Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study.

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis.

BACKGROUND: Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. METHODS: Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. RESULTS: For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. CONCLUSIONS: The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

TB Alliance regimen development for multidrug-resistant tuberculosis.

The recent approval of new tuberculosis (TB) drugs raises hope for new and more effective anti-tuberculosis treatment regimens. The Global Alliance for TB Drug Development (TB Alliance) is committed to ensuring that new anti-tuberculosis drugs fulfill the needs of patients, their families and the local health services that serve the communities. Here we present highlights of the TB Alliance's pipeline of regimen development, with novel regimens for patients with drug-susceptible, multidrug-resistant and extensively drug-resistant TB. The ongoing clinical trials (STAND, NC-005, Nix-TB and LIN-CL001) are outlined and their rationale and goals presented.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial.

Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.

Effect of moderate weight loss on health-related quality of life: an analysis of combined data from 4 randomized trials of sibutramine vs placebo.

OBJECTIVES: To determine whether (1) patients who experience greater weight loss also experience correspondingly greater improvements in health-related quality of life (HRQOL); (2) the improvement in HRQOL is noticeable for patients achieving moderate (5%-10%) weight reduction; and (3) the relationship between weight reduction and HRQOL is similar for patients receiving sibutramine hydrochloride vs placebo. STUDY DESIGN: We combined data from 4 double-blind, randomized, controlled trials of administration of sibutramine (20 mg/d) vs placebo. PATIENTS AND METHODS: Patients (n = 555) were mildly to moderately obese and had type 2 diabetes mellitus, dyslipidemia, or hypertension that was well controlled with an angiotensin-converting enzyme inhibitor or calcium channel blocker. The HRQOL was operationalized using the Impact of Weight on Quality of Life (IWQOL) and the Medical Outcomes Study 36-Question Short-Form (SF-36) instruments. The main statistical technique was a patient-level analysis of variance predicting change in HRQOL from study, treatment, and weight change. RESULTS: Moderate weight loss was associated with a statistically significant improvement in HRQOL for approximately half of the subscales evaluated (P < .05). The greatest sensitivity to change was shown by the SF-36 general health perception and change in health since last year subscales and the IWQOL overall health, mobility, and total subscales. Greater weight loss was associated with the most improvement in HRQOL. Weight losses of 5.01% to 10.00% were associated with 2-unit changes in the SF-36 general health perception subscale and 10-unit changes in the IWQOL total subscale. Results were similar across study and treatment. CONCLUSIONS: Moderate weight loss is associated with noticeably improved HRQOL. Improvements in HRQOL are achievable by patients receiving sibutramine.

Effects of sibutramine on body weight and serum lipids: a double-blind, randomized, placebo-controlled study in 322 overweight and obese patients with dyslipidemia.

BACKGROUND: Cardiovascular risk factors associated with obesity, including dyslipidemia, can be improved by weight loss. The main dyslipidemia associated with obesity is elevated serum triglyceride and decreased serum high-density lipoprotein cholesterol (HDL-C) levels. METHODS: A total of 322 obese patients (body mass index > or = 27) with serum triglyceride levels > or = 250 mg/dL and < or = 1000 mg/dL and serum HDL-C levels < or = 45 mg/dL (women) and < or = 40 mg/dL (men) were placed on a step I American Heart Association diet and subsequently randomized to sibutramine 20 mg (n = 162) or placebo (n = 160) once daily for 24 weeks. RESULTS: Patients taking sibutramine had significantly greater mean weight loss than those receiving placebo (-4.9 kg vs -0.6 kg, P < or = .05). Forty-two percent of the sibutramine group lost > or = 5% of baseline weight and 12% lost > or = 10% compared with 8% and 3%, respectively, of the placebo group (P < or = .05). Mean decreases in serum triglyceride levels among 5% and 10% weight-loss responders in the sibutramine group were 33.4 mg/dL and 72.3 mg/dL, respectively, compared with an increase of 31.7 mg/dL among all patients receiving placebo (P < or = .05). Mean increases in serum HDL-C levels for 5% and 10% weight-loss responders in the sibutramine group were 4.9 mg/dL and 6.7 mg/dL, respectively, compared with an increase of 1.7 mg/dL among all patients in the placebo group (P < or = .05). Adverse events and discontinuation rates were similar in the sibutramine and placebo groups, although sibutramine-treated patients had mean increases in systolic and diastolic blood pressure of 2 to 3 mm Hg relative to placebo. CONCLUSIONS: In overweight and obese patients with high serum triglyceride levels and low serum HDL-C levels, treatment with sibutramine was associated with significant improvements in body weight and in serum triglyceride and HDL-C levels.

Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Obesity is a highly prevalent medical condition and is commonly accompanied by hypertension. This study assessed the efficacy and safety of treatment with sibutramine hydrochloride for promoting and maintaining weight loss in obese patients with controlled hypertension, including a subset analysis of African American patients. PATIENTS AND METHODS: Obese patients with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) between 27 and 40 and a history of hypertension controlled with a calcium channel blocker (with or without concomitant thiazide diuretic treatment) were randomized to receive sibutramine (n = 150) or placebo (n = 74) with minimal behavioral intervention for 52 weeks. African Americans constituted 36% of enrolled patients. Efficacy assessments were body weight and related parameters (BMI and waist and hip circumferences), metabolic parameters (serum levels of triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, glucose, and uric acid), and quality-of-life measures. Safety assessments included recording of blood pressure, pulse rate, adverse events, and reasons for discontinuation. RESULTS: For patients receiving sibutramine, weight loss occurred during the first 6 months of the trial and was maintained to the end of the 12-month treatment period. Among patients receiving sibutramine, 40.1% lost 5% or more of body weight (5% responders) and 13.4% lost 10% or more of body weight (10% responders) compared with 8.7% and 4.3% of patients in the placebo group, respectively (P<.05). Changes in body weight were similar among African Americans and whites. Sibutramine-induced weight loss was associated with significant improvements in serum levels of triglycerides, HDL-C, glucose, and uric acid. Waist circumference and quality-of-life measures also improved significantly in patients receiving sibutramine. Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure (2.0 mm Hg) and pulse rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<.05); these changes were similar among African Americans and whites. Most adverse events were mild to moderate in severity and transient. The most common adverse event resulting in discontinuation among patients receiving sibutramine was hypertension (5.3% of patients receiving sibutramine vs 1.4% of patients receiving placebo). CONCLUSIONS: In obese patients with controlled hypertension, sibutramine was an effective and well-tolerated treatment for weight loss and maintenance. Sibutramine-induced weight loss resulted in improvements in serum levels of triglycerides, HDL-C, uric acid, and glucose, and in waist circumference and quality-of-life measures. Blood pressure and heart rate increased by a small amount. Efficacy and safety profiles for sibutramine among African American and white obese patients with controlled hypertension were similar.

Abuse liability assessment of sibutramine, a novel weight control agent.

RATIONALE: Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor marketed for weight control. Previous studies demonstrated low abuse potential for 20 and 30 mg sibutramine (doses near the therapeutic range); however, no data existed on supratherapeutic doses. This study, therefore, examined 25 and 75 mg sibutramine in humans compared to d-amphetamine (20 mg) as a positive control and placebo as a negative control. OBJECTIVES: The study examined the acute subjective, reinforcing, and physiological effects of sibutramine to assess its abuse liability. METHODS: Twelve polydrug abusers with no history of drug dependence participated in this double-blind, inpatient/outpatient study. Volunteers participated in four drug sessions, in which they completed subjective effects scales including the Profile of Mood States (POMS), Visual Analog Scales (VAS), and the Addiction Research Center Inventory (ARCI). The Multiple Choice Procedure (MCP) was used to evaluate reinforcing efficacy. RESULTS: Sibutramine 25 mg produced subjective effects that were indistinguishable from placebo. Sibutramine 75 mg produced significant unpleasant effects, such as Anxiety, Confusion, and decreased Vigor. On the MCP, volunteers chose to give up an average of $4.04 from their study pay rather than receive the higher dose of sibutramine again. In contrast, d-amphetamine 20 mg produced positive mood changes and was well liked. CONCLUSIONS: These data indicate sibutramine lacks amphetamine-type abuse liability when administered acutely.

Absence of cardiac valve dysfunction in obese patients treated with sibutramine.

OBJECTIVE: Serotonin-releasing agents prescribed as weight-loss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIA) is a serotonin and norepinephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutraminetreated patients. RESEARCH METHODS AND PROCEDURES: Obese patients with type 2 diabetes mellitus enrolled in an ongoing double-blind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function. RESULTS: A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean+/-Standard Deviation age was 54+/-9 years, and the mean duration of treatment was 229+/-117 days (approximately 7.6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutramine 3/133, or 2.3%; placebo 2/77, or 2.6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension. CONCLUSION: The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7.6 months.

Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers.

AIMS: The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied. METHODS: In a randomized, crossover study with four periods, twenty-four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1-4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively. RESULTS: The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15-mg rizatriptan were 16, 33, 72, and 127 ng ml-1 h, respectively, in males; and 19, 42, 97, and 161 ng ml-1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was approximately 40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min-1, respectively, in males; and 821 and 174 ml min-1, respectively, in females. CONCLUSIONS: The disposition kinetics of oral rizatriptan were linear for doses of 2. 5-10 mg in males, and for doses of 2.5-5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.

Sibutramine produces dose-related weight loss.

OBJECTIVE: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. RESEARCH METHODS AND PROCEDURES: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. RESULTS: Weight loss was dose-related and statistically significant vs. placebo (p<0.05) across all time-points for a 5 mg/day to 30 mg/day dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. DISCUSSION: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.

Effects of dexamethasone on IL-1beta, IL-6, and TNF-alpha production by mononuclear cells of newborns and adults.

The effects of dexamethasone on the production of interleukin (IL) 1beta, IL-6, and tumor necrosis factor alpha were studied in preterm newborns, term infants, and adults. Twenty preterm and 22 term newborns and 30 healthy adults were included in the study. Mononuclear cells (MC) isolated from cord blood of newborns and peripheral blood of adults were incubated without or with lipopolysaccharide in the absence or presence of dexamethasone at concentrations between 10(-8) and 10(-5) M. The cytokine concentration in the supernatants was tested using enzyme-linked immunosorbent assay kits. Although a dose-dependent inhibition of the cytokine production was observed at pharmacological doses of dexamethasone in individuals of the three groups, differences in the intensity of the effect were observed between the groups. Spontaneous secretion of IL-1beta or IL-6 by MC of preterm neonates was less inhibited by dexamethasone as compared with cells from adults. In contrast, the inhibitory effect of the drug on lipopolysaccharide-induced IL-6 and tumor necrosis factor alpha production was more pronounced on neonatal cells. As for term newborns, MC were more sensitive to the inhibitory effect of the drug on LPS-induced IL-6 production than cells of adults. The results suggest that dexamethasone treatment of preterm newborns may affect cytokine production with a consequent modulation of the host's immune response.

Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability.

AIMS: The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra-arterial substance P infusion in the forearm of healthy man. METHODS: On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128 pmol min(-1). Blood flow was measured in both arms using venous occlusion plethysmography. RESULTS: Substance P induced dose-dependent vasodilatation in the human forearm which had a log-linear relationship to dose. At doses of 1-8 pmol min(-1), mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of < or = 64 pmol min(-1) with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non-infused forearm vasodilatation, occurred at doses of > or = 16 pmol min(-1). CONCLUSIONS: Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK1 receptor function.

Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man.

Previous studies have indicated the existence of common mechanisms regulating sleep and somatotropic activity. In the present study, we investigated the effects of prolonged treatment with a novel, orally active, growth hormone secretagogue (MK-677) on sleep quality in healthy young and older adults. Eight young subjects (18-30 years) followed a double-blind, placebo-controlled, three-period crossover design. Each subject participated in three 7-day treatment periods (with bedtime drug administration), presented in random (Latin square) order, and separated by at least 14 days. Doses were 5 and 25 mg MK-677 and matching placebo. Six older subjects, ages 65-71 years, each participated in two 14-day treatment periods (with bedtime drug administration) separated by a 14-day washout. Doses were 2 and 25 mg MK-677 during the first and second periods, respectively. Baseline sleep and hormonal data were obtained on the 2 days preceding the beginning of the first 14-day treatment period. In young subjects, high-dose MK-677 treatment resulted in an approximately 50% increase in the duration of stage IV and in a more than 20% increase in REM sleep as compared to placebo (p < 0.05). The frequency of deviations from normal sleep decreased from 42% under placebo to 8% under high-dose MK-677 (p < 0.03). In older adults, treatment with MK-677 was associated with a nearly 50% increase in REM sleep (p < 0.05) and a decrease in REM latency (p < 0.02). The frequency of deviations from normal sleep also decreased (p < 0.02). The present findings suggest that MK-677 may simultaneously improve sleep quality and correct the relative hyposomatotropism of senescence.

Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men.

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentration as measured by equilibrium dialysis.

Heparin can cause an artifactual elevation in the concentration of unbound (free) thyroxine (T4) in the plasma, particularly when measured by equilibrium dialysis. The lipase released into the plasma by heparin acts on substrate (triglycerides; TG) in the plasma in vitro to release nonesterified (free) fatty acids (FFA), which, in high concentrations, inhibit the binding of T4 to its plasma binding proteins. This artifact occurs only in the presence of sufficient substrate (serum TG greater than approximately 180 mg/dL), and is most pronounced in methods requiring long incubation times. We observed this artifact in a patient receiving intralipid and subcutaneous (sc) heparin. Plasma-free T4, when measured by equilibrium dialysis, was elevated, but was normalized when the in vitro generation of FFA during equilibrium dialysis was prevented by prior treatment of the sample with protamine to inhibit lipoprotein lipase and with an antibody to hepatic triglyceride lipase. This observation caused us to investigate formally whether heparin, at standard sc doses or at iv doses even lower than those that are commonly used to flush iv lines (100-300 U), could also cause this artifact. We gave increasing doses of heparin at weekly intervals to each of three normal volunteers and measured FFA generation in their plasma (supplemented with 250 mg/dL triglycerides) under conditions simulating equilibrium dialysis. We found that, indeed, iv doses of heparin as low as 0.08 U/kg (5.6 U in a 70-kg subject) as well as a standard dose of sc heparin (5000 U) could release significant lipase activity into the plasma and, in the setting of sufficient substrate, cause enough in vitro generation of FFA to artifactually increase the serum-free T4 concentration when measured by equilibrium dialysis. These results indicate that equilibrium dialysis may not always be the best method for assessing serum-free T4 concentrations in hospitalized patients, and should be taken into account when interpreting previous studies demonstrating inhibitors of T4-serum protein binding in sera from hospitalized patients.