Safety, tolerability and pharmacokinetic study of recombinant human parathyroid hormone in healthy male Chinese subjects

AIM： To determine the safety, tolerability and pharmacokinetic parameters of a new drug recombinant human parathyroid hormone [ rhPTH （1-84）] in healthy male Chinese subjects. METHODS： domly divided Thirty-six healthy male volunteers were rangroups received into 3 groups. The volunteers in these single subcutaneous injection of rhPTH （ 1-84） in a dosage of 1, 2 and 4 μg/kg respectively. Blood samples were obtained before and after administration within 24 hours. The rhPTH concentrations in sennn were determined by enzyme linked immunosorbent assay （ELISA）. The pharmacokinetic parameters determined with use of standard noncompartmental analysis were the maximum serum concentration （ Cmax ）, the time to attain that concentration （ tmax ）, and the area under the serum concentration-time curve up to 24 hours（ AUC0-24 ） and up to infinity （AUC0-∞）. Dose proportionality of pharmacokinetic parameters （AUC, Cmax of every volunteer of each dosage and A UC was computed from log transformed data） and was examined by mean of analysis of variance （ANOVA） using SPSS software package. In the study, subjects＇ symptoms, objective signs, and vital signs, including blood pressure, heart rate, respiratory rate and body temperature, were checked and 12-lead electrocardiography was recorded before and after drug administration within 24 hours. Routine laboratory tests, including hematology, blood biochemistry, serum electrolyte, and urinalysis, were performed before and after drug administration within at 24 hours.[第一段]     

伐地那非的安全性和耐受性

本文回顾了伐地那非治疗勃起功能障碍(erectile dysfunction,ED)的安全性和耐受性,包括其总体安全性、心血管安全性和视觉安全性。临床试验和实际应用的实践经验证明,最常见的不良事件为头痛、颜面潮红和鼻充血,并且多为轻、中度和一过性。无论在一般ED人群中还是在难治性ED人群中,无论是短期还是长期应用,伐地那非均有良好的安全性和耐受性。     

Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation

In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml^–1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg^–1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l^–1 directly after the infusion. Following the 8.0 ml·kg^–1 dose a more pronounced increase from 12.4 to 21.2 g·l^–1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l^–1 in the 4.0 ml·kg^–1 group, but were still significantly increased at 15.2 g·l^–1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml^–1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min^–1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.     

A Comparative Study of Dihydroartemisin in Compounds in Treatment of Uncomplicated Falciparum Malaria in Kampong of Cambodia

Objective: To compare the safety and efficacy of two compounds of dihydroartemisinin(DHA) -Artekin and Artekin (T) in the treatment of uncomplicated falciparum malaria. Methods:The regimen of 8-tablet for 2 days of Artekin and Artekin (T) were applied to 100 patients with uncomplicated falciparum malaria, who were randomly divided into two groups. Each group contained 50 cases. The cure rate, the mean parasites clearance time, the mean fever clearance and side-effects were observed to assess the safety and efficacy of the compounds used. Results: The mean parasites clearance time was 31. 7±9.0 hours in the Artekin group and 32. 8±8. 8 hours in Artekin (T) group respectively; the mean fever clearance time was 12. 7±7. 2 hours in Artekin group and 16. 5±7. 9 hours in Artekin (T) group; there were no recrudescence case in both groups within the 28 days of follow-up, the cure rates in Artekin group and Artekin (T) groups were 100%. It indicated that the tolerability of both compounds were very good, the     

Single-dose and steady-state pharmacokinetics of sabeluzole in senile dementia of Alzheimer type patients

Summary The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type.After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng·ml^–1. On repeated dosing (10 mg b. d.), steady-state was virtually attained after 3 days of treatment. Steadystate mean trough and peak plasma concentrations fluctuated between 53 and 94 ng·ml^–1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h.Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen.     

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer

ObjectivesMany trials conclude “no clinically meaningful detriment” to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration.MethodsThis study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months.ResultsGenerally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms.ConclusionsIn trials with moderate to large differences in symptomatic toxicity by arm, reporting “no meaningful difference in functioning and HRQL between arms” based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.     

A placebo-controlled crossover study of ketanserin in elderly hypertensive patients

Summary The results of the European Working Party for Hypertension in the Elderly Study showed that treatment of high blood pressure reduced the morbidity and mortality from strokes and myocardial infarction and reduced the incidence of heart failure in elderly patients. The largest number of hypertensive patients are elderly, and it is in this group of patients that the maximum benefit of treatment might be expected. The present study was designed to study in detail the efficacy and tolerability of ketanserin in an elderly population. Seventeen elderly (> 70 years) patients with a lying systolic blood pressure of 160 mmHg and/or a diastolic blood pressure of 90 mmHg were included in the study. For the 12 patients who completed the study, the mean blood pressure was significantly reduced on ketanserin compared with placebo (p<0.001) in the supine and erect positions. The mean net changes in blood pressure after 8 weeks were 21/17 mmHg and 23/16 mmHg erect. Heart rate was also significantly reduced (p<0.001) by a mean of 8 beats/min lying and 9 beats/min erect. Analysis of ambulatory 24-hour ECG tapes showed no significant effect of ketanserin on heart rhythms. Ketanserin therapy had no significant effect on routine hematology, plasma electrolytes, biochemistry, or urinalysis. Total exchangeable sodium and potassium and body weight were also unchanged. On ketanserin treatment, the overall quality of life score was significantly improved (p=0.002; analysis of variance on log transformed data) compared with the placebo phase.     

Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.     

Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.

BACKGROUND: ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors. PATIENTS AND METHODS: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. RESULTS: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing. CONCLUSIONS: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.     

Pharmacological treatment of generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging.

Areas covered: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: ‘generalized anxiety disorder AND treatment’ and ‘generalized anxiety disorder AND therapy’. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD).

Expert opinion: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.