30 of the treatment. No significant clinical differences were found, as all the plantar lesions regressed completely by the end of the treatment. Our conclusion was that in the case reported, the topical antifungal agents Isoconazole and Terbinafine demonstrated identical efficacy as a clinical cure. We also suggest the inclusion of injuries caused by arthropods of the Diplopoda Class in the differential diagnosis of Tinea nigra plantaris, due to the persistent acral hyperpigmentation. University of Vale, Itajaí/Univali, SC Pharmaceuticals-Biochemistry from the University of Vale, Itajaí/Univali, SC Univ. Estadual Paulista, SP

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:28:10Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:48:06Z : No. of bitstreams: 1 2-s2.0-84872204045.pdf: 559294 bytes, checksum: c00bda75a01a0ae1686efb971eaf1f48 (MD5) Made available in DSpace on 2014-05-27T11:28:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-01-16 Background: Hepatic encephalopathy (HE) is a severe complication in patients with hepatic cirrhosis, which causes numerous hospital admissions and deaths. Antibiotics are the best options in HE treatment, but head-to-head comparisons between these drugs are scarce. Erythromycin combines the antimicrobial effect and prokinetic properties in the same drug, but it has never been used in HE treatment. Our aim was to evaluate the efficacy of erythromycin as an HE treatment.Methods: We achieved a randomized controlled trial of adult patients with HE and hepatic cirrhosis admitted in our hospital. After randomization, the subjects received either erythromycin 250 mg or neomycin 1 g orally QID until hospital discharge or prescription of another antibiotic. All subjects were blindly evaluated every day towards quantifying clinical, neuropsychometric, hepatic and renal exams. Statistical analysis was employed to compare the groups and correlate the variables with hospitalization duration.Results: 30 patients were evaluated (15 treated with each drug). At hospital admission, the groups were homogeneous, but the erythromycin group subjects achieved a shorter hospitalization stay (p = 0.032) and a more expressive reduction in alanine aminotranspherase levels (p = 0.026). Hospitalization duration was positively correlated with C reactive protein levels measured previous to (p = 0.015) and after treatment (p = 0.01).Conclusions: In the sample evaluated erythromycin was associated with significant reductions in hospital stay and in alanine aminotranspherase values. Hospitalization time was positive correlated with C reactive protein levels measured before and after the treatments. © 2013 Romeiro et al.; licensee BioMed Central Ltd. Department of Internal Medicine Faculdade de Medicina de Botucatu UNESP - Universidade Estadual Paulista, Botucatu Biological and Health Sciences Institute Campus Médio Araguaia UFMT -Universidade Federal do Mato Grosso, Barra do Garças Health Sciences Center UNCISAL - Universidade Estadual de Ciências da Saúde de Alagoas, Maceió Department of Physics and Biophysics Instituto de Biociências de Botucatu UNESP - Universidade Estadual Paulista, Botucatu Department of Internal Medicine - Botucatu Medical School UNESP- Universidade Estadual Paulista, Distrito de Rubião Jr. s/n zip code 18 608 917, Botucatu, São Paulo Department of Internal Medicine Faculdade de Medicina de Botucatu UNESP - Universidade Estadual Paulista, Botucatu Department of Physics and Biophysics Instituto de Biociências de Botucatu UNESP - Universidade Estadual Paulista, Botucatu Department of Internal Medicine - Botucatu Medical School UNESP- Universidade Estadual Paulista, Distrito de Rubião Jr. s/n zip code 18 608 917, Botucatu, São Paulo

Background: Children with cow's milk allergy (CMA) need a cow's milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children. Methods. All children with suspected CMA under our care (Oct'05 - Jun'09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the 'lowest observed adverse effect level' (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child. Results: 116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged ≤ 12 months in our study group have a higher cumulative distribution of MED than older children. Conclusions: Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers. © 2013 Dambacher et al; licensee BioMed Central Ltd.

OBJECTIVE: To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of proton pump inhibitors (PPIs). METHODS: CYP2C19*2,*3,*4, *5,*6 and*17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2*2/*17 and 1*2/*2 were included in a randomized investigator-blinded crossover study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-hour pH monitoring was performed on days 0, 1 and 5 of oral dosing. RESULTS: A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at days 1 and 5. CONCLUSIONS: Esomeprazole provides acid inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype.

Peppermint oil (PO) has been shown to reduce abdominal pain in patients with Irritable Bowel Syndrome (IBS). Menthol, the main constituent of PO, induces intestinal smooth muscle relaxation and desensitizes nociceptive nerve afferents. Enteric-coated (EC PO) capsules that release PO mainly in the small intestine are commercially available. In order to increase local, colonic anti-nociception, a colon-targeted-delivery peppermint oil (CTD PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of both formulations and to evaluate safety and tolerability. In this randomized, double blind, placebo-controlled study, subjects received 182 mg of either EC PO or CTD PO in a crossover design with ≥14 days washout period in between. After baseline measurements and drug administration, blood samples to determine menthol-glucuronide (menthol is rapidly metabolized to menthol-glucuronide), blood pressure and heart rate measurements were collected at several time points. Side effects were evaluated using questionnaires. The primary outcome was Tmax: time to reach peak menthol-glucuronide concentration in plasma. Eight healthy volunteers (50% female), aged between 20 and 65 years (median 22.2, IQR 20.8-28.8) were included. The Tmax of CTD PO was significantly longer (in all volunteers) compared to EC PO with a median (IQR) of 360 (360-405) vs 180 (120-180) min, respectively, p

Background: Noninferiority trials are conducted to investigate whether the efficacy of the test drug is not worse than the active comparator based on a predefined noninferiority margin. There is no consensus on a preferred method for defining the noninferiority margin, and previous studies showed that the rationale for its choice is often not reported. Objectives: To investigate how the noninferiority margin is defined in the published literature, and whether its reporting has changed over time. Methods: A systematic PubMed search was conducted for all published randomized, double-blind, noninferiority trials from January 1, 1966, to February 6, 2015. The time trend of defining the margin since the first published noninferiority trial was analyzed using Poisson regression analysis. The impact of the 2010 US Food and Drug Administration (FDA) draft guidance for noninferiority clinical trials on the choice of the margin, and the impact of the extension of the Consolidated Standards of Reporting Trials (CONSORT) Statement on the reporting of noninferiority margins were analyzed using generalized estimating equations to account for the clustering of the margins within articles. Results: We included 275 articles, which account for 283 trials and 328 noninferiority margins. The rationale for the choice of the margin was not reported for 191 margins (58.2%). The under-reporting of the rationale for the choice of the margin has not improved neither since the first published noninferiority trial in this review in 2000 (P=0.86), nor since the publication of the extension of the CONSORT Statement in 2006 (P=0.96). The other 137 margins were mainly defined based on the historical evidence of the active comparator (n=56) or subjectively based on expert opinions (n=46). There was a 3.5-fold increase in the use of the fixed-margin method, the recommended method by the FDA to define the margin, after the publication of the FDA draft guidance (from 2.6% to 9%, P=0.04). Conclusions: Margins in noninferiority trials are poorly reported and this has not improved over recent years. Authors, reviewers, and editors need to take notice of reporting this critical information to allow for better judgment of noninferiority trials.

Summary Background The rate of gastric emptying (GE) and subsequent release of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are critical determinants of postprandial glycaemia in health and type 2 diabetes. Slowing of GE may be the dominant mechanism by which exogenous GLP-1, and some GLP-1 analogues, improve postprandial glycaemia. Aim To determine the effect of sitagliptin on GE in healthy subjects, and the relationships between GE with glycaemia and incretin hormone secretion. Methods Fifteen volunteers (22.8 ± 0.7 years) were studied on two occasions following 2 days dosing with sitagliptin (100 mg/day) or placebo. GE (scintigraphy), glycaemia and plasma GLP-1 and GIP (total and intact), insulin and glucagon were measured for 240 min following a mashed potato meal (1808 kJ). Results There was no difference in GE between sitgaliptin and placebo [50% emptying time (T50): P = 0.4]. Mean blood glucose was slightly less (P = 0.02) on sitagliptin. Sitagliptin reduced plasma glucagon between 75 and 120 min (P

Dopamine agonists such as pramipexole (PPX) have first been proposed as adjunctive treatment to levodopa (L-DOPA) for patients with Parkinson’s disease (PD) and then as a monotherapy alternative to alleviate dyskinesia. Treatment with PPX has overall been associated with improvement in parkinsonian symptoms. Although the majority of placebo-controlled studies demonstrated that dyskinesia was more prevalent in the PPX compared to the placebo groups, some studies did not detect any dyskinesia as a side effect of this medication. PPX was consistently associated with lower risk for developing dyskinesia compared to L-DOPA. Moreover, the presence of these symptoms in the placebo groups suggests involvement of non-PPX-related factors for developing dyskinesia. It is suggested that future research should aim at ascertaining whether cotherapy with L-DOPA, PPX dosage, and other patient characteristics are contributory factors for the development of PPX-related dyskinesia in patients with PD.

Aim. The aim of this study was to assess the efficacy of continuous low-pressure suction drainage compared with closed high-pressure suction following total knee arthroplasty. Background. Closed wound drainage systems are used in surgical interventions to reduce the incidence of haematomas, promote wound healing and reduce infections. However, evidence shows that using a closed wound drainage system can increase transfusion requirements. Data sources. A randomized, double-blind and parallel controlled trial was performed. Adult knee replacement patients recruited between May 2006 and March 2007 were assigned to receive low-pressure suction of 50mmHg (experimental drainage) or high-pressure suction of 700mmHg (comparator drainage). Methods. The primary outcome was total blood loss after surgery. Secondary outcomes were incidence of transfusion, complications and mortality. Statistical analysis was based on an intention-to-treat approach. Linear regression was performed to account for factors that could influence blood loss. Results. A total of 169 patients were included. Mean age was 73 (±6) years, 128 women and 41 men. A total of 84 patients were randomized to the experimental drainage and 85 to the comparator drainage. Analysis showed a total postoperative blood loss of 541·8mL in the experimental group and 524·4mL in the comparator group (P=0·734). The only factor that showed an association with blood loss was the length of surgery. Linear regression did not show differences between the groups. Conclusion. Continuous low-pressure suction of 50mmHg is not more effective than the higher aspiration pressure system to diminish the blood loss in total knee arthroplasty. The results do not support any change in current nursing practice relating to the use of this drain system. © 2011 Blackwell Publishing Ltd.

Objective: To evaluate the efficacy and safety of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes. Materials and Methods: A 16-week, randomized, double-blind, placebo-controlled, multinational study evaluating colesevelam in participants with primary hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] level > 100 mg/dL) and prediabetes (fasting plasma glucose level > 110 to less than 125 mg/dL, or 2-hour postload glucose level > 140 to less than 200 mg/dL during an oral glucose tolerance test) was conducted between January 14, 2008 and April 3, 2009. Participants were randomized 1:1 to colesevelam 3.75 g/day or placebo. The primary efficacy endpoint was mean change from baseline in LDL-C level with colesevelam compared with placebo. Participants who self-identifed as Hispanic during enrollment were included in this exploratory analysis evaluating the effcacy of colesevelam in Hispanics with primary hyperlipidemia and prediabetes. Results: From a total of 216 subjects with primary hyperlipidemia and prediabetes, 153 Hispanics were included in this post hoc analysis; 77 subjects were randomized to colesevelam and 76 subjects were randomized to placebo. At week 16, LDL-C levels were significantly reduced with colesevelam compared with placebo (mean treatment difference, -19.4%; P less than 0.0001). Achievement of LDL-C level less than 100 mg/dL was more frequent with colesevelam than with placebo (27% vs 11%; P = 0.002). In addition, significant mean reductions in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B levels (P less than 0.0002 for all), and a significant median increase in triglyceride levels (P = 0.003), were seen with colesevelam compared with placebo. At study end, there was a significant mean reduction in glycated hemoglobin levels and median reduction in fasting plasma glucose levels with colesevelam compared with placebo (P less than 0.02 for both). A fasting plasma glucose level less than 100 mg/dL was achieved in 44% of colesevelam recipients compared with 23% of placebo recipients (P less than 0.05). Overall, colesevelam was well tolerated. Conclusion: Colesevelam may be a treatment option for Hispanic subjects with primary hyperlipidemia and prediabetes, mainly to reduce LDL-C levels, with added beneficial effect on glucose levels. © Postgraduate Medicine.

Rationale Quantitative analysis of electroencephalographic signals (EEG) and their interpretation constitute a helpful tool in the assessment of the bioavailability of psychoactive drugs in the brain. Furthermore, psychotropic drug groups have typical signatures which relate biochemical mechanisms with specific EEG changes. Objectives To analyze the pharmacological effect of a dose of alprazolam on the connectivity of the brain during wakefulness by means of linear and nonlinear approaches. Methods EEG signals were recorded after alprazolam administration in a placebo-controlled crossover clinical trial. Nonlinear couplings assessed by means of corrected cross-conditional entropy were compared to linear couplings measured with the classical magnitude squared coherence. Results Linear variables evidenced a statistically significant drug-induced decrease, whereas nonlinear variables showed significant increases. All changes were highly correlated to drug plasma concentrations. The spatial distribution of the observed connectivity changes clearly differed from a previous study: changes before and after the maximum drug effect were mainly observed over the anterior half of the scalp. Additionally, a new variable with very low computational cost was defined to evaluate nonlinear coupling. This is particularly interesting when all pairs of EEG channels are assessed as in this study. Conclusions Results showed that alprazolam induced changes in terms of uncoupling between regions of the scalp, with opposite trends depending on the variables: decrease in linear ones and increase in nonlinear features. Maps provided consistent information about the way brain changed in terms of connectivity being definitely necessary to evaluate separately linear and nonlinear interactions.

Background: The bile acid sequestrant colesevelam has been shown to significantly reduce low-density lipoprotein particle concentration (LDL-P) in adults with primary hyperlipidemia or type 2 diabetes mellitus (T2DM). Objective: To assess the effect of initial combination therapy with metformin plus colesevelam on lipoprotein particles in patients with T2DM (secondary efficacy variables). Methods: This 16-week, randomized, double-blind, placebo-controlled study enrolled drug-naïve adults with T2DM, glycated hemoglobin 6.5%-10.0%, low-density lipoprotein cholesterol (LDL-C) ?100 mg/dL, and triglycerides less than 500 mg/dL. Patients were randomized 1:1 to either open-label metformin (titrated to 1700 mg/day) plus double-blind colesevelam 3.75 g/day or open-label metformin plus double-blind placebo. Results: In total, 286 patients were randomized (metformin plus colesevelam [n = 145]; metformin plus placebo [n = 141]). Compared with metformin plus placebo, the combination of metformin plus colesevelam significantly reduced LDL-C (mean treatment difference: -16.3%), total cholesterol (-6.1%), non-high-density lipoprotein cholesterol (-8.3%), and apolipoprotein (apo) B (-8.0%) and significantly increased triglycerides (median treatment difference: 18.6%) and apoA-I (mean treatment difference: 4.4%; all P less than .001). Metformin plus colesevelam significantly reduced total LDL-P (mean treatment difference: absolute change -186 nmol/L [percent change -11.7%]; both P less than .0001), largely attributable to a reduction in small LDL-P, and increased total very-low-density lipoprotein particle concentration (mean treatment difference: absolute change 6 nmol/L; P =.03 [percent change 8.3%; P =.06]) and total high-density lipoprotein particle concentration (1.0 ?mol/L; P =.03 [4.5%; P =.01]) versus metformin plus placebo. Conclusion: Initial combination therapy with metformin plus colesevelam improved the atherogenic lipoprotein profile of patients with early T2DM by significantly reducing LDL-P. ClinicalTrials.gov identifier: NCT00570739. © 2012 National Lipid Association. All rights reserved.

Objective To compare the effects of metoclopramide infusion in emergency department (ED) patients complaining of nausea to determine the changes in its therapeutic effect and prevention of side effects such as akathisia and sedation. Methods A prospective, randomised, double blind trial, from 1 March 2007 to 1 May 2008 in the ED of Pamukkale University Faculty of Medicine. Patients with moderate to severe nausea were randomised and divided into two groups: group 1 received 10 mg metoclopramide as a slow intravenous infusion over 15 min plus placebo (SIG); group 2 received 10 mg metoclopramide as an intravenous bolus infusion over 2 min plus placebo (BIG). The whole procedure was observed, and nausea scores, akathisia and vital changes were recorded. Results 140 patients suffering from moderate to severe nausea in the ED were included in the study. There was no significant difference between the groups in terms of mean nausea scores during follow-up (p=0.97). A significant difference in akathisia incidence was observed between the groups (18 (26.1%) in the BIG and 5 (7%) in the SIG) (p=0.002). There was also a significant difference in sedation incidence between the groups (19 (27.5%) in the BIG and 10 (14.5%) in the SIG) (p=0.05). Conclusion Even though slowing the rate of infusion of metoclopramide does not affect the rate of improvement in nausea, it may be an effective strategy for reducing the incidence of akathisia and sedation in patients with nausea.

Objective To determine the analgesic efficacy and safety of intravenous single-dose paracetamol versus morphine in patients presenting to the emergency department with renal colic. Methods A randomised double-blind study was performed to compare the efficacy of intravenous paracetamol (1 g) and 0.1 mg/kg morphine in patients with renal colic. The efficacy of the study drugs was measured by a visual analogue scale and a verbal rating scale at baseline and after 15 and 30 min. The adverse effects and need for rescue medication (1 μg/kg intravenous fentanyl) were also recorded at the end of the study. Results 133 patients were eligible for enrolment in the study, with 73 patients included in the final analysis (38 in the paracetamol group and 35 in the morphine group). The mean±SD age of the subjects was 30.2±8.6 years and 51 (70%) were men. The mean reduction in scores at 30 min after study drug administration was 63.7 mm (95% CI 57 to 71) for paracetamol and 56.6 mm (95% CI 48 to 65) for morphine. The difference between pain reduction scores for the two groups at 30 min was 7.1 mm (95% CI -18 to 4), demonstrating no statistical or clinical significance. Two adverse events (5.3%) were recorded in the paracetamol group and five (14.3%) in the morphine group (difference 9%, 95% CI -7% to 26%). Conclusion Intravenous paracetamol is effective in treating patients presenting with renal colic to the emergency department. Clinical trials registration no ClinicalTrials.gov ID number NCT01318187.

Background Epidemiological studies have suggested the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular health, but only limited data are available describing n-3 PUFA regulated pathways in humans. The aim of this study was to investigate the effects of n-3 PUFA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. Methods Differentially expressed genes were detected after four hours, one week and twelve weeks of supplementation with either fish oil (FO) or corn oil in normo- and dyslipidemic men using whole genome microarrays. Results Independent of the oil, a significantly higher number of genes was regulated in dyslipidemic subjects compared to normolipidemic subjects. Pathway analyses discovered metabolisms dominantly affected by FO after twelve weeks of supplementation, including the lipid metabolism, immune system and cardiovascular diseases. Several pro-inflammatory genes, in particular, were down-regulated in dyslipidemic subjects, indicating the immune-modulatory and anti-inflammatory capability of FO and its bioactive FAs, eicosapentaenoic acid and docosahexaenoic acid. Conclusions This is the first study showing significant differences in gene expression profiles between normo- and dyslipidemic men after FO supplementation. Further studies need to clarify the exact role of n-3 PUFAs in pathways and metabolisms which were identified as being regulated after FO supplementation in this study. Trial registration ClinicalTrials.gov (ID: NCT01089231)

Objective: To evaluate initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with type 2 diabetes mellitus. Research Design and Methods: Patients self-identifed as Hispanic from a previous study were included in this exploratory post hoc analysis. Patients were randomized to metformin plus colesevelam or metformin plus placebo. The primary effcacy parameter was the mean change in glycated hemoglobin (HbA1c) levels from baseline. Results: Metformin plus colesevelam had a greater mean HbA1c reduction (-1.2 ± 0.1%) than metformin plus placebo (-0.8 ± 0.1%; P = 0.001) from mean baselines of 7.7% and 7.6%, respectively. Low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein (apo) B levels were also reduced (P and lt; 0.0001 for all), while triglyceride (P and lt; 0.0001) and apoA-I (P and lt; 0.05) levels were increased with metformin plus colesevelam treatment compared with metformin plus placebo. With metformin plus colesevelam versus metformin plus placebo, more patients achieved an HbA1c of, 7.0% (75% vs 56%) and LDL-C of, 100 mg/dL (49% vs 14%; both P, 0.05). Conclusion: Metformin plus colesevelam may be an effective initial treatment option for Hispanic patients with early type 2 diabetes mellitus. © Postgraduate Medicine.

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of the 7-day lower-dose (5, 10 and 20?gh) buprenorphine transdermal patch (BuTrans®, Norspan®) in the management of chronic non-malignant pain, with a focus on European labelling for the drug. Buprenorphine is a semi-synthetic opioid analgesic that acts primarily as a partial agonist at the mu opioid receptor. The transdermal formulation provides continuous delivery of buprenorphine, resulting in relatively consistent plasma drug concentrations throughout the 7-day dosing interval.The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip andor knee has been demonstrated in several randomized controlled trials, which have shown the formulation to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol tablets, noninferior to codeine plus paracetamol (acetaminophen) combination tablets (when transdermal buprenorphine was used together with regularly scheduled oral paracetamol) and generally superior to a matching transdermal placebo patch. Transdermal buprenorphine was significantly more effective than placebo in reducing chronic low back pain of at least moderate severity in two randomized, double-blind, crossover trials. Other clinical trials, including a randomized, double-blind, maintenance-of-analgesia study, have also demonstrated the analgesic efficacy of transdermal buprenorphine in patients with chronic non-malignant pain of various causes.In general, serious adverse events with transdermal buprenorphine are similar to those for other opioid analgesics. Transdermal buprenorphine has a ceiling effect for respiratory depression, and the main risk is when it is combined with other CNS depressants. The most frequently reported adverse events with transdermal buprenorphine are headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus, erythema, application site pruritus and application site reactions. Transdermal buprenorphine was better tolerated than sublingual buprenorphine in a 7-week, randomized, double-blind trial in patients with osteoarthritis pain. Nevertheless, as with other opioids, persistence with transdermal buprenorphine therapy is difficult for many patients because of adverse events or other reasons.Thus, transdermal buprenorphine has generally demonstrated good efficacy and tolerability in clinical trials in chronic non-malignant pain, providing effective background analgesia as part of pain management strategies for patients with osteoarthritis, low back pain and other persistent pain syndromes of at least moderate severity. It also has favourable pharmacodynamic and pharmacokinetic properties, which have beneficial clinical implications, most notably the convenience of once-weekly administration and no need for dosage adjustments in the elderly or those with compromised renal function, making it an opioid of choice in these patients, and a useful therapeutic option overall in the management of chronic non-malignant pain. © 2011 Adis Data Information BV. All rights reserved.

Background Patellar tendinopathy is a chronic overuse injury of the patellar tendon that is especially prevalent in people who are involved in jumping activities. Extracorporeal Shockwave Therapy is a relatively new treatment modality for tendinopathies. It seems to be a safe and promising part of the rehabilitation program for patellar tendinopathy. Extracorporeal Shockwave Therapy originally used focused shockwaves. Several years ago a new kind of shockwave therapy was introduced: radial shockwave therapy. Studies that investigate the effectiveness of radial shockwave therapy as treatment for patellar tendinopathy are scarce. Therefore the aim of this study is to compare the effectiveness of focussed shockwave therapy and radial shockwave therapy as treatments for patellar tendinopathy. Methods/design The TOPSHOCK study (Tendinopathy Of Patella SHOCKwave) is a two-armed randomised controlled trial in which the effectiveness of focussed shockwave therapy and radial shockwave therapy are directly compared. Outcome assessors and patients are blinded as to which treatment is given. Patients undergo three sessions of either focused shockwave therapy or radial shockwave therapy at 1-week intervals, both in combination with eccentric decline squat training. Follow-up measurements are scheduled just before treatments 2 and 3, and 1, 4, 7 and 12 weeks after the final treatment. The main outcome measure is the Dutch VISA-P questionnaire, which asks for pain, function and sports participation in subjects with patellar tendinopathy. Secondary outcome measures are pain determined with a VAS during ADL, sports and decline squats, rating of subjective improvement and overall satisfaction with the treatment. Patients will also record their sports activities, pain during and after these activities, and concurrent medical treatment on a weekly basis in a web-based diary. Results will be analysed according to the intention-to-treat principle. Discussion The TOPSHOCK study is the first randomised controlled trial that directly compares the effectiveness of focused shockwave therapy and radial shockwave therapy, both in combination with eccentric decline squat training, for treating patellar tendinopathy. Trial registration Trial registration number NTR2774.