Showing papers in "Current Therapeutic Research-clinical and Experimental in 2008"

Genistin-Rich Soy Isoflavone Extract in Substrate Reduction Therapy for Sanfilippo Syndrome: An Open-Label, Pilot Study in 10 Pediatric Patients

Abstract: Background: Mucopolysaccharidoses (MPSs) are a group of severe metabolic disorders caused by deficiencies in enzymes involved in the degradation of glycosaminoglycans (GAGs)—long chains of sugar carbohydrates in cells that help build bone, cartilage, tendons, corneas, skin, and connective tissue. Although enzyme replacement therapy has become available for the treatment of some types of MPS, effective treatment of neurodegenerative forms of MPS has yet to be determined. Recently, genistein (4',5,7-trihydroxyisoflavone), a specific inhibitor of protein tyrosine kinase, has been found to inhibit GAG synthesis and to reduce GAG concentrations in cultures of fibroblasts of MPS patients. Therefore, a potential substrate reduction therapy has been proposed. Objective: The aim of this study was to examine urinary GAG concentration, hair morphology, and cognitive function in patients receiving genistin treatment for Sanfilippo syndrome (MPS type III). Methods:Patients aged 3 to 14 years with a biochemically confirmed diagnosis of MPS IIIA or MPS IIIB were eligible to enroll in this open-label, pilot study. Genistin-rich soy isoflavone extract 5 mg/kg/d was administered PO for 12 months. Urinary GAG concentration, hair morphology,and cognitive function (measured using a modified version of the Brief Assessment Examination [BAE] and parent observations)were measured at baseline and after 12 months of treatment. Results: Ten patients (6 girls, 4 boys; mean age, 8 years [range,3\2-14 years];mean weight, 28 kg [range, 17\2-43 kg]) were included in the study. All patients had Sanfilippo syndrome; 5 patients had MPS IIIA and 5 had MPS IIIB. After 1 year, statistically significant improvement was found in urinary GAG concentration, hair morphology, and cognitive function. Urinary GAG concentration decreased significantly in all 5 patients with MPS IIIA and in 2 patients with MPS IIIB (P = 0.028). Hair morphology improved significantly in all 5 MPS IIIA patients and in 3 MPS IIIB patients (P = 0.012). A significant increase in the BAE score (by 2-6 points) was noted in 8 patients, while the scores of 2 patients did not change after 12 months of treatment (P = 0.012). No adverse events (AEs) considered related to treatment were reported. Moreover, no AEs not related to the treatment (apart from classical symptoms of MPS III) were noted. Conclusions: This pilot study found some improvements in GAG concentration, hair morphology, and cognitive function in these pediatric patients with Sanfilippo syndrome treated with genistin-rich soy isoflavone extract for 1 year. Clinical trials are needed to evaluate the efficacy and safety of this potential treatment.

Preconditionin effects of dexmedetomidine on myocardial ischemia/reperfusion injury in rats.

Abstract: Background: Preconditioning might protect the myocardium against ischemia/ reperfusion injury by reducing infarct size and preventing arrhythmias. Dexmedetomidine (DEX) is a highly selective α2-agonist used for sedoanalgesia in daily anesthetic practice. The cardioprotective effects of DEX on infarct size and on the incidence of arrhythmias observed after regional ischemia/reperfusion injury in vivo have not been reported. Objective: The aim of this study was to determine whether DEX exhibits a preconditioning effect and reduces infarct size and the incidence and duration of arrhythmias in a regional cardiac ischemia/reperfusion model in rats. Methods: Adult male Sprague-Dawley rats were anesthetized with sodium thiopental and mechanically ventilated (0.9 mL/100 g at 60 strokes/min) through a cannula inserted into the trachea after tracheotomy. Cardiac ischemia was then produced by ligating the left main coronary artery for 30 minutes, followed by a reperfusion period of 120 minutes. Blood pressure (BP) and heart rate (HR) were monitored and echocardiograms (ECGs) were performed. Arrhythmia was scored based on incidence and duration. The animals were randomly divided into 3 groups. The ischemic preconditioning (IPC) group underwent 5 minutes of ischemia followed by 5 minutes of reperfusion before the 30-minute ischemia/120-minute reperfusion period. In the DEX group, intraperitoneal (IP) DEX 1 mL (100 μg/kg) was administered 30 minutes before the ischemia/ reperfusion period. In the control group, IP saline 1 mL was administered 30 minutes before the ischemia/reperfusion period. After reperfusion, the heart was excised, demarcated with saline and ethanol to identify the occluded and nonoccluded myocardium, and cut into slices ~2 mm thick, that were then stained and placed between 2 glass plates. The risk zone and the infarct zone were compared between groups. The investigator assessing the infarcts was blinded to the study group. Results: Twenty-one adult (aged 4-6 months) male Sprague-Dawley rats weighing 280 to 360 g were included in the study; 7 rats were assigned to each group. BP, HR, and ECG readings were not significantly different between groups and did not change during the study. Arrythmias occurred during ischemia and reperfusion in all groups. The duration of the arrhythmias was significantly shorter and the arrhythmia score was significantly lower in the IPC group (all, P<0.05), compared with the control group; however, they were not significantly different in the DEX group. During the ischemic period, duration of ventricular tachycardia (VT) and ventricular premature contractions (VPC) in the DEX group was significantly longer than that observed in the IPC group (all, P<0.05). The duration of VPC was also significantly shorter than that observed in the control group (both, P<0.05). Duration of VT during the reperfusion period in the DEX group was significantly longer than that observed in both IPC and control groups (both, P<0.05). The mean (SD) percentage of damage was significantly lower in the IPC group (44.1% [2.0%]) and the DEX group (26.7% [2.0%]) compared with the control group (69.0% [3.0%]; both, P<0.05). The percentage of damage in the DEX group was also significantly lower compared with the IPC group (P<0.05). Conclusions: This small, experimental in vivo study found that DEX was associated with reduced infarct size in ischemia/reperfusion injury in regional ischemia in this rat model but had no effect on the incidence of arrhythmias. Future studies are needed to clarify these findings.

The state of health economic and pharmacoeconomic evaluation research in Zimbabwe: A review

Abstract: BACKGROUND: Economic evaluation of health care has developed into a substantial body of work, and its contribution to medical decision making is increasingly being recognized. OBJECTIVE: The aim of the study was to describe the characteristics and quality of health economic (including pharmacoeconomic) evaluation research studies related to Zimbabwe. METHODS: A review of the literature was conducted to identify published health economic evaluation studies related to Zimbabwe. HEED, PubMed, MEDLINE, HealthSTAR, EconLit, and PsycINFO databases and sociological and dissertation abstracts were used to search for economic analyses. The searches used the following terms alone and in combination: costs, budgets, fee, economics, health, pharmacy, pharmacy services, medicines, drugs, health economics, cost-effectiveness, cost-benefit, cost-minimization, cost utility analysis, and Zimbabwe. Only original applied economic evaluations addressing a health-related topic pertaining to Zimbabwe and published in full were included. Two reviewers independently evaluated and scored each study in the final sample using the data collection form designed for the study. RESULTS: Fifty-nine studies were identified in the database searches, 18 of which were excluded because they were not about Zimbabwe (3 studies) or were not health related (15). Of the 41 remaining studies, 8 were excluded after further review because they were not original research, 6 because they were not economic analyses, and 1 because it was not about Zimbabwe. The final 26 studies appeared in 13 different journals (based mostly [17 (65%)] outside of Zimbabwe). The mean (SD) number of authors of each study was 3.36 (2.13); most of the authors had medical/clinical training. The number of studies peaked between 1994 and 1997. Based on a 10-point scale, with 10 indicating the highest quality, the mean (SD) quality score for all studies was 5.40 (1.56); 8 of the studies (31%) were considered to be of poor quality (score ≤4). The quality of the studies reviewed was significantly (all, P pharmaceutical interventions), the number of authors (more authors = higher), and year of publication (more recent = higher). CONCLUSION: This study indicated that the use of health economic (including pharmacoeconomic) evaluation research in Zimbabwe was low, and 31 % of the studies were of poor quality. More and better quality health economic research in Zimbabwe is warranted.

Cost evaluation of adverse drug reactions in hospitalized patients in Taiwan: A prospective, descriptive, observational study.

Abstract: Background: Adverse drug reactions (AADRs) are a leading cause of morbidity and mortality. In the United States, ADR-related morbidity and mortality costs have been estimated at US $330 billion to US $1130 billion annually. Objectives: The aim of this study was to evaluate the incidence of ADRs in Taiwan, to identify the drug classes that are most commonly related to ADRs, and to determine the direct medical costs to hospitals associated with prolonged hospitalizations due to ADRs. Methods: In this prospective, descriptive, observational study, patients who experienced ADRs during their hospitalization at a Taiwan teaching hospital or who were admitted due to an ADR from January 1, 2002, through December 31, 2004, were included in the study. The patients were identified actively by clinical pharmacists and passively by physicians and nurses who reported ADRs. The World Health Organization (WWHO) definition of ADR severity was adopted, and degrees of probability for each ADR were determined using the Naranjo algorithm. The direct medical costs incurred to the hospital in the treatment of ADRs that prolonged hospitalization were calculated (ie, costs of emergency department [ED] visits, intensive care unit visits, extra days of hospitalization, monitoring and laboratory studies, pharmacist dispensing fees, physician fees, room charges, ED charges). Results: During the study period, 43 of the 142,295 hospitalized patients (00.03%)) were admitted because of an ADR. A total of 564 (00.40%)) of the hospitalized patients were verified to have ADRs. Three hundred eighteen of the patients (56.44%) with ADRs were male and the overall mean (SD) age was 66(2) years. The most common drug classes associated with the ADRs were antibiotics (219 patients [38.8% ]), analgesics (62 [11.0%]), and cardiovascular agents (56 [9.9%]). The systems most commonly involved in ADRs were cutaneous (296 patients [52.5%]), hematologic (61 [10.8%]), and cardiovascular (54 [9.66%]). The causes of the ADRs were anaphylactic (464 patients [82.3%]), drug overdose (78 [13.8%]), and drug-drug interactions (22 [3.9%]). Of the ADRs, 474 (884.0%) were idiosyncratic type B reactions (predictable). ADR-related costs, estimated at US $3489/ADR, were mostly due to prolonged length of stay. Based on the WHO definition, of the 564 ADRs, 330 (58.5%) and 40 (7.1%) were classified as moderate and severe, respectively. Two patients died of ADRs associated with allopurinol. Conclusion: In this hospital, 0.40% of patients were identified as having ADRs that were associated with high direct costs, mostly due to extended hospitalizations.

Kanglaite injection plus chemotherapy versus chemotherapy alone for non-small cell lung cancer patients: A systematic review and meta-analysis.

Abstract: Background: Kanglaite (KLT) is a botanically sourced, molecularly targeted agent that is prepared as a microemulsion for IV use. The active substance is extracted from the herb Semen coicis. Objective: The aim of this study was to evaluate the effectiveness and tolerability of KLT injection in patients with primary non-small cell lung cancer (NSCLC). Methods: We electronically searched the literature of the China National Knowledge Infrastructure (Chinese language, 1979-March 2008), CBMdisc (Chinese, 1978-March 2008), The Cochrane Library (English, Issue 4, 2007), MEDLINE (English, 1966-March 2008), and EMBASE (English, 1984-March 2008), and manually searched 20 Chinese-language oncology journals to identify randomized controlled trials (RCTs) of KLT injection plus chemotherapy versus chemotherapy alone, regardless of their having been published or not, blinding, duration of treatment, or duration of follow-up. The quality of the included trials was assessed using the method recommended by The Cochrane Collaboration. The studies were assigned to 1 of the following 3 categories: A = all quality criteria met, low risk of bias; B = ≥1 of the quality criteria only partially met, moderate risk of bias; or C = ≥1 of the quality criteria not met, high risk of bias. If heterogeneity existed among subgroups, then overall results were calculated based on a random-effects model; otherwise, a fixed-effects model was used. Results: Electronic database searches yielded 596 citations. A title review eliminated 377 manuscripts; 219 citations were marked for further evaluation. Finally, we identified 26 trials that met the inclusion and exclusion criteria. The 26 RCTs included in this meta-analysis included 2209 patients with NSCLC; no study was graded A, 9 were graded B, and 17 were graded C. The sample size of each trial varied from 40 to 305 patients; none of the trials had precalculated sample sizes. Pooled analyses performed using both fixed- and random-effects models revealed that compared with chemotherapy alone, KLT injection plus chemotherapy improved the response rate (relative risk [RR], 1.34; 95% CI, 1.19–1.51 and RR, 1.35; 95% CI, 1.20–1.51, respectively) and quality of life as measured by an increase ≥10 points in the Karnofsky Performance Status score (RR, 2.05; 95% CI, 1.60–2.64). KLT injection plus chemotherapy was associated with improvement in the symptoms of cough, dyspnea, chest pain, fatigue, and anorexia. KLT injection plus chemotherapy was also associated with significant reduction in the incidence of the following adverse events (AEs) based on the fixed and random effects models, respectively: grade II to IV leukopenia (RR, 0.29; 95% CI, 0.22–0.39 and RR, 0.33; 95% CI, 0.22–0.48), anemia (RR, 0.54; 95% CI, 0.42–0.70 and RR, 0.55; 95% CI, 0.40–0.76), thrombocytopenia (RR, 0.39; 95% CI, 0.21–0.71 and RR, 0.40; 95% CI, 0.21–0.78), nausea and vomiting (RR, 0.44; 95% CI, 0.34–0.57 and RR, 0.44; 95% CI, 0.35–0.57), phlebitis (RR, 3.44; 95% Cl, 1.30–9.15 and RR, 3.38; 95% CI, 1.28–8.89), and hepatic dysfunction (RR, 0.44; 95% CI, 0.15–1.35 and RR, 0.44; 95% CI, 0.24–0.81). Conclusion: This meta-analysis found that KLT injection in combination with chemotherapy was associated with improved response rate, quality of life, and symptoms, and a reduced incidence of AEs compared with chemotherapy alone in patients with NSCLC. These findings should be viewed with caution because of the low quality of the included trials.

Prescription and nonprescription drug use in isfahan, Iran: An observational, cross-sectional study

Abstract: Background: In Iran, nonprescription (ie, over-the-counter [OTC]) and prescription- only drugs are available at pharmacies. Self-medication and self-prescription practices are widespread. Objective: The aim of this study was to assess self-medication and self-prescription practices in Iran, with an emphasis on determining the extent to which prescription-only drugs are obtained without a prescription and dzaracterizing those who engage in this practice. Methods: This observational, cross-sectional study was conducted at pharmacies in Isfahan, Iran, between August 2001 and March 2002. The pharmacies were randomly selected from clusters categorized by the number of prescriptions handled or claims submitted to a major insurance company. Drug requesters were categorized accordingly: those who requested drugs with a prescription and those who requested drugs without a prescription. Prescription-only and nonprescription drug items requested at pharmacies were identified and included in the analysis. Cluster sampling was used to determine sample size and also to ensure that the results were reflective of the population studied. In addition, questionnaires were completed by persons who were seeking drugs without a prescription. Observations were also carried out in each pharmacy. To ensure measurement reliability, we conducted a pilot study before the commencement of this study. We determined sample size based on a >90% power to detect change. Results: Fifty pharmacies were selected for inclusion in the study. A total of 33,282 drug items were identified on prescriptions presented at the pharmacies. This number served as sample size for this study. Of this number, 10,101 items were requested without a prescription, of which 9653 items (95.6%) were available and dispensed. Of the items dispensed, 5504 (57.0%) were prescription items. The percentage of prescription-only drugs sold without prescription to total pharmacy sales was 21.9%, 22.8%, 19.5%, and 10.7% in pharmacies with the fewest to the largest (<500, 500–999, 1000–1499, ≥1500) number of prescriptions, respectively. Individuals requesting OTC and prescription-only drugs without presenting a prescription used 1 of 3 behaviors: (1) verbal request (85.0%); (2) presenting the empty box, blister pack, or a sample of the drug (12.1%); or (3) showing a piece of paper (which was not a prescription) bearing the name of the drug (2.9%). The percentage of those with medical insurance who sought a drug without a prescription was significantly greater than the percentage of those who did not have medical insurance (61.6% [663] vs 38.4% [413], respectively; P < 0.001). Conclusions: The common practice of requesting and obtaining prescription-only drugs without a prescription in Iran, especially among persons with medical insurance, warrants research to identify the motives for this behavior and to improve the enforcement of existing laws regarding the dispensing of prescription-only drugs.

Effect of equivalent doses of fentanyl, sufentanil, and remifentanil on the incidence and severity of cough in patients undergoing abdominal surgery: A prospective, randomized, double-blind study.

Abstract: Background: Fentanyl congeners have been found to induce cough during induction of general anesthesia. Studies of fentanyl and sufentanil have found incidence rates of 28% to 65% and 15%, respectively. However, no study has assessed the occurrence of cough induced by remifentanil. Objective: The aim of this study was to assess the effect of equivalent doses of fentanyl, sufentanil, and remifentanil on cough. Methods: Patients rated American Society of Anesthesiologists class I or II of either sex, aged 18 to 60 years, who were scheduled for elective abdominal surgery with general anesthesia were randomly and equally assigned to 3 groups using a computer-generated table of random numbers. The patients received equivalent doses of fentanyl 2 μg/kg, sufentanil 0.2 μg/kg, or remifentanil 2 μg/kg via IV push. Vital signs (systolic blood pressure [SBP], heart rate [HR], and oxygen saturation via pulse oximetry [SpO2]) and the occurrence and severity of cough were recorded for 2 minutes after drug administration by an anesthesiologist who was blinded to the drug treatment. The severity of cough was graded as none (0), mild (1–2), moderate (3–5), or severe (>5). Results: A total of 315 Chinese patients (197 women, 118 men; mean [SD] age, 37.9 [10.4] years) were approached for enrollment and assigned to 3 groups of 105 patients each; all patients completed the study protocol. The 3 treatment groups were similar in terms of demographic characteristics and type of abdominal surgery. The incidence of cough was significantly greater in the remifentanil group (57 [54.3%] patients) than in the fentanyl group (35 [33.3%]; P < 0.01) or the sufentanil group (32 [30.5%]; P < 0.01). The severity of cough was significantly greater in the remifentanil group (severe, moderate, mild, none: 24, 7, 26, 48) than in the fentanyl (7, 9, 19, 70; P < 0.01) or sufentanil group (4, 2, 26, 73; P < 0.01). In all 3 groups, when the patients coughed, significant increases were observed in their SBP (128 [12]–139 [16] mm Hg; P < 0.01) and HR (74 [10]–87 [16] beats/min; P < 0.01). Within 2 minutes after drug administration, 62 patients (59%) in the remifentanil group experienced hypoxemia (SpO2 <90%) necessitating manually assisted mask ventilation, while no patients experienced hypoxemia in the fentanyl or sufentanil group. Three patients (2.9%) in the remifentanil group experienced muscle rigidity and deterioration of SBP, HR, and SpO2. No other adverse events were recorded. Cunclusion: Remifentanil was associated with a significantly greater incidence and severity of cough than equivalent doses of fentanyl or sufentanil. Fentanyl and sufentanil appeared comparable in these Chinese patients undergoing abdominal surgery.

Dexmedetomidine as an adjunct to epidural analgesia after abdominal surgery in elderly intensive care patients: A prospective, double-blind, clinical trial.

Abstract: Background: The ideal postoperative analgesia management of elderly surgical patients in intensive care units (ICUs) is continually being investigated. Objective: The purpose of this study was to assess the effectiveness and tolerability of IV administration of dexmedetomidine as an adjunct to a low-dose epidural bupivacaine infusion for postoperative analgesia after abdominal surgery in elderly patients in the ICU. Methods: ICU patients aged >70 years undergoing abdominal surgery were eligible for the study. A lumbar epidural catheter was inserted at the beginning of the surgery with no medication. On arrival at the ICU, the catheter was loaded with 0.25% bupivacaine 25 mg at the T8 to T10 sensory level, and a continuous infusion of 0.125% bupivacaine was started at 4 to 6 mL/h in combination with patient-controlled epidural analgesia (PCEA) of fentanyl (4 μg/bolus) for pain treatment. Patients in the treatment group received dexmedetomidine as an IV loading dose of 0.6 pg/kg for 30 minutes followed by continuous infusion at 0.2 μg/kg · h-1. Patients in the control group were not administered dexmedetomidine. The effectiveness of the pain relief was determined using a visual analog scale (VAS) (0 = no pain to 10 = worst pain imaginable) at rest. VAS score, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and arterial blood gases were monitored periodically for 24 hours after surgery. If required, tenoxicam (20-mg IV bolus) was used to ensure a VAS score of ≤3. The number of times PCEA and tenoxicam were administered and the occurrence of adverse events (AEs) were also recorded. Results: Sixty patients (34 men, 26 women; mean [SD] age, 75.96 [4.25] years; mean [SD] weight, 74.13 [10.62] kg) were included in the study. VAS scores were significantly lower in the dexmedetomidine group compared with the control group at hours 1, 2, and 12 (VAS [hour 1]: 2.8 [0.4], P < 0.001; VAS [hour 2]: 2.7 [0.5], P < 0.001; and VAS [hour 12]: 0.9 [0.7], P 0.044). The mean number of administrations of fentanyl via PCEA was significantly greater in the control group compared with the dexmedetomidine group (2.20 vs 6.63 times; P < 0.001). The mean number of administrations of tenoxicam was significantly lower in the treatment group than the control group (0.27 vs 1.07 times; P < 0.001). In the control group, the decreases in sedation at 0, 8, 12, 16, and 20 hours were significant compared with baseline (P = 0.024, P = 0.001, P = 0.020, P < 0.001, and P = 0.005, respectively). Mean HR, SBR and AEs (eg, bradycardia [HR <60 beats/min], respiratory depression [respiratory rate <8 breaths/min], hypotension \SBP <90 mm Hg], oversedation, hypoxia, and hypercapnia) decreased significantly in the dexmedetomidine group (all, P < 0.05). Significantly more patients in the dexmedetomidine group rated their satisfaction with postoperative pain control as excellent compared with the control group (12 vs 6 patients; P = 0.014). Conclusion: Intravenous dexmedetomidine was effective and generally well tolerated as an analgesic adjunct to epidural low-dose bupivacaine infusion for pain treatment, with lower need for opioids after abdominal surgery in these elderly intensive care patients than in the control group.

Lidocaine for prevention of propofol injection-induced pain: A prospective, randomized, double-blind, controlled study of the effect of duration of venous occlusion with a tourniquet in adults

Abstract: Background: Many patients experience pain on injection of propofol. The use of lidocaine to prevent propofol injection pain is common. The analgesic effect of pre-injected lidocaine has been found to increase when a tourniquet is used. Objective: The aim of this study was to compare the effectiveness of various venous occlusion times with lidocaine analgesia to prevent pain during propofol injection. Methods: In this prospective, randomized, double-blind, controlled study, women aged 18 to 45 years, classifed as American Society of Anesthesiologists physical sta- tus I or II, who were scheduled to undergo elective surgery under general anesthesia induced with propofol, were randomly assigned to 1 of 5 groups: group 1, 2% lidocaine 20 mg in saline in a total volume of 10 mL and no venous occlusion; group 2, 2% lidocaine 20 mg in saline in a total volume of 10 mL plus venous occlusion for 15 seconds; group 3, 2% lidocaine plus venous occlusion for 30 seconds; group 4, 2% lidocaine plus venous occlusion for 60 seconds; and group 5, saline 10 mL and no venous occlusion. When the first 25% of the calculated propofol dose was administered, patients were asked about propofol-induced pain using a verbal pain scale (0 = no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain). All patients and the anesthesiologist who evaluated pain severity were blinded to the study preparation being used. Results: The study comprised 100 women who were randomly divided into 5 groups of 20 patients each. Significantly more patients in group 5 (18 [90%] patients; P < 0.05) reported pain compared with the other treatment groups. In groups 2, 3, and 4, in which venous occlusion was applied, pain was reported during propofol injection in 6 (30%), 7 (35%), and 2 (10%) patients, respectively. The incidence of reported pain was significantly greater in group 1 (lidocaine without venous occlusion) than in group 4 (P < 0.05); however, the incidence of pain was similar in group 1 compared with groups 2 and 3. Conclusions: The present study found that pretreatment with lidocaine 20 mg with or without venous occlusion significantly reduced the incidence and the severity of pain during the injection of propofol when compared with the group with no venous occlusion administered saline. In addition, pretreatment with lidocaine 20 mg plus venous occlusion for 60 seconds significantly reduced the incidence of propofol-induced pain compared with lidocaine without venous occlusion.

A probable case of oral bisphosphonate-associated osteonecrosis of the jaw and recovery with parathyroid hormone treatment

Abstract: Introduction: Bisphosphonates are effective for treating osteoporosis, Paget's disease of bone, and malignancy-associated bone diseases. Bisphosphonate-associated osteonecrosis of the jaw (ONJ) is a rare but serious adverse effect of bisphosphonate therapy. Due to inhibitory actions on bone turnover, bisphosphonate therapy may result in the accumulation of microdamage. Case summary: A 74-year-old Korean woman (height, 150 cm; weight, 51 kg) was referred to the Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, South Korea, for evaluation of pain and persistent abnormal exposure of jaw bone after extraction of teeth. She had been receiving weekly oral alendronate treatment for osteoporosis for ~5 years. The patient had the clinical features of bisphosphonate-associated osteonecrosis of the mandible, which was precipitated by teeth extraction ~14 months prior to the outpatient referral visit. At her clinical baseline visit, serum hormone concentrations and bone turnover markers were as follows: thyroid-stimulating hormone, 0.88 μIU/mL (reference range, 0.25–5.00 μIU/mL); 25-hydroxyvitamin D3, 20.9 (9.0–37.6) ng/mL; parathyroid hormone (PTH), 57 (11–62) pg/mL; serum osteocalcin, 8.7 (12.9–55.9) ng/mL; and urine N-telopeptide 21 (26–124) nM/mM creatinine. She had multiple systemic risk factors for ONJ, including older age, type 2 diabetes mellitus, and long duration of bisphosphonate therapy. There was no mandibular lesion improvement despite repeated surgical procedures performed within a 14-month period. Bisphosphonate therapy was discontinued and PTH therapy was started. After 2 months, exposed oral mucosa had healed. After 4 months of treatment, the pain had completely subsided, and after 6 months the patient's eating and drinking habits returned. The serum concentration of osteocalcin, a bone formation marker, which was initially suppressed (8.7 ng/mL), increased 174% (15.1 ng/mL) from baseline after 6 months of treatment with PTH. Conclusions: Here we report a probable case of oral bisphosphonate-associated ONJ featuring suppressed bone turnover. Treatment with the bone formation-stimulating agent PTH was beneficial.

Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study

Abstract: Background:The potential combinations of antihypertensive agents are many, and making rational choices depends on the characteristics of each drug and on their complementary mechanisms of action. Objective: The aim of this study was to evaluate the effectiveness of adding hydrochlorothiazide (HCTZ) 12.5 mg to olmesartan 20 mg or telmisartan 80 mg on blood pressure (BP) in patients with moderate hypertension. Methods: Consecutive outpatients at the Centro per l'Ipertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy, of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) ->99 mm Hg and 90 mm Hg) received HCTZ 12.5 mg QD for 8 additional weeks. Clinical and ambulatory BPs were measured at the end of the washout period and at the end of both treatment periods. Adverse events (AEs) were recorded from spontaneous reports and direct inquiry from investigators. Results: One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. A total of 126 white patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive monotherapy. Of these, 35 patients (56%) in the olmesartan group and 33 (52%) in the telmisartan group had previously received antihypertensive therapy. At the end of monotherapy, the 52 patients in the olmesartan group and the 49 patients in the telmisartan treatment group who were still in the study and had their BP inadequately controlled by treatment had HCTZ 12.5 mg QD added to their treatment regimen. Both combinations induced a greater ambulatory mean (SD) systolic BP (SBP) and DBP reduction than monothera- py (SBP: 145.3 [6.1] in the olmesartan group and 140.1 [6.4] in the telmisartan group, P < 0.05; DBP: 88.1 [5.1] in the olmesartan group and 84.9 [4.9] in the telmisartan group, P < 0.05). The mean (SD) reduction from baseline in the telmisartan/HCTZ-treated patients (21.5 [10.1]/14.6 [5.2] mm Hg for 24 hours, 21.8 [10.2]/14.9 [5.2] mm Hg for daytime, and 20.4 [10.3]/13.7 [5.9] mm Hg for nighttime; all, P < 0.001 vs baseline) was significantly greater than that observed in the olmesartan/HCTZ-treated patients (18.8 [9.8]/12.3 [4.9] mm Hg for 24 hours, 19.3 [9.8]/12.8 [4.9] mm Hg for daytime, and 17.4 [10.2]/10.6 [5.5] mm Hg for nighttime; all, P < 0.001 vs baseline), with a significant difference between the 2 treatment groups (P < 0.01). Compared with mono- therapy, the add-on effect of HCTZ 12.5 mg QD administration was significantly greater in the telmisartan group than in the olmesartan group (P < 0.05); the differ- ence being more evident for nighttime BP values (SBP, P 0.031; DBP, P 0.025). Reported AEs were similar in the olmesartan/HCTZ and the telmisartan/HCTZ groups (4 patients [7%] vs 3 patients [6%]). Conclusion: The addition of HCTZ 12.5 mg to telmisartan 80 mg monothera- py was associated with greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 nag monotherapy in these patients previously uncontrolled on monotherapy.

Gabexate mesylate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review and meta-analysis update.

Abstract: Background: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP), and the benefit of pharmacologic treatment of the condition is unclear. Although prophylactic use of gabexate mesylate (GM) for the reduction of pancreatic injury after ERCP has been evaluated, uncertainty remains regarding the effectiveness of GM treatment in post-ERCP pancreatitis (PEP). Objective: The aim of this study was to determine through systematic review and meta-analysis the effectiveness and tolerability of GM in the prophylaxis of PEP. Methods: MEDLINE (January 1966–July 2007), EMBASE (January 1966– July 2007), the Cochrane Controlled Trials Register on The Cochrane Library (Issue 2, 2007), and the China Biological Medicine Database (January 1978–July 2007) were searched. We used the method recommended by The Cochrane Collaboration to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) of GM in the prevention of PEP. Results: Of the 38 studies identified, 31 were excluded for the following reasons: they were reviews or editorials (9 articles); were meta-analyses (4); had differences in cointerventions (4); were nonrandomized controlled trials or had incorrect randomization (4); were repeat publications (2); lacked a placebo group (1); or other (7). Seven RCTs, totaling 2883 patients, conducted in a variety of languages were included in the meta-analysis. When the RCTs were analyzed, odds ratios for GM were 0.65 (95% CI, 0.36–1.18; P 0.16) for PER 1.90 (95% CI, 0.54–6.65; P 0.32) for severe PEP, 0.55 (95% CI, 0.17–1.77; P 0.32) for the case-fatality ratio of PEP, 0.88 (95% CI, 0.74–1.05; P 0.16) for post-ERCP hyperamylasemia, and 0.78 (95% CI, 0.49 1.25; P 0.30) for post-ERCP abdominal pain. No evidence of publication bias was found. Conclusions: No beneficial effects of GM on acute pancreatitis, the PEP mortality rate, or post-ERCP abdominal pain or hyperamylasemia were found; therefore, GM cannot be recommended for the prophylaxis of PEP.

Role of selective cyclooxygenase-2 inhibitors in exacerbation of inflammatory bowel disease: A systematic review and meta-analysis

Abstract: Background: In the general population, selective cyclooxygenase (COX)-2 inhibitors have been associated with fewer gastrointestinal adverse effects (AEs) than NSAIDs, but whether they are associated with exacerbations in patients with inflammatory bowel disease (IBD) remains controversial. Objective: The aim of this study was to review published and unpublished findings to determine whether the use of COX-2 inhibitors increased the risk for IBD exacerbations relative to placebo in the treatment of IBD. Methods: A systematic search of MEDLINE (1966-July 2007), EMBASE (1980-July 2007), the Cochrane Library (2007 Issue 4), US Food and Drug Administration records, and data on file at Novartis Pharmaceuticals Corporation, Pfizer US Pharmaceutical Group, and Merck & Co., Inc., using the search terms celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib, cyclooxygenase 2 inhibitor, Crohn's disease, ulcerative colitis, and inflammatory bowel disease, was performed to identify randomized, placebo-controlled clinical trials of 5 COX-2 inhibitors in patients with IBD. The publications were fully reviewed for quality. Data on trial design, patient characteristics, intervention drugs, dosages, and outcomes were collected using a predetermined data-extraction form. A meta-analysis was performed based on the publications that met the inclusion/exclusion criteria. Results: Of 588 studies identified in the electronic search, 574 were excluded after screening the titles and abstracts. Fourteen related to the use of COX-2 inhibitors in patients with IBD were reviewed. Two randomized, controlled trials comparing COX-2 inhibitors with placebo were identified. In the first trial, 82 patients were randomized to receive etoricoxib (60–120 mg/d) and 77 to receive placebo. The exacerbation rates were 10.5% (8/76) in the active-treatment group and 11.4% (8/70) in the placebo group (relative risk [RR], 0.92; 95% CI, 0.37–2.32). In the second trial, 112 patients were treated with celecoxib (200 mg BID) and 110 received placebo. The exacerbation rates were 3.7% (4/107) in the celecoxib group and 2.7% (3/110) in the placebo group (RR, 0.73; 95% CI, 0.17–3.18). Of these patients, 5 were lost to follow-up because of AEs. In the meta-analysis comparing COX-2 inhibitors and placebo, the RR was 0.86 (95% CI, 0.39–1.88). No statistically significant differences in IBD relapse rates were found between COX-2 inhibitors and placebo. Conclusions: The results from this meta-analysis suggest that insufficient data were available to determine the impact of COX-2 inhibitors on IBD exacerbations. The relatively smaller risk for AEs makes the short-term use of COX-2 inhibitors potentially attractive, but the long-term benefits remain unclear. Further studies with sound methodology and large sample sizes are needed to evaluate the tolerability of COX-2 inhibitors in the treatment of IBD.

Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study

Abstract: Background: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness. Objectives: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness. Methods: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5–10 mg/d) or candesartan (8–12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment. Results: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (−7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect. Conclusion: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT.

Effects of silymarin and pentoxifylline on matrix metalloproteinase-1 and -2 expression and apoptosis in experimental hepatic fibrosis

Abstract: Background: Many therapeutic strategies have been proposed to treat liver fibrosis, but no drugs have been proved effective. Matrix metalloproteinases (MMPs) have been reported to play a role in some cellular cascades of hepatic inflammation and fibrosis. Objective: The purpose of this study was to investigate whether silymarin and pentoxifylline (PTX) have hepatoprotective and antifibrotic effects in experimental hepatic fibrosis. Methods: Sprague-Dawley rats were divided into 4 groups: silymarin group (silymarin 4 mg/kg · d−1 orally, common bile duct ligation [CBDL]); PTX group (PTX 2 mg/kg · d−1 intraperitoneally, CBDL); sham group (common bile duct [CBD] exploration only); and control group (saline 1 mL/d orally, CBDL). The CBD was explored and dissected sufficiently to allow passage of a 3/0 silk suture via midline laparotomy. On day 10, all animals were euthanized via cervical dislocation. Then, 5-cm3 liver samples from the right lobe were removed for histomorphologic evaluation and 3-mL blood samples were taken via cardiac puncture for biochemical analyses. Apoptosis was determined using the terminal deoxynucleotidyltransferase-biotin nick end-label (TUNEL) staining method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase; total and indirect bilirubin concentration; hepatic MMP-1 and -2 and tissue inhibitor of MMP (TIMP)-l and -2 activity; and transforming-growth factor (TGF)-β1 concentration were measured. Collagen content was determined by measuring hydroxyproline in liver samples. Malondialdehyde (MDA) was used to estimate lipid peroxidation. Results: Thirty-two adult male Sprague-Dawley rats were divided into 4 groups: silymarin group (n = 7), PTX group (n = 7), sham group (n = 9), and control group (n = 9). Compared with the control group (14.6 [2.44]), mean (SD) hepatocyte apoptosis (as measured by the ratio of TUNEL-positive cells) was significantly suppressed in the silymarin group (1.2 [0.13]; P = 0.001) and the PTX group (3.8 [0.34]; P = 0.001). Mean (SD) MMP-2 activity in the silymarin group (57.35 [9.89] μg/mL; P = 0.04) and the PTX group (46.88 [9.56] μg/mL; P = 0.04) was significantly lower than that observed in the control group (232.32 [79.76] μg/mL). Compared with the control group (1.37 [0.38] μg/mL), TIMP-2 activity was significantly lower in the silymarin group (0.55 [0.13] μg/mL; P = 0.04) and the PTX group (0.42 [0.09] μg/mL; P = 0.01). Compared with the control group (909.17 [117.35] μg/mL), TGF-β1 was significantly lower in the silymarin group (518.24 [30.34] μg/mL; P = 0.01) and the PTX group (519.57 [47.27] μg/mL; P = 0.01). Histomorphologic changes were significantly greater in the sham group than in the silymarin and PTX groups: hemorrhage (2.44 [0.29] vs 1.29 [0.18] and 1.57 [0.20], respectively; both, P = 0.04); sinusoidal dilatation (2.22 [0.22] vs 1.57 [0.20] and 1.71 [0.18]; both, P = 0.04); presinusoidal polymorphonuclear cell infiltration (3-44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively); and inflammation (3.44 [0.24] vs 2.57 [0.20] and 2.14 [0.26]; P = 0.03 and P = 0.008, respectively). In the control group, all biochemical markers were elevated, supporting the presence of liver injury. Compared with the control group (630.00 [46.80] U/L), plasma AST activity was significantly lower in the silymarin group (443.11 [78.73]; P = 0.04) and the PTX group (349.42 [34.00]; P = 0.03). Compared with the control group (191.12 [32.93] U/L), plasma ALT activity was significantly lower in the silymarin group (86.14 [4.97]; P = 0.04) and the PTX group (84.14 [11.21]; P = 0.04). MDA concentration was significantly lower in the silymarin group compared with the control group (0.08 [0.01] vs 0.22 [0.03] nmol/mL; P = 0.004); MDA was also significantly lower in the silymarin group than in the PTX group (0.11 [0.02]; P = 0.03). Conclusions: Silymarin and PTX were associated with lower histopathologic liver damage, hepatocyte apoptosis, and regulation of extracellular matrix proteins. Lipid peroxidation in hepatocytes was significantly lower in the silymarin group compared with the PTX group. Silymarin and PTX appeared to have hepatoprotective effects in this experimental liver fibrosis model, but further clinical and experimental studies are needed.

Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

Abstract: Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). Conclusion: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily.

Effect of intravenous administration of antioxidants alone and in combination on myocardial reperfusion injury in an experimental pig model.

Abstract: Background: Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These studies were done primarily in experimental protocols that did not approximate clinical situations. Objective: The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model. Methods: Farm-raised domestic male pigs (aged 3–5 months, weight of 30–35 kg) were assigned to 1 of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (210 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method. Results: The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular atrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured. Conclusion: In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did not reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis.

Pharmacokinetics and Postoperative Analgesia of Epidural Tramadol : A Prospective, Pilot Study

Abstract: Background: Tramadol, a centrally acting analgesic drug, can be administered via multiple routes and is generally well tolerated. Objective: This study was designed to assess the pharmacokinetics of epidural tramadol administered preoperatively in Japanese patients undergoing upper abdominal surgery. Method: Japanese patients who were scheduled to undergo upper abdominal surgery in The Kitasato Institute Hospital, Tokyo, Japan, were included. Patients received tramadol 2 mg/kg with 5 mL of 1% mepivacaine epidurally 10 minutes before incision. The serum concentration of tramadol was determined by high-performance liquid chromatography for 21 hours after administration. Serum concentration was determined before tramadol administration and 10, 20, 30, and 60 minutes after tramadol administration, first postoperative night, and first postoperative day. Pain score and adverse events (AEs) were assessed at 1, 3, 6, 12, 18, 24, 36, and 48 hours after surgery by patient interview. Results: Eleven patients were assessed for enrollment. Seven patients (6 men, 1 woman; mean [SD] age, 61.3 [12.6] years; mean [SD] weight, 59.9 [8.9] kg) provided consent and completed the study. The mean (SD) serum Cmax of tramadol was 1385.5 (390.8) ng/mL, Tmax was 0.33 (0.22) hour, and terminal elimination half-life (t1/2β) was 10.5 (2.3) hours. Four patients complained of nausea; however, only 1 patient was administered an antiemetic. No other AEs were reported. Conclusion: This pilot study found that epidural tramadol administered before incision induced a Cmax within 30 minutes of administration. The drug was detected in serum at ∼21 hours after surgery.

Self-reported influence of television-based direct-to-consumer advertising on patient seasonal allergy and asthma medication use: An internet survey

Abstract: Background: Direct-to-consumer advertising (DDTCA) of medications, a marketing tool used by the pharmaceutical industry to increase patient awareness of products, affects both consumer behavior and, ultimately, physician prescribing practices. Billions of dollars are budgeted each year for DTCA, and its influence is far-reaching. However, little information is available about patient-initiated physician interactions in which television-bbased DTCA has played a role in consumer behavior. Objective: The objective of this study was to explore the influence of television-based DTCA on treatment changes in patient-initiated medication use. Methods: A 68-item survey instrument consisting of dichotomous, multiple-choice, and open-ended questions was constructed and sent to a convenience sample of US residents during 3 consecutive months ending in February 2005. The survey, which was accessed through an Internet link provided in the e-mail, was designed to capture data about patient perceptions and behaviors regarding television-based DTCA of prescription medications used for seasonal allergy and asthma as well as demographic information. Inferential and descriptive analyses were performed. Key tests included Crosstabs analysis and normal approximation to the binomial test with the z score. Results: Surveys were sent to 2500 individuals. A total of 427 valid surveys were returned for a 17.1% response rate. Of the 402 respondents (94.1%) who stated that they had seen DTCA for seasonal allergy medication, 50 (12.4%) said they had discussed the advertised medication with their physician and 22 of those discussions (44.0%) resulted in a change in treatment. Three hundred forty-two respondents (80.1%) stated that they had viewed DTCA for prescription asthma medications, and 23 of those respondents (6.7%) said that they had discussed the brand of asthma medication viewed on television with their physician. Those discussions resulted in a change in treatment for 9 respondents (39.1%). Conclusion: Within th his limited, self-reported, survey sample, patient-initiated discussions with physicians regarding television-based DTCA of allergy and asthma medications resulted in a change of treatment in 44.0% and 39.1% of respondents, respectively.

Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study

Abstract: Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae. Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects. Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters. Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4.0), 12.6 (5.8), and 9.4 (1.1) hours; AUC0−t, 3344 (1635), 8389 (5164), and 9361 (2428) ng/mL · h−1; and Cmax , 218.7 (68.6), 435.7 (202.1), and 553.4 (152.8) ng/mL. The plasma glucuronidated genistein concentrations were directly proportional to the administered dose over the range of 50 to 100 mg and increased nonproportionately with the 300-mg dose. No statistically significant differences in pharmacokinetic parameters were found in the fasting group compared with the postprandial group. In the multiple-dose group, the mean (SD) steady-state pharmacokinetic parameters on day 9 were similar to those following a single dose of genistein on day 1 (Tmax, 6.0 [1.0] vs 5.9 [1.5] hours, respectively; tl/2, 9.5 [1.5] vs 9.1 [1.5] hours; AUC0−t, 2830 [1541] vs 2078 [1308] ng/mL · h−1; Cmax, 203.1 [130.9] vs 168.4 [105.7] ng/mL). All AEs were assessed as mild or moderate and resolved without treatment, with the exception of elevated alanine aminotransferase and aspartate aminotransferase activities in one subject that resolved with treatment. Conclusions: The pharmacokinetics of glucuronidated genistein appeared to fit the linear-dose range of genistein 50 to 100 mg, but not the 300-mg dose in these healthy Chinese volunteers. Food consumption did not significantly affect the pharmacokinetic properties. No significant differences were observed in the pharmacokinetic parameters after multiple doses of genistein compared with a single dose, suggesting that the drug did not accumulate after multiple doses.

Effects of nebivolol on skin flap survival: A randomized experimental study in rats.

Abstract: Background: Skin flaps are among the basic treatment options in the reconstruction of soft tissue defects. To improve skin flap survival, a variety of methods, including pharmacologic agents, have been investigated. The effectiveness of anticoagulants, antioxidants, anti-inflammatory drugs, and vasodilatory drugs in improving flap survival has been studied. Nebivolol is a new-generation selective β1-adrenoreceptor blocking agent that has vasodilatory, antithrombotic, antioxidative, and anti- inflammatory effects. Objective: The aim of this experimental study was to investigate the effects of nebivolol (50 mg/kg/d) on random pattern skin flap survival in rats. Methods: Male Wistar rats weighing 290 to 310 g were randomly divided into 2 groups—the nebivolol group and the control group. Random patterned, caudally-based, ~3 × 10-cm skin flaps were elevated on the back of each rat. In the nebivolol group, nebivolol 50 mg/kg/d (1 mL, of a racemic solution of nebivolol) was administered orally 2 days before surgery to reach steady-state drug blood concentrations and was continued for 6 days. In the control group, 1 mL/d of sterile saline solution was orally administered 2 days before surgery and was continued for 6 days. To observe the effects of nebivolol, cutaneous blood flow was examined using a laser Doppler flow-meter before and after surgery on days 1, 3, 5, and 7, and flap tissue, malondialdehyde (MDA) and glutathione (GSH) concentrations, and superoxide dismutase (SOD) activity were measured 7 days postsurgery. Flap viability was evaluated 7 days after surgery by measuring necrotic flap area and total flap area. Results: All 20 rats (nebivolol group, n = 10; control group, n = 10) survived throughout the study period. Mean (SD) MDA concentration was significantly lower in the nebivolol group than in the control group (69.25 [5.82] vs 77.67 [6.87] nmol/g tissue; P = 0.009). GSH concentration was significantly higher in the nebivolol group than in the control group (2.14 [0.15] vs 1.88 [0.22] nmol/mg tissue; P = 0.004). SOD activity was significantly greater in the nebivolol group than in the control group (49.28 [5.49] vs 42.09 [4.95] U/g tissue; P = 0.007). The percentage of the flap that was necrotic was significantly lower in the nebivolol group than in the control group (40.27 [4.08] vs 48.87 [6.35]; P = 0.007). Conclusions: This small, experimental, in vivo animal study found that nebivolol was associated with reduced necrotic random pattern skin flap area. Further studies are needed to clarify these findings.

Bioequivalence evaluation of two capsule formulations of amoxicillin in healthy adult male bangladeshi volunteers: A single-dose, randomized, open-label, two-period crossover study

Abstract: Background: Amoxicillin, a semisynthetic penicillin antibiotic, is widely prescribed in Bangladesh due to its extended spectrum and its rapid and extensive oral absorption with good tolerability. Although a number of generic oral formulations of amoxicillin are available in Bangladesh, a study of the bioequivalence and pharmacokinetic properties of these formulations has not yet been conducted in a Bangladeshi population. Objective: The aim of this study was to assess the pharmacokinetic properties and bioequivalence of 2 formulations of amoxicillin 500-mg capsules (test, SK-mox®; reference, Amoxil-Bencard®) using serum data. Methods: This single-dose, randomized, open-label, 2-period crossover study was conducted in healthy male subjects in compliance with the Declaration of Helsinki and International Conference on Harmonisation guidelines. Subjects were assigned to receive the test or the reference drug as a single-dose, 500-mg capsule under fasting conditions after a 1-week washout period. After oral administration, blood samples were collected and analyzed for amoxicillin concentration using a validated high-performance liquid chromatography method. The pharmacokinetic parameters were determined using a noncompartmental method. The formulations were considered bioequivalent if the natural log-transformed ratios of pharmacokinetic parameters were within the predetermined equivalence range of 80% to 125%, according to the US Food and Drug Administration (FDA) requirement. Results: Twenty-four healthy adult male Bangladeshi volunteers (mean [SD] age, 26.92 [3.37] years; age range, 23–34 years; mean [SD] body mass index, 23.O9 [1.58] kg/m2) participated in the study. Using serum data, the values obtained for the test and reference formulations, respectively, were as follows: Cmax, 9.85 (2.73) and 10.63 (2.12) μg/mL; Tmax, 1.29 (0.58) and 1.33 (0.49) hours; and AUC0–12, 27.09 (7.62) and 28.56 (6.30) μg/mL · h−1. No period, sequence, or formulation effects were observed; however, significant variation was found among subjects with regard to AUC0–12 (P < 0.001), AUC0−∞ (P = 0.002), area under the moment curve (AUMC) from 0 to 12 hours (P < 0.001), and AUMC0−∞ (P = 0.017). All CIs for the parameters measured were within the FDA-accepted limits of 80% to 125%. Conclusion: The present study suggests that the test 500-mg amoxicillin capsule was bioequivalent to the reference 500-mg capsule according to the FDA regulatory definition, in this population of healthy adult male Bangladeshi volunteers.

Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study.

Abstract: Background: The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro Objective: The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats Methods: This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment Latency was defined as time elapsed between the first mount and intromission Results: A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP (400 and 800 mg/kg) compared with the controls There was also no between-group difterence in mating behavior among the active treatment groups All rats survived up to study completion, with normal behavior (weight gain, food intake, daily observations, without any sign of toxicity) There were no observable adverse events during the study Conclusions: D-004 and LESP administered as a single dose or repeated doses for 30 days did not significantly affect male rat sexual activity behavior compared with a vehicle control group

Antihypertensive effect of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension according to their cardiovascular risk level: A post hoc analysis.

Abstract: Background: International guidelines recommend the use of angiotensin-converting enzyme inhibitors, possibly in combination with other antihypertensive drugs, to treat hypertension with associated risk factors. Objective: The aim of this study was to compare the antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension, according to their cardiovascular risk level. Methods: This was a post hoc analysis of a previously published efficacy and tolerability study. After a 4-week placebo washout, patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95-115 mm Hg), aged 18 to 75 years, were randomized at a ratio of 2:1:1 to treatment with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or monotherapy with zofenopril 30 mg or hydrochlorothiazide 12.5 mg for 12 weeks in an international, multicenter, double-blind study. This period was followed by 24 weeks of open-label treatment. Systolic BP [SBP] and DBP were measured by mercury sphygmomanometry, and changes associated with treatment were calculated. Patients' cardiovascular risk was computed using the Heart Score algorithm. Patients were classified in quartiles according to distribution of cardiovascular risk level, and comparisons were limited to the zofenopril plus hydrochlorothiazide and zofenopril monotherapy treatment groups. The primary end point was change in office DBP. Results: Two hundred forty-six patients (139 men, 107 women; mean [SD] age, 54 [11] years) were included in the analysis. Mean baseline cardiovascular risk was similar in the zofenopril plus hydrochlorothiazide group and the zofenopril monotherapy group (7% vs 9%). DBP and SBP reductions with treatment were significantly greater (both, P < 0.01) with combination treatment than with monotherapy for each quartile of cardiovascular risk. Cardiovascular risk reduction at the end of the 12 weeks of double-blind treatment was greater in the zofenopril plus hydrochlorothiazide group than in the zofenopril monotherapy group (1.9% vs 0.2%; P < 0.01), particularly in the group of patients with the highest cardiovascular risk at baseline (5.2% vs 2.0%). At the end of the 24-week open-label treatment period, the mean reduction in cardiovascular risk was also significantly greater in the combination treatment group than in the monotherapy group (1.4% vs 0.5%; P < 0.01). Conclusions: In these hypertensive patients, combination treatment with zofenopril plus hydrochlorothiazide was associated with a significantly greater decrease in BP compared with zofenopril monotherapy, regardless of the patient's cardiovascular risk. The difference between combination treatment and monotherapy was particularly evident for the group of patients at highest risk.

Ultrastructural changes in rat thyroid tissue after acute organophosphate poisoning and effects of antidotal therapy with atropine and pralidoxime: A single-blind, ex vivo study

Abstract: Background: Organophosphate (OP) insecticides are widely used in both agricultural and landscape pest control, and the potential for human exposure to these compounds is significant. Objectives: The aims of this study were to investigate the effects of acute poisoning with the OP methamidophos and the effects of antidotal therapy with atropine and pralidoxime on rat thyroid tissue ultrastructure. Methods: In this single-blind, ex vivo study, male Wistar albino rats weighing 220 to 230 g were divided into 4 treatment groups. Group 1 received a median lethal dose of methamidophos (30 mg/kg) via oral gavage. Group 2 received saline via oral gavage and served as the control group for group 1. Group 3 received methamidophos (30 mg/kg) via oral gavage, and after 8 minutes atropine 0.05 mg/kg and pralidoxime chloride (2-FAM) (40 mg/kg) were administered intraperitoneally (IP). Atropine was titrated to reverse signs of cholinergic excess. Group 4 received saline via oral gavage followed by IP injections and served as the control for group 3. Rat thyroid tissues were examined using electron microscopy, and the histologic changes were examined by a histopathologist who was blinded to treatment. All rats were euthanized by intracardiac blood collection. The rats in groups 1 and 2 were euthanized 8 minutes after treatment. The rats in groups 3 and 4 were euthanized 96 hours after treatment. Results: Thirty-four male rats (aged 16 weeks) were included in the study. The rats were grouped accordingly: group 1 (n = 10); group 2 (n = 7); group 3 (n = 10); and group 4 (n = 7). The mean (SD) pseudocholinesterase (FCE) activity was significantly lower in the methamidophos-treated rats (group 1) compared with the corresponding control group (group 2) (32.6 [17.0] vs 579.4 [59.0] U/L, respectively; P < 0.001). PCE activity was significantly higher in rats treated with atropine and 2-PAM (group 3) (392.5 [39.4] U/L; P < 0.001) compared with those not receiving antidotal therapy (group 1). Group 1 experienced changes in thyrocytes and organelles that were not detected in the antidote-treated rats in group 3. These changes included follicular cell nuclei exhibiting an increase in chromatin content, pyknotic nuclei, mitochondrial degeneration, dilated granular endoplasmic reticulum cisternae, reduced microvilli, and intraluminal cellular debris. Within follicular cells, formation of vacuoles filled with fine granular material was noted. Conclusion: Acute OP poisoning was associated with histopathologic effects in rat thyroid tissue that appeared to be mitigated by antidotal therapy in this small animal study. More extensive studies using immunohistochemical methods are needed.

Comparison of Methimazole/Hydrocortisone Ointment with Oral Methimazole in Patients with Graves Disease : A Prospective, Randomized, Open-Label, Parallel-Group, 18-Month Study

Abstract: Background: Thionamide antithyroid drugs (ATDs) have certain disadvantages and are associated with some adverse events (AEs). To overcome the problems associated with ATDs, a compound antithyroid ointment (CATO) containing methimazole (MMI) and hydrocortisone has been developed for use as a local thyroid treatment (LTT). Objective: The aim of this study was to assess the clinical effectiveness and tolerability of CATO LTT in patients with Graves disease (GD). Methods: This was a prospective, randomized, open-label, parallel-group clinical trial conducted at the Provincial Hospital Affiliated to Shandong University (Jinan, China). Patients with GD aged 19 to 65 years were randomized to receive either CATO LTT 0.3 g/d or oral MMI 37.5 mg/d (control group) treatment for 18 months, with a 4-year follow-up period. Hyperthyroid symptoms, thyroid function, granulocyte count, liver function, and AEs were assessed at baseline and every 2 weeks until serum thyroid hormone (TH) concentration normalized, at which point patients were assessed monthly. The primary efficacy end points were the duration of treatment required for serum TH concentration to normalize and the remission rate after completing the 18-month treatment regimen. Results: A total of 154 patients (133 women, 21 men; mean [SD] age, 39.6 [11.8] years; all Han Chinese) participated in the study; all patients completed the 18-month treatment period. Compared with the MMI group (n 76), the CATO- treated group (n 78) had a significantly shorter median (range) time to restoration of normal serum thyroid hormone concentration (43 [12–150] vs 22 [7–60] days; P < 0.001), a significantly lower rate of recurrence of hyperthyroidism (309/1520 [20.3%] vs 193/1368 [14.1%] person-time; P < 0.001), a significantly lower drug hypothyroidism rate (185/1520 [12.2%] vs 54/1368 [3.9%] person-time; P < 0.001), and a higher remission rate (year 1:46/69 [66.7%] vs 65/72 [90.3%] patients, P 0.001; year 2:40/69 [58.0%] vs 60/72 [83.3%] patients, P - 0.001; year 3:34/69 [49.3%] vs 57/72 [79.2%] patients, P < 0.001; and year 4:30/69 [43.5%] vs 55/72 [76.4%] patients, P < 0.001). Systemic AEs occurred in 6 patients (7.9%) in the MMI group (drug neutropenia, 2 patients [2.6%]; epistaxis, 1 [1.3%]; hepatopathy, 1 [1.3%]; and other systemic AEs, 2 [2.6%]), while no systemic AEs were observed/reported in the CATO group. Conclusion: This study suggests that CATO LTT was well tolerated and more effective than oral MMI treatment in controlling thyrotoxicosis and promoting remission of GD in these Han Chinese patients.

Effects of D-003, a mixture of high-molecular-weight sugar cane wax acids, on lipid peroxidation markers in older individuals: A randomized, double-blind, placebo-controlled study

Abstract: Background: Aging is associated with increased lipid peroxidation (LP). D-003, a mixture of long-chain aliphatic primary acids purified from sugar cane wax, has been found to inhibit LP in experimental models and in healthy subjects. Objectives: The aim of this study was to assess the effects of D-003 on LP markers and the lipid profile of older individuals. Methods: This randomized, double-blind, placebo-controlled study was conducted at the Plaza Veterans' House, Havana City, Cuba. Male and female patients aged ≥60 years with total cholesterol values of <6.1 mmol/L were eligible for inclusion in the study. After a 3-week lead-in and baseline assessment period, patients were randomized to receive PO D-003 5 mg/d, D-003 10 mg/d, or placebo for 8 weeks. The effect on copper-induced LP of low-density lipoprotein (LDL) particles was the primary variable, and the effects on plasma total antioxidant status (TAS), plasma malondialdehyde (MDA) concentration, plasma antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activities, and the lipid profile were secondary variables. A clinical examination was performed at each visit (baseline, weeks 4 and 8). A clinical examination, LP, and blood tests (lipid profile, hematologic, and blood biochemistry safety indicators) were performed at baseline and after 8 weeks of treatment. Compliance and adverse events (AEs) were assessed at weeks 4 and 8. A 2-tailed P < 0.05 was considered statistically significant for comparisons of both continuous and categoric variables. Results: Fifty-four patients aged ≥60 years were assessed for inclusion in the study, and 51 patients (40 women, 11 men; mean [SD] age, 67 [6] years) were included in the study. The lag phase of conjugated diene formation increased significantly and in a dose-dependent manner in the group treated with D-003 5 mg (24.7%; P < 0.01) and in the group treated with D-003 10 mg (29.3%; P < 0.01) compared with placebo. The maximal rate of conjugated diene propagation decreased significantly in the D-003 5- and 10-mg groups −22.7% and −25.8%, respectively; both, P < 0.05) compared with placebo. TAS increased significantly (17.7% and 23.0%, respectively; both, P < 0.01) in both active treatment groups compared with placebo. Plasma MDA concentration decreased significantly in the D-003 10-mg group (−28.6%; P < 0.05) but not in the D-003 5-mg group, compared with placebo. These changes were also significant compared with baseline. Antioxidant enzyme activities did not change in the active treatment groups compared with placebo or baseline. In the D-003 5- and 10-mg groups, significant decreases were found in LDL cholesterol concentration (−15.8% and −23.8%, respectively; both, P < 0.001) and total cholesterol concentration (−13.0% and −16.8%, both, P < 0.05) compared with placebo. High-density lipoprotein cholesterol concentration increased significantly in the D-003 5-mg group (5.7%; P < 0.05) and the D-003 10-mg group (18.2%; P < 0.001) compared with placebo. Changes in the lipid profile were also significant compared with baseline. In the placebo group, no variable changed significantly compared with baseline. D-003 was well tolerated at both dose levels, and no patient withdrew from the study. There were a total of 3 AEs reported: insomnia and acidity in 2 patients receiving placebo; and heartburn in 1 patient receiving D-003 5 mg. Conclusions: D-003 5 and 10 mg/d administered to these older individuals (aged ≥60 years) for 8 weeks inhibited LP of LDL and increased TAS in a dose-dependent manner, while plasma MDA concentration decreased in the patients receiving D-003 10 mg/d only. D-003 was well tolerated at both doses

Ecstasy-induced recurrent toxic hepatitis in a young adult.

Abstract: BACKGROUND: The drug 3,4-methylenedioxymethamphetamine (MDMA), otherwise known as “ecstasy,” is a synthetic amphetamine that produces euphoria, increases sociability and energy, and is often used as a “weekend” recreational drug by young adults. CASE SUMMARY: A 23-year-old male (height, 184 cm; weight, 68 kg) presented to the emergency department of Marmara University Hospital, Istanbul, Turkey, with jaundice and nausea lasting for 6 days. The patient reported that he had been a chronic user of MDMA for 2 years. He also reported that 1 week before presenting, he had ingested twice (2 tablets) the usual amount (1 tablet) of the drug at the same time. Blood tests were performed and hematologic findings were as follows: aspartate aminotransferase (AST), 1423 U/L (reference range, 10–37 U/L); alanine aminotransferase (ALT), 2748 U/L (10–40 U/L); alkaline phosphatase, 271 U/L (0–270 U/L); γ-glutamyl transpeptidase, 124 U/L (7–49 U/L); total bilirubin, 13.23 mg/dL (0.2–1 mg/dL); direct bilirubin, 8.75 mg/dL (0–0.3 mg/dL); amylase, 80 U/L (0–220 U/L); prothrombin time, 21.2 sec; activated partial thromboplastin time, 37.3 sec; and international normalized ratio, 1.66. Liver enzymes and bilirubin levels were found to be extremely high (AST = 40x normal, ALT = 70x normal, and bilirubin = 13x normal). Viral, autoimmune, and metabolic causes were excluded. Serologic tests for hepatitis A, B, and C viruses, mononucleosis, cytomegalovirus, and HIV infection were all negative. A diagnosis of ecstasy-induced toxic hepatitis was made. The patient's medical history further revealed that the current incident was actually his second occurrence of jaundice and acute hepatitis associated with the ingestion of higher amounts (twice the usual amount of MDMA he ingested at the same time). Supportive therapy (IV saline and vital sign monitoring) was initiated and liver enzymes, bilirubin levels, and prothrombin times were monitored daily. All had returned to normal values in 2 weeks. CONCLUSIONS: MDMA, or the recreational drug ecstasy, might be responsible for acute hepatitis and/or acute liver failure, particularly in young people. Physicians might need to be alert to the possibility of ecstasy-induced liver damage occurring in younger patients, although the presence of other hepatotoxins and alternative diagnoses requires exclusion. The use of this drug should be investigated in young patients with severe hepatitis of unknown origin.

Effectiveness and Tolerability of Warm-Supplementing Kidney Yang Added to Risperidone in Improving Cognitive Impairment in Patients with Schizophrenia : An 8-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract: Background: Certain herbal medicines have been reported to be effective in the treatment of psychiatric conditions, and combination treatment with drugs and herbal medicines has been reported to be useful in enhancing treatment efficacy and reducing recovery time and adverse events (AEs). Objective: The purpose of this study was to investigate the effectiveness and tolerability of warm-supplementing kidney yang (WSKY) added to risperidone in improving cognitive impairment and negative symptoms (ie, cognitive function) in patients with schizophrenia. Methods: This 8-week, multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in patients who met the clinical classification for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Patients were recruited from 3 centers (including inpatient and outpatient clinics) and were evenly randomized to receive WSKY or placebo added to risperidone for 8 weeks. Primary assessments were conducted at weeks 2, 4, and 8. A clinical response was defined as a ≥50% reduction score (from baseline) on the Positive and Negative Syndrome Scale (PANSS), a ≥30% reduction score (from baseline) on the Scale for the Assessment of Negative Symptoms (SANS), or a ≥50% reduction score (from baseline) on the Hamilton Rating Scale for Depression (HAM-D-17). Cognitive function was assessed using the Wisconsin Card Sorting Test (WCST) at baseline and end point. Extrapyramidal AEs were assessed weekly using the Abnormal Involuntary Movement Scale (AIMS) and the Rating Scale for Extrapyramidal Side Effects (RSESE). AEs were assessed by patient interviews conducted at each clinic visit and also by the Treatment Emergent Symptoms Scale (TESS) scores. Results: One-hundred twenty patients (62 males, 58 females; mean [SD] age, 34.4 [9.4] years; range, 18–45 years; baseline mean [SD] PANSS score, 88.7 [12.3]) were included in this study. Risperidone- and WSKY-treated patients had statistically significant improvements at end point in the number of completed categories (P = 0.019), perseverative responses (P = 0.041), perseverative errors (P = 0.040), and total errors (P = 0.049) on the WCST compared with placebo. The improvements in the PANSS, SANS, and HAM-D-17 scores were not significantly different between the 2 groups at week 8 for observed case and last-observation-carried-forward (LOCF) analyses. The response rates (LOCF) for the PANSS scores in the WSKY and placebo groups were 55.0% and 35.0%, respectively (P = 0.028), while the SANS scores were 63.3% and 45.0% (P = 0.044) and the HAM-D-17 were 35.0% and 45.0% (P = 0.264). There were no significant between-group differences in scores on the AIMS, RSESE, or TESS. Conclusions: The results of this study suggest that WSKY added to risperidone significantly improved cognitive function in these patients, as measured by the number of completed categories, perseverative responses, perseverative errors, and total errors on the WCST compared with placebo. The response rates in the WSKY group for the PANSS and SANS scores were significantly higher compared with placebo. All treatments were generally well tolerated.

The effects of montelukast on random pattern skin flap survival: An experimental study in rats

Abstract: Background: A variety of methods to improve skin flap survival, including the use of pharmacologic agents, have been intensively investigated. Decreasing neutrophil-mediated inflammation and tissue injury has been reported to be effective in improving flap survival. Montelukast is a selective reversible cysteinyl leukotriene receptor-1 antagonist that has been found to have protective effects against renal ischemia reperfusion injury and burn-induced oxidative injury of the skin in rats. However, its effects on skin flap survival have not been previously reported. Objective: The aim of this study was to investigate the effects of montelukast on neutrophil-mediated random pattern skin flap survival. Methods: Male Sprague-Dawley rats weighing 230 to 250 g were randomly divided into 2 groups—the montelukast-treated group and the control group. Caudally based rectangular random pattern skin flaps 3 × 9 cm were elevated on the backs of the rats. The flaps were sutured into their original places. In the montelukast group, 1 mL of solution containing 10 mg/kg montelukast was administered intraperitoneally (IP) 30 minutes before surgery and then daily for 6 days. In the control group, 1 mL of saline was administered IP 30 minutes before surgery and then daily for 6 days. To observe the effects of montelukast, myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, was measured from extracted skin tissue 12 hours after flap elevation. Flap viability was evaluated 7 days after surgery by measuring necrotic flap area and total flap area. Results: Sixteen rats (mean [SD] weight, 240.6 [6.6] g) were equally divided between the 2 groups. All rats survived throughout the study period. Mean (SD) MPO activity in flap tissue was significantly lower in the montelukast group than in the control group (14.57 [2.33] vs 21.28 [4.86] U/g protein; P = 0.005). The percentage of necrotic flap area was significantly lower in the montelukast group than in the control group (17.17 [7.95] vs 37.51 [10.72]; P = 0.001). Conclusion: This small, experimental, in vivo animal study found that montelukast was associated with both lower MPO activity and a lower percentage of necrotic random pattern skin flap area. Future studies are needed to clarify these findings.