Search

Background/Objectives: Nephrolithiasis (kidney stones) is a frequently occurring urologic condition resulting in significant patient morbidity and healthcare costs. Despite the higher prevalence of metabolic risk factors for nephrolithiasis among Black women, there have been few epidemiologic studies of kidney stones focusing on this group. Methods: We describe demographic and health characteristics, diagnostics, and metabolic profiles of US Black women with self-reported kidney stones. The women were participants in the Black Women's Health Study (BWHS), a large prospective cohort of US Black women (median age 38 years) begun in 1995. Results: Among the 2750 BWHS participants who completed an online supplemental questionnaire assessing urologic health, 201 women reported nephrolithiasis. Of this number, 62% had completed ≥ 16 years of education, and 82% reported access to health care. Overall, 39% reported experiencing ≥ 2 stones in their lifetime, and 29% required surgery to treat the condition. Thirty-two percent reported having completed a metabolic evaluation, while 70% had undergone a CT scan to diagnose nephrolithiasis. The frequency of metabolic evaluation increased with the number of metabolic components reported: 3% (0 components) to 43% (3-4 components). Conclusions: Our findings are consistent with reports of lower rates of metabolic evaluation among Black patients despite their having multiple risk factors for nephrolithiasis. Further study is needed to identify the barriers and facilitators of metabolic and diagnostic workup of nephrolithiasis in Black women.

Self-compassion in healthcare professionals (HCPs) is under-researched and undervalued. Promoting self-compassion within healthcare could have far-reaching benefits. This research study explores the experience of four NHS HCPs receiving a single short self-compassion training, with recommended at-home practices completed over 4 weeks. Subsequently, semi-structured interviews gathered information about their experience, resultant wellbeing and any impact on colleagues and patients. The main themes emerging from analysis of the interviews were motivation, permission and prioritisation. The motivation to practise self-compassion, and share this learning resulted from improved understanding of its potential benefits. Permission ties in with the notion of common humanity in self-compassion and its impact on negative self-talk and negative attitudes to self-compassion in a workplace. Prioritisation acknowledges the challenges for HCPs of investing time in self-compassion practice despite overstretched HCP workloads. Further consideration of these themes may help to better target any future research into strategies for enabling self-compassion among HCPs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A surrogate is commonly used for process validations. The industry often uses the target log cycle reduction for the test (LCR Test ) microorganism (surrogate) to be equal to the desired log cycle reduction for the target (LCR Target ) microorganism (pathogen). When the surrogate is too conservative with far greater resistance than the pathogen, the food may be overprocessed with quality and cost consequences. In aseptic processing, the Institute for Thermal Processing Specialists recommends using relative resistance (D Target )/(D Test ) to calculate LCR Test (product of LCR Target and relative resistance). This method uses the mean values of D Target and D Test and does not consider the estimating variability. We defined kill ratio (KR) as the inverse of relative resistance.The industry uses an extremely conservative KR of 1 in the validation of food processes for low-moisture foods, which ensures an adequate reduction of LCR Test , but can result in quality degradation. This study suggests an approach based on bootstrap sampling to determine conservative KR, leading to practical recommendations considering experimental and biological variability in food matrices. Previously collected thermal inactivation kinetics data of Salmonella spp. (target organism) and Enterococcus faecium (test organism) in Non-Fat Dried Milk (NFDM) and Whole Milk Powder (WMP) at 85, 90, and 95°C were used to calculate the mean KR. Bootstrapping was performed on mean inactivation rates to get a distribution of 1000 bootstrap KR values for each of the treatments. Based on minimum temperatures used in the industrial process and acceptable level of risk (e.g., 1, 5, or 10% of samples that would not achieve LCR Test ), a conservative KR value can be estimated. Consistently, KR increased with temperature and KR for WMP was higher than NFDM. Food industries may use this framework based on the minimum processing temperature and acceptable level of risk for process validations to minimize quality degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Radiofrequency (RF) heating has been extensively studied for pasteurizing low-moisture foods. Currently, bulk foods are treated with radiofrequency; potential cross-contamination may occur during packaging of pasteurized products. As an alternative, in-package RF processing was evaluated for Salmonella inactivation on black peppercorns and dried basil leaves and prevention of cross-contamination during storage postprocessing. In-package steaming refers to the process in which the samples were heated in a steam vent package to generate and retain steam during the treatment. This treatment achieved good heating uniformity which could be because of the circulation of steam within the package. One-way steam vent allowed the release of excess steam once a threshold pressure was achieved and later returned to its original position to seal the package, when the RF energy was removed. In-package RF steaming of black peppercorns and dried basil leaves for 135 s and 40 s, respectively, resulted in more than 5 log reduction of Salmonella. The steam vent remained stable posttreatment and properly sealed the package to protect the product from any external contamination. These results indicate that the use of steam vent could effectively pasteurize black peppercorns and dried basil leaves could be beneficial in preventing the potential cross-contamination postprocessing., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nephrolithiasis is a common urologic condition and a significant source of patient morbidity and healthcare expenditure. There are few epidemiologic studies of kidney stones focusing exclusively on Black women. We retrospectively assessed the prevalence and correlates of self-reported kidney stones within the Black Women's Health Study (BWHS). Descriptive statistics and multivariable logistic regression models were used to explore factors associated with nephrolithiasis. As of the 2005 follow-up questionnaire, a cumulative total of 1063 women among 43,178 reported ever being diagnosed with kidney stones for a prevalence of 2.64%. Women with a history of nephrolithiasis were older, slightly heavier, and were more likely to have a comorbid condition (e.g., type-2 diabetes, gallstones), drink alcohol, and consume a Western-style diet. A history of gallstone disease was associated with an odds ratio (OR) of 3.59 (95% confidence interval (CI) 3.09-4.17). The OR for consuming ≥ 7 alcoholic beverages/week, compared to none was 0.61 (0.39-0.94), while the OR for high adherence to the Western diet, compared to low adherence was 1.53 (1.23-1.90). Our findings are consistent with previous studies of primarily white populations relating lifestyle-associated risk factors with nephrolithiasis. Despite their lower prevalence of kidney stones, it is important to focus on vulnerable populations such as Black women given their disproportionate burden of metabolic conditions (e.g., obesity, diabetes) related to kidney stone disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Inhibiting sodium-glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters., Research Design and Methods: Using a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h., Results: Changes from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed., Conclusions: Changes from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069)., (© 2022 by the American Diabetes Association.)

Fine ground black pepper generally consumed as a seasoning without any further processing has been associated with Salmonella enterica outbreaks. Thermal inactivation kinetics data is necessary to develop a pasteurization process for fine ground black pepper. This study investigates the influence of temperature and water activity on thermal inactivation kinetics of Salmonella in fine ground black pepper. It also assesses the suitability of Enterococcus faecium as a surrogate for Salmonella. Fine ground black pepper of varying water activities, a w (0.40, 0.55, 0.70) was subjected to isothermal treatments at different temperatures (65-80 °C) for five equidistant time points with intervals ranging from 18 s to 250 min. The survival data were used to fit two primary models (log-linear and Weibull) and two secondary models (response surface and Modified Bigelow). Results indicated that among the two primary models, the Weibull model explained the thermal inactivation kinetics better with lower RMSE (0.24 - 0.56 log CFU/g) and AIC c values at all a w and temperatures. Water activity and treatment temperature significantly enhanced the thermal inactivation of Salmonella. E. faecium NRRL B-2354 was found to be a suitable surrogate for Salmonella in fine ground black pepper at all tested treatment conditions. The developed modified Bigelow model based on the Weibull model could be applied to predict the inactivation kinetics of Salmonella in black pepper and would benefit the spice industry in identifying process parameters for thermal pasteurization of fine ground black pepper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. ( S )-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) ( 34 ) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 ( 34 ) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 ( 34 ) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).

Introduction: To compare pelvic ultrasound (PUS) and transrectal ultrasound (TRUS) to magnetic resonance imaging (MRI) in the estimation of prostate size., Materials and Methods: After IRB approval, we performed a single-center, retrospective study of 91 patients who had prostate sizing between August, 2013 and June, 2017. Correlation, reliability, and agreement between PUS, TRUS, and MRI were calculated through the Pearson coefficient, intraclass correlation coefficient, and Bland-Altman analysis, respectively. Data was stratified by prostate size, body mass index, and time between imaging acquisition., Results: A total of 91 patients underwent all three imaging methods. Median age was 64, median body mass index (BMI) was 27 kg/m2, and median PSA value prior to PUS was 7.1 ng/mL. Pearson coefficient for MRI versus TRUS and MRI versus PUS was 0.90 and 0.87, respectively. Intraclass correlation coefficient was 0.90 (0.87-0.93) comparing all three modalities. BA analysis for MRI versus TRUS and MRI versus PUS showed that for prostates ≤ 50 cc, greater than 79% of the data fell within limits of agreement. Percentages decreased with increasing prostate size to 46% and 41% for prostates > 50 cc and ≤ 80 cc and to 28% and 25% for prostates > 80 cc for MRI versus TRUS and MRI versus PUS, respectively., Conclusions: MRI may be considered clinically interchangeable with TRUS and PUS for prostate sizing at prostate volumes ≤ 50 cc. For larger prostates and when minor changes in prostate size would drastically alter surgical management, cross-sectional imaging should be considered.

Introduction: Ureteroscopy and laser lithotripsy is a common treatment option for upper urinary tract calculi. Currently, ureteral stents are placed after uncomplicated ureteroscopy for up to 1 week, but the optimal length of placement is not well defined. Ureteral stents are associated with significant morbidity, particularly stent discomfort. This study aims to determine differences in postoperative unplanned clinic or ED visits based on duration of stent placement., Materials and Methods: This is a single-institution, IRB-approved, retrospective cohort study of 559 ureteroscopy cases with laser lithotripsy for urinary tract calculi performed from 2016 to 2018. The primary outcome was unplanned ED or clinic visits within 30 days following surgery and there. The patients were separated into three groups based on stent duration: 1 (0-3 days), 2 (4-6 days), and 3 (> 6 days)., Results: Fifty-eight (10.31%) patients experienced an unplanned visit within 30 days of the procedure. There was no significant difference in unplanned visits among groups for stent duration (p = 0.45). A Clavien grade analysis showed no difference in grades between groups (p = 0.59). A Cox regression model showed no difference in risk of unplanned visit comparing those in groups 2 and 3 to group 1 (p = 0.157 and 0.374, respectively). This also remains to be the case after adjusting for age, sex, and surgeon (p = 0.166 and 0.376, respectively)., Conclusions: We found no difference in unplanned visits in patients based on the duration of stent placement following routine ureteroscopy. Stent removal within 3 days of surgery appears to be sufficient to minimize morbidity after uncomplicated ureteroscopy.

The outbreaks linked to foodborne illnesses in low-moisture foods are frequently reported due to the occurrence of pathogenic microorganisms such as Salmonella Spp. Bacillus cereus, Clostridium spp., Cronobacter sakazakii, Escherichia coli, and Staphylococcus aureus. The ability of the pathogens to withstand the dry conditions and to develop resistance to heat is regarded as the major concern for the food industry dealing with low-moisture foods. In this regard, the present review is aimed to discuss the importance and the use of novel thermal and nonthermal technologies such as radiofrequency, steam pasteurization, plasma, and gaseous technologies for decontamination of foodborne pathogens in low-moisture foods and their microbial inactivation mechanisms. The review also summarizes the various sources of contamination and the factors influencing the survival and thermal resistance of pathogenic microorganisms in low-moisture foods. The literature survey indicated that the nonthermal techniques such as CO 2 , high-pressure processing, and so on, may not offer effective microbial inactivation in low-moisture foods due to their insufficient moisture content. On the other hand, gases can penetrate deep inside the commodities and pores due to their higher diffusion properties and are regarded to have an advantage over thermal and other nonthermal processes. Further research is required to evaluate newer intervention strategies and combination treatments to enhance the microbial inactivation in low-moisture foods without significantly altering their organoleptic and nutritional quality., (© 2021 Institute of Food Technologists®.)

Purpose: Large meta-analyses demonstrate the noninferiority of laser enucleation to transurethral resection of the prostate (TURP) with regard to long-term efficacy and reoperation rate. Although the 1470 nm diode laser enucleation of the prostate (DiLEP) is superior in hemostasis and surgical visibility, its complexity and associated longer operative time limit its widespread usage. The objective of this study was to generate long-term cost estimates for bipolar TURP and DiLEP, taking into account perioperative and adverse event costs. Materials and Methods: This is a retrospective review of patients who underwent DiLEP ( n  = 114; November 2016 to February 2020) or TURP ( n  = 194; January 2016 to December 2018). A decision analysis model was constructed to compare costs of the primary procedure and subsequent complications taking into account disposable costs, operating room time, length of stay, reoperation rates, and readmissions. Costs were estimated from internal data, published literature and Medicare procedure costs. Markov modeling was used to create cost projections up to 10 years. Results: DiLEP was associated with shorter length of stay and fewer total complications, but longer operative times and greater initial costs. Cost were recuperated at 8 years postoperatively. At 10 years postoperatively, DiLEP represented approximately $664 cost savings per patient over TURP. Conclusions: DiLEP is a cost-effective alternative to TURP for the treatment of benign prostatic hyperplasia in the properly selected patient. DiLEP has greater initial costs due to longer operative times. Costs are recuperated by 10 years postoperatively due to higher rate of same-day discharges, and lower complication and reoperation rates, incurring a $664 cost savings per patient treated by DiLEP relative to TURP.

Purpose: For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief., Methods: Both randomized, placebo-controlled studies' primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation., Findings: The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing., Implications: These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate., Materials and Methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect., Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P  = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% ( P  < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P  < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms., Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system., Competing Interests: Dr. Pavlovich reports grants and personal fees from Exact Imaging during the conduct of the study., (© 2020 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Aims: To assess the dose-related effects of sotagliflozin, a novel dual inhibitor of sodium-glucose co-transporters-1 and -2, in type 1 diabetes (T1D)., Materials and Methods: In this 12-week, multicentre, randomized, double-blind, placebo-controlled dose-ranging trial, adults with T1D were randomized to once-daily placebo (n = 36) or sotagliflozin 75 mg (n = 35), 200 mg (n = 35) or 400 mg (n = 35). Insulin was maintained at baseline doses. The primary endpoint was least squares mean (LSM) change in glycated haemoglobin (HbA1c) from baseline. Other endpoints included proportion of participants with ≥0.5% HbA1c reduction and assessments of 2-hour postprandial glucose (PPG), weight, and urinary glucose excretion (UGE)., Results: From a mean baseline of 8.0% ± 0.8% (full study population), placebo-adjusted LSM HbA1c decreased by 0.3% (P = .07), 0.5% (P < .001) and 0.4% (P = .006) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively, at week 12. In the placebo and sotagliflozin 75 mg, 200 mg and 400 mg groups, 33.3%, 37.1%, 80.0% and 65.7% of participants achieved an HbA1c reduction ≥0.5%. Placebo-adjusted PPG decreased by 22.2 mg/dL (P = .28), 28.7 mg/dL (P = .16) and 50.2 mg/dL (P = .013), UGE increased by 41.8 g/d (P = .006), 57.7 g/d (P < .001) and 70.5 g/d (P < .001), and weight decreased by 1.3 kg (P = .038), 2.4 kg (P < .001) and 2.6 kg (P < .001) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively. One case of severe hypoglycaemia occurred in each sotagliflozin group and one case of diabetic ketoacidosis (DKA) occurred with sotagliflozin 400 mg., Conclusions: Combined with stable insulin doses, sotagliflozin 200 mg and 400 mg improved glycaemic control and weight in adults with T1D. Sotagliflozin 400 mg reduced PPG levels. UGE increased with all sotagliflozin doses. Rates of severe hypoglycaemia and DKA were low (NCT02459899)., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients ( N  = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%, P  < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%, P  < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659)., (© 2018 The authors.)

Objective: To compare newly diagnosed localized prostate cancer patients who did and did not view a decision aid (DA) on their knowledge of the rationale for active surveillance (AS)., Methods: A cross-sectional study was conducted among 452 newly diagnosed low-risk localized prostate cancer patients. Patients were mailed the video/DVD DA and completed a web-based questionnaire that contained two multiple choice questions assessing knowledge of the rationale for AS. Multivariable logistic regression was used to estimate the effect of the DA on knowledge of the rationale for AS., Results: Patients who watched the DA were more likely to correctly respond to each rationale for AS question; both comparisons were statistically significant. After adjustment, men who viewed the DA were 2.9 times as likely to correctly respond to both rationale for AS questions than men who did not view the DA (95% CI: 1.9-4.5)., Conclusion: Patients who viewed a DA better understand the reasons why AS is a viable treatment option for localized prostate cancer than patients who did not view a DA., Practice Implications: Urology clinics and practices should implement the utilization of a treatment DA for newly diagnosed, localized prostate cancer prior to the patients' first cancer consultation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A 58-year-old woman presented with a 4 cm obstructing choledocolith within the proximal common bile duct. She had an extensive operative history resulting in common bile duct to jejunum anastomosis after cholecystectomy. Endoscopic retrograde cholangiopancreatography (ERCP) removal was unsuccessful, and surgical exploration was contraindicated due to multiple comorbidities. Interventional radiologist placement of bilateral transhepatic ureteral access sheaths allowed Urologist evaluation of the biliary tract by ureteroscope. Holmium laser lithotripsy was performed with successful fragmentation of the stone and clearance of the obstruction, without complication. The case is relevant to the growing literature on the management of refractory biliary stones after failed ERCP.

Background and Objective: The effect of renal impairment on colchicine pharmacokinetics in patients with chronic kidney disease (CKD) has not been studied previously. We evaluated the effect of renal impairment on colchicine pharmacokinetics in patients with CKD., Methods: The pharmacokinetics and safety of a single, oral 0.6-mg dose of colchicine was evaluated in an open-label study in eight healthy subjects with normal renal function; eight subjects each with mild, moderate, or severe renal impairment; and eight subjects with end-stage renal disease (ESRD) who received a single dose prior to receiving, and again following, hemodialysis., Results: Colchicine exposure was similar for subjects with normal renal function, mild impairment, or ESRD prior to and during hemodialysis (24.7-31.7 ng·h/mL), but was up to twofold higher in subjects with moderate or severe renal impairment (48.9 and 48.0 ng·h/mL, respectively). A very small amount of the colchicine dose (mean of 5.2 %) was recovered in dialysate., Conclusions: It appears that patients with mild or moderate renal impairment or those actively receiving hemodialysis do not show accumulation of colchicine, whereas those with severe renal impairment show a doubling of exposure. All patients with renal impairment taking colchicine should be closely monitored, especially as many patients taking colchicine often have other comorbidities and may be taking other medications.

Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Fluopyram, a broad spectrum fungicide, caused an increased incidence of thyroid follicular cell (TFC) adenomas in males at the highest dose evaluated (750ppm equating to 105mg/kg/day) in the mouse oncogenicity study. A series of short-term mechanistic studies were conducted in the male mouse to characterize the mode of action (MOA) for the thyroid tumor formation and to determine if No Observed Effect Levels (NOELs) exist for each key event identified. The proposed MOA consists of an initial effect on the liver by activating the constitutive androstane (Car) and pregnane X (Pxr) nuclear receptors causing increased elimination of thyroid hormones followed by an increased secretion of thyroid stimulating hormone (TSH). This change in TSH secretion results in an increase of TFC proliferation which leads to hyperplasia and eventually adenomas after chronic exposure. Car/Pxr nuclear receptors were shown to be activated as indicated by increased activity of specific Phase I enzymes (PROD and BROD, respectively). Furthermore, evidence of increased T4 metabolism was provided by the induction of phase II enzymes known to preferentially use T4 as a substrate. Additional support for the proposed MOA was provided by demonstrating increased Tsh β transcripts in the pituitary gland. Finally, increased TFC proliferation was observed after 28days of treatment. In these dose-response studies, clear NOELs were established for phase 2 liver enzyme activities, TSH changes and TFC proliferation. Furthermore, compelling evidence for Car/Pxr activation being the molecular initiating event for these thyroid tumors was provided by the absence of the sequential key events responsible for the TCF tumors in Car/Pxr KO mice when exposed to fluopyram. In conclusion, fluopyram thyroid toxicity is mediated by activation of hepatic Car/Pxr receptors and shows a threshold dependent MOA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Objective: Colchicine is commonly prescribed for gout. While minimally metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme, colchicine is a substrate for P-glycoprotein (P-gp). Atorvastatin is metabolized primarily by CYP3A4 and is a P-gp inhibitor. Patients with gout often have dyslipidemia; therefore, the potential for co-administration of atorvastatin and colchicine exists. The objective of this study was to determine the effect of oral atorvastatin on the pharmacokinetics of a single, oral dose of colchicine., Methods: Twenty-four healthy adult subjects were enrolled in this single-center, open-label, non-randomized, one-sequence, two-period drug-drug interaction study. On day 1, subjects received a single oral dose of colchicine 0.6 mg. After a 14-day washout, subjects received atorvastatin 40 mg once daily for 14 days followed by a single dose of colchicine 0.6 mg co-administered with atorvastatin 40 mg on day 28. Main outcome measures were colchicine maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC last), and AUC from time zero to infinity (AUC∞), which were compared with and without concurrent atorvastatin., Results: Colchicine AUC last, AUC∞, and C max increased by 27, 24, and 31 %, respectively, when co-administered with atorvastatin. Corresponding 90 % confidence intervals around the ratios were outside the established no-effect 80-125 % interval., Conclusion: Increased colchicine exposure was observed after a single dose of colchicine was administered with steady-state atorvastatin. Additional studies with multiple dosing of both drugs are needed to further determine the clinical implications of these results.

Purpose: Prostate cancer ranks as one of the most common malignancies and currently represents the second leading cancer-specific cause of death in men. The current use of single modality transrectal ultrasound (TRUS) for biopsy guidance has a limited sensitivity and specificity for accurately identifying cancerous lesions within the prostate. This study introduces a novel prostate cancer imaging method that combines TRUS with electrical impedance tomography (EIT) and reports on initial clinical findings based on in vivo measurements., Methods: The ultrasound system provides anatomic information, which guides EIT image reconstruction. EIT reconstructions are correlated with semiquantitative pathological findings. Thin plate spline warping transformations are employed to overlay electrical impedance images and pathological maps describing the spatial distribution of prostate cancer, with the latter used as reference for data analysis. Clinical data were recorded from a total of 50 men prior to them undergoing radical prostatectomy for prostate cancer treatment. Student's t-tests were employed to statistically examine the electrical property difference between cancerous tissue and benign tissue as defined through histological assessment of the excised gland., Results: Example EIT reconstructions are presented along with a statistical analysis comparing EIT and pathology. An average transformation error of 1.67% is found when 381 spatially coregistered pathological images are compared with their target EIT reconstructed counterparts. At EIT signal frequencies of 0.4, 3.2, and 25.6 kHz, paired-testing demonstrated that the conductivity of cancerous regions is significantly greater than that of benign regions ( p < 0.0304)., Conclusions: These preliminary clinical findings suggest the potential benefits electrical impedance measurements might have for prostate cancer detection.

Objective: Review the magnitude and clinical relevance of drug-drug interactions between a new formulation of colchicine, used to treat gout, and antibiotics. SETTING AND PRACTICE DESCRIPTION: Relevant to community and institutional pharmacists servicing patients with gout., Practice Innovation: Pharmacists have clear roles for the identification of drug-drug interactions, providing recommendations for alternative therapy or dose adjustments/modifications, and monitoring for interactionrelated adverse events., Main Outcome Measures: Colchicine is metabolized via cytochrome P450 3A4 (CYP3A4); therefore, coadministration with agents that inhibit this isoenzyme can produce elevated colchicine plasma concentrations, resulting in severe and sometimes fatal adverse events. Knowledge of the potential for drug-drug interactions involving antibiotics (e.g., macrolide antibiotics, azole antifungals) allows pharmacists to help patients avoid serious adverse events., Results: Pharmacokinetic studies have demonstrated that the maximum plasma concentration (C(max)) and drug exposure (as assessed by area under the plasma concentration time curve [AUC]) of colchicine are increased by 277% and 282%, respectively, after coadministration with clarithromycin. Similarly, coadministration with ketoconazole increases colchicine C(max) and AUC by 102% and 212%, respectively. Other antibiotics that are strong CYP3A4 inhibitors include itraconazole and telithromycin, whereas erythromycin and fluconazole are moderate inhibitors of the isoenzyme CYP3A4. Coadministration of CYP3A4 inhibitors (particularly clarithromycin) and colchicine has resulted in acute colchicine toxicity manifested by severe gastrointestional toxicity, bone marrow suppression, multiorgan failure, and death., Conclusion: Pharmacist awareness of potentially clinically significant interactions between colchicine and antibiotics that inhibit CYP3A4 can help to ensure the efficacy of colchicine is realized while mitigating serious toxicities and minimizing the risk of adverse events.

Background: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug-drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported., Objective: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers., Methods: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mg dose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes., Results: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered with Seville orange juice, a moderate inhibitor, C(max) and AUC were decreased by ∼24% and ∼20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in T(max). Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events., Conclusions: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased T(max), but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials.gov identifiers: NCT00960193 and NCT00984009., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Objective: Colchicine and cyclosporine are often administered together, particularly in patients who have undergone solid-organ transplantation. However, the potential for drug-drug interactions between these agents resulting in colchicine toxicity is high., Methods: This study sought to determine the effect of cyclosporine (100-mg capsule) on the pharmacokinetics of the US Food and Drug Administration-approved formulation of colchicine (0.6-mg tablet) after single oral-dose administration in 24 healthy subjects under fasted conditions in a phase 1, single-sequence, 2-period drug-drug interaction trial., Results: Coadministration of cyclosporine increased colchicine maximum observed plasma concentration, area under the plasma concentration-time curve to the last measurable time point, and area under the plasma concentration-time curve to time infinity on average by 224%, 216%, and 215% (ie, almost doubled), respectively, and decreased colchicine oral clearance on average by 72% (from 48.24 to 13.42 L/h), indicating substantially higher colchicine exposures when combined with cyclosporine, compared with colchicine alone., Conclusion: The dose of colchicine should be reduced by ≥ 50% when colchicine and cyclosporine are administered concurrently for treatment and prophylaxis of gout flares or treatment of patients with familial Mediterranean fever. Health care professionals should be vigilant for potential adverse events during colchicine/cyclosporine coadministration, notably in patients who have undergone solid-organ transplantation., Trial Registration: www.ClinicalTrials.gov identifier NCT00983931 (http://clinicaltrials.gov/ct2/show/NCT00983931).

Introduction: The objective of this study was to compare the relative bioavailability of the US Food and Drug Administration-approved formulation of colchicine after a single 0.6 mg dose in young (18-30 years of age) and elderly (≥60 years of age) healthy subjects to determine whether dosing adjustments are required in elderly patients., Methods: A single-dose, single-drug, parallel-group study was performed in 20 young subjects with normal renal function (defined as creatinine clearance [CrCl] ≥80 mL/min) and 18 elderly subjects with normal or mild renal impairment (CrCl ≥50 mL/min) in otherwise good health. Blood samples were collected for up to 72 hours postdose and analyzed for colchicine using a validated liquid chromatography/tandem mass spectrometry method. Noncompartmental pharmacokinetic parameters were compared using analysis of variance methods., Results: There were no statistically significant (P < 0.05) differences in mean colchicine pharmacokinetic parameters between young and elderly subjects, including peak plasma concentration (C(max)) (2.53 vs. 2.56 ng/mL), time to C(max) (1.25 vs. 1.25 hours), area under the plasma concentration-time curve to infinity (22.29 vs. 25.01 ng/h/mL), elimination half-life (25.4 vs. 30.1 hours), oral clearance (0.40 vs. 0.35 L/h/kg), and apparent volume of distribution (14.3 vs. 14.8 L/kg), respectively., Conclusion: The lack of any significant differences in colchicine pharmacokinetic parameters between young and elderly healthy subjects, with some of the latter including mild renal impairment, suggests that dose modification of colchicine may not be necessary in healthy elderly patients. However, when evaluating the use of colchicine dosing in an elderly patient, the confounding effect on overall exposure and safety from comorbid conditions, the use of concomitant medications, and the administration of multiple doses should be considered.

Synechiae are intracavitary adhesions; although rarely reported, they may occur within the urinary tract. They are well recognized within the gynecologic literature but are rarely reported as a cause of urologic pathology. We describe the endoscopic appearance of two such lesions, describing their pathologic role and the endoscopic management in two patients.

Transfluthrin, a pyrethroid insecticide, induced urinary bladder tumors in rats but not in mice in 2-year bioassays. We investigated the urothelial effects of transfluthrin in vivo in rats and the effects of its major metabolite tetrafluorobenzoic acid (TFBA) in vitro on rat (MYP3) and human (1T1) urothelial cell lines. Rats were fed diet containing 0, 2000 or 5000 (with and without 1.25% NH(4)Cl) ppm transfluthrin for 4 weeks or 0 or 2000 ppm transfluthrin for 13 weeks. After 4 weeks, there was no evidence of hyperplasia or increased proliferation in any treatment group. After 13 weeks treatment with 2000 ppm, cytotoxicity and necrosis of the rat urothelial superficial layer were detected by scanning electron microscopy. The urinary concentration of TFBA in rats fed 2000 ppm transfluthrin was 2.94±0.67 mM. The LC(50) of TFBA was 2.25 mM for MYP3 cells and 2.43 mM for 1T1 cells. These studies support cytotoxicity and regenerative proliferation as the mechanism for induction of bladder tumors with high oral doses of transfluthrin due to metabolism of transfluthrin to the weakly cytotoxic TFBA which is excreted at high concentrations in the urine of rats administered high doses of transfluthrin (≥2000 ppm) for an extended period., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: Patients can search the Internet for prostate cancer information, and YouTube is a popular Web site that they may consult. We analyzed the prostate cancer videos on YouTube for information content and the presence of bias., Methods: YouTube was searched for videos about prostate-specific antigen (PSA) testing, radiotherapy, and surgery for prostate cancer. The included videos were in English and <10 minutes long. Two physician viewers watched each video and assigned a score for information content (excellent, fair, poor) and bias (for, against, neutral, or balanced). A third viewer arbitrated any discrepancies. The kappa statistic was used to measure interobserver variability, and Pearson's test was used to assess correlation., Results: A total of 14 PSA videos, 5 radiotherapy videos, and 32 surgery videos were analyzed. The PSA testing videos averaged 1480 +/- 2196 views and 146 +/- 174 s long and had an average viewer rating of 3.1 +/- 2.1 (viewer rating scale 0-5). The surgery videos averaged 2044 +/- 3740 views and 172 +/- 122 s long and had an average viewer rating of scored 3 +/- 2.2. The radiotherapy videos averaged 287 +/- 255 views and 97 +/- 45 s long and had a score of 1.8 +/- 2.5. The information content was fair or poor for 73% of all videos. The bias for surgery, radiotherapy, or PSA testing was present in 69% of videos; 0% of videos were biased against treatment or PSA testing. The interobserver variability was well above than expected by chance alone., Conclusions: The results of our study have shown that although some videos are robust sources of information, given the preponderance of modest and unbalanced information among reviewed videos, YouTube is an inadequate source of prostate cancer information for patients., (2010 Elsevier Inc. All rights reserved.)

Background: Patients taking aspirin for cardioprotection may occasionally take over-the-counter (OTC) ibuprofen for pain relief, which might interfere with the antiplatelet effects of aspirin., Objective: The present study was undertaken to determine whether ibuprofen, taken according to OTC label directions, would affect inhibition of thromboxane B2 (TXB2), a surrogate for platelet inhibition., Methods: This was a prospective, multiple-dose,single-center, double-blind, randomized, parallel, placebo-controlled study. Eligible subjects received chewable, immediate-release aspirin 81 mg QD for 8 days, and were then randomized to receive either ibuprofen 400 mg TID or placebo TID, in addition to aspirin, for 10 days., Results: Fifty-one subjects were randomized; 47(24 placebo, 23 ibuprofen) completed the study. No subjects withdrew prematurely. Subjects were predominantly white (49%) or black (38%), and 53% were male. The mean (SD) age was 38.4 (9.8) years and mean (SD) body weight was 173.2 (26.7) pounds. On days 1, 3, 7, and 10 of the study period, mean TXB2 inhibitions were 99.24%, 98.88%, 97.75%, and 98.17% for ibuprofen and 98.82%, 98.93%, 98.75%, and 98.83% for placebo. Although a statistically significant reduction of TXBZ inhibition was seen in the ibuprofen group at days 7 and 10 (P = 0.003 and P = 0.023, respectively), TXBZ inhibition was >90% on all days tested in all subjects. Aspirin, ibuprofen, and placebo were all well tolerated. There were 3 adverse events (1 mild and 2 moderate) during the aspirin run-in period and 8 (2 mild and 6 moderate) during the randomized study period., Conclusions: No clinically meaningful loss of cardioprotection was found, as reflected by TXB2 inhibition in healthy volunteers who received OTC doses of ibuprofen. When using this regimen of OTC ibuprofen with immediate-release, low-dose aspirin, concerns about the loss of cardioprotective antiplatelet effects of aspirin are not supported by this study.

Aim: This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination., Methods: This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of > or = 3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs)., Results: A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (< 12%) but statistically significant (P = 0.02) increase in donepezil C(max) was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the t(max) or AUC(0-24 h) of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone., Conclusions: The co-administration of once-daily oral donepezil HCl 5 mg for 15 days and once-daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed.

Background: Patients with seasonal allergic rhinitis experience many nasal and concomitant nonnasal symptoms. Many patients also experience headaches and facial pain, pressure, or discomfort. Standard over-the-counter therapy with antihistamines and nasal decongestants often does not completely relieve all symptoms associated with allergic rhinitis., Objective: To establish the contribution of ibuprofen when used with pseudoephedrine and chlorpheniramine, a standard over-the-counter regimen, to relieve the symptoms of seasonal allergic rhinitis., Methods: In this 7-day, multicenter, randomized, placebo-controlled, double-blind, double-dummy, parallel-group trial, qualified subjects were randomly assigned to 1 of 4 treatment groups that received combined ibuprofen/pseudoephedrine/chlorpheniramine (200/30/2 mg or 400/60/4 mg), combined pseudoephedrine/chlorpheniramine (30/2 mg), or placebo. Therapy began when the subject experienced a minimum of moderate allergy-associated pain, and it continued 3 times a day for 7 consecutive days., Results: Mean pain intensity reduction in both ibuprofen/pseudoephedrine/chlorpheniramine treatment groups was 40% greater than in the placebo group and 33% greater than in the pseudoephedrine/chlorpheniramine treatment group (P < .001). Mean changes from baseline in total and nonpain symptom scores for both ibuprofen/pseudoephedrine/chlorpheniramine doses were significantly greater than for placebo (P < .001) and pseudoephedrine/chlorpheniramine (P < .001-.05) but were not different from each other. Ibuprofen enhanced the chlorpheniramine and pseudoephedrine effects, resulting in incremental 33% to 34% pain relief and 17% to 22% allergy symptom relief compared with pseudoephedrine/chlorpheniramine., Conclusions: In both doses of the triple combination, ibuprofen added to the effects of chlorpheniramine and pseudoephedrine, resulting in superior relief of pain and all nonpain allergy symptoms compared with pseudoephedrine/chlorpheniramine treatment. Furthermore, the superior efficacy of the lower dose of the triple combination allowed for a decrease in the incidence of adverse effects.

A 28-day oral gavage toxicity study in the rat with 17alpha-methyltestosterone was conducted as part of the international validation exercise on the modified Enhanced OECD Test Guideline 407 (Organisation for Economic Co-operation and Development, Paris). Special emphasis was placed on the endocrine mediated effects exerted by 17alpha-methyltestosterone, a potent androgen agonist. The test compound was administered daily by oral gavage for at least 28 days to groups of 7-week-old-Wistar rats. Dose levels were 0, 10, 40 and 200 mg/kg body weight per day for males and 0, 10, 100 and 600 mg/kg body weight per day for females. In addition, and outside the remit of the enhanced protocol, testosterone levels in males, oestradiol levels in females and luteinizing hormone (LH) levels in both sexes were measured, to provide a broader profile on the hormonally mediated effects of 17alpha-methyltestosterone. Furthermore, stage-specific quantification of Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling (TUNEL)-labeled germ cells (apoptotic germ cells) in the seminiferous tubules was also performed, in an effort to demonstrate the precise stages in the spermatogenic cycle 17alpha-methyltestosterone exerts its effect. In this study, the most critical additional parameters contained in the Enhanced OECD Test Guideline 407 for the detection of endocrine disruption were considered to be the histopathological assessment and organ weight data of endocrine-related tissues. Beyond the scope of this validation exercise, an increase in apoptosis in specific germ cell types was detected using the TUNEL assay in male rats treated at 200 and 40 mg/kg.

Objective: To compare the clinical effects of a new oral synthetic conjugated estrogens, A (SCE), versus placebo in a clinically relevant population on the reduction in the mean number of moderate to severe vasomotor symptoms., Design: A total of 120 healthy pre- and postmenopausal women (72 active, 48 placebo) were enrolled into a randomized, placebo-controlled, double-blind, multi-center clinical trial. Women of all races were enrolled, using minimal inclusion and exclusion criteria. Each subject received either orally administered SCE, in doses of 0.3 mg, 0.625 mg or 1.25 mg per day, or placebo. Analysis of variance was performed on the primary efficacy variable (change from baseline to weeks 4, 8, and 12 in the mean number of moderate to severe vasomotor symptoms)., Results: Changes in moderate to severe vasomotor symptoms in the intent to treat population showed statistically significant differences between the active and placebo treatments at week 4 (P < .022), week 8 (P < .010), and week 12 (P < .010). By week 12, the mean percentage reduction in moderate to severe vasomotor symptoms was 81%, from an average baseline of 96.8, to 16.5 hot flashes per week for the active treatment group. The overall incidence of expected estrogen-related adverse effects was modest. Laboratory tests and vital sign measurements did not reveal clinically significant changes or abnormalities from screening to the final visit in either treatment group., Conclusions: The results of this study confirm the efficacy and safety of SCE in the treatment of moderate to severe vasomotor symptoms in menopausal women. In addition, the study also demonstrated that the use of more liberal entry criteria did not materially affect the efficacy outcome.

The aim of this study was to determine the effects of olestra and sorbitol consumption on three accepted objective measures of diarrhea (stool output >250 g/day, liquid/watery stools, bowel movement frequency >3/day), and how stool composition influences reports of common gastrointestinal symptoms. A double-blind, placebo-controlled study compared the effects of sorbitol (40 g/day in candy), a poorly absorbed sugar-alcohol with known osmotic effects, with those of olestra (20 or 40 g/day in potato chips), a nonabsorbed fat, on objective measures of stool composition and GI symptoms. Sixty-six subjects resided on a metabolic ward for 12 days: 2 days lead-in, 4 days baseline, 6 days treatment. Sorbitol 40 g/day resulted in loose/liquid stools within 1-3 h of consumption. In contrast, olestra resulted in a dose-responsive stool softening effect after 2-4 days of consumption. Subjects reported "diarrhea" when mean stool apparent viscosity (peak force (PF), g) decreased from a perceived "normal" (mean +/- SE, 1355 +/- 224 g PF; firm stool) to loose (260 +/- 68 g PF) stool. Mean apparent viscosity of stool during treatment: placebo, 1363 +/- 280 g (firm); olestra 20 g/day 743 +/- 65 g (soft); olestra 40 g/day, 563 +/- 105 g (soft); and sorbitol 40 g/day, 249 +/- 53 g (loose). Of the 1098 stool samples collected, 38% (419/1098) were rated by subjects as "diarrhea," yet only 2% of treatment days (all in the sorbitol treatment group) met commonly accepted criteria for a clinical diarrhea. Sorbitol, but not olestra, increased the severity of abdominal cramping, urgency and nausea compared to placebo. Olestra consumption, at levels far in excess of normal snacking conditions, resulted in a gradual stool softening effect after several days of consumption, did not meet any of the three objective measures of diarrhea, and did not increase GI symptoms. Sorbitol consumption, at only 80% of the dose requiring a "laxative effect" information label, resulted in rapid onset loose/liquid stools and a significant increase in abdominal cramping, urgency and nausea. Overall, subjects categorized stool as "diarrhea" when stool decreased from their perceived "normal," but the vast majority of these reports were not associated with clinically significant diarrhea., (Copyright 2000 Academic Press.)

Heart transplantation has become a highly successful, life-saving treatment for a number of otherwise fatal heart diseases. A major limiting factor in the growth of transplantation surgery has been the relative lack of suitable donor organs, and the appropriate criteria for selection of donor organs have been a topic of significant interest. Despite relatively favorable survival rates in the few patients who have received organs from victims of many types of poisonings and drug overdoses, patients dying of toxicologic causes are not usually considered suitable organ donors. Some centers routinely reject such individuals. Criteria for donor selection continue to be vague, unclear, or nonexistent in regard to organ transplantation from victims of all types of poisoning and toxic exposures. Carbon monoxide (CO) is a ubiquitous poison, and although victims of CO poisoning have occasionally served as suitable organ donors, heart transplantation in this scenario is still a very rare event. We describe the successful transplantation of the heart from a CO poisoning victim--to our knowledge, only the third such transplantation. Because the emergency department is a critical site for organ procurement, emergency physicians must be aware that patients dying of CO exposure may be acceptable organ donors.

We present a case of a six-week-old infant who developed life-threatening complications after unintentional sodium bicarbonate intoxication. Baking soda was being used by the mother as a home remedy to "help the baby burp." A review of the literature regarding the use (or misuse) of baking soda follows. Our patient, along with the other noted case reports, emphasizes the need for warnings on baking soda products whose labels recommend its use as an antacid. Poisonings must be high in the differential diagnosis of any patient, regardless of age, who presents with altered mental status or status epilepticus.

Physicians who prescribe viscous lidocaine preparations should be aware of the adverse effects and the high risk for overdose in pediatric patients. Owing to altered pharmacokinetics (increased absorption, decreased clearance, and prolonged half-life), doses that are innocuous for adults may present a significant potential toxic hazard in children. Lidocaine should not be used to treat painful mouth lesions in children until further safety data are available. Benzocaine may be considered as a safe alternative to lidocaine. Its low incidence of side effects makes it a safer choice for infants and children. If no other choices are appropriate, then very specific instructions should be given to parents. The amount, frequency, maximum daily dose, and mode of administration should be clearly communicated (eg, cotton pledget to individual lesions, one-half dropper to each cheek every four hours, or 20 minutes before meals). They should never be prescribed on a "PRN" basis.

An 11-week-old infant experienced toxicity following the intranasal instillation of a four percent cocaine solution in preparation for an examination to rule out choanal stenosis. The child recovered fully but required the use of anticonvulsants and admission to the hospital. To our knowledge, this is the first case report where cocaine toxicity was experienced following this routine practice. We present our case and a review of the literature involving other instances where there have been complications with the use of topical cocaine. This report should alert the medical community to the potential complications of using topical cocaine for its anesthetic properties.

We studied five children with carbamazepine overdose. Two patients had acute overdose without previous exposure to carbamazepine while three presented with acute-on-chronic overdose. Multiple doses of activated charcoal were administered to four patients. One acute-on-chronic patient did not receive any activated charcoal. The mean half-life of carbamazepine was as follows: a) Acute vs. Acute-On-Chronic overdose: 8.63 h vs. 12.01 h (p less than 0.05); b) No Activated Charcoal vs. 30-50 g Activated Charcoal vs. 60-90 g Activated Charcoal: 23.3 h vs. 10.17 h vs. 7.21 h (p less than 0.05); c) No Activated Charcoal vs. 2-3 doses vs. 7-12 doses: 23.3 h vs. 8.96 h vs 7.55 h (ns). Although the half-life of carbamazepine decreased in a linear relationship with the total amount of activated charcoal administered (r = -0.86), there was no relationship between the time to complete recovery and administration of multiple doses of activated charcoal. Although multiple doses of activated charcoal increased the clearance of carbamazepine in our patients with overdose, it was not associated with clinical benefits.

A railroad accident in Somerville, Massachusetts, led to spillage of phosphorus trichloride liquid. Attempted clean-up with water led to the liberation of phosphorus trichloride, phosphoric acid, hydrochloric acid, and phosphorus oxides. Seventeen people exposed to this mixture were studied. Patients experienced eye irritation, lacrimination, nausea, vomiting, and dyspnea. Six patients had transient elevation of lactic dehydrogenase. Although all patients had normal chest roentgenographic findings, pulmonary function tests showed statistically significant decreases in vital capacity (p = 0.02), maximal breathing capacity (p = 0.02), forced expiratory volume in one second (p = 0.02), and maximal expiratory flow rate at 25 percent of vital capacity (p = 0.05) in those closest to the accident site. Further, patients exposed for less than one and a half hours had significantly greater maximal expiratory flow rates at 25 percent of vital capacity when compared with patients who had been exposed longer (p = 0.02). In seven patients, repeated pulmonary function tests one month later showed improvement, suggesting strongly that the acute effects may have been due to phosphorus trichloride toxicity.