Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects.

OBJECTIVE: The clinical use of growth hormone-releasing hormone (GHRH) is limited by its short half-life. Polyethylene glycol-conjugated GHRH (PEG-GHRH) was developed to provide increased stability compared with the currently available GHRH(1-29). This study aimed to evaluate the safety, tolerability and pharmacodynamics of PEG-GHRH. DESIGN: PEG-GHRH was administered by subcutaneous injection to young healthy men (n = 12) and elderly men and women (aged > 60 years; n = 20). RESULTS: In both groups, administration of PEG-GHRH generated a clear increase in circulating GH compared with placebo. Following single-dose (0.25, 0.5, 2 or 4 mg) administration to young subjects, the effect persisted for 12 h, but a sustained increase was observed on repeated administration to the elderly. Serum insulin-like growth factor-I also increased in response to PEG-GHRH treatment. Injection-site reactions were more frequent with PEG-GHRH compared with placebo, but these were mild and transient; other adverse events were similar to those observed after placebo. Some impairment of glucose tolerance was observed in the elderly following repeated administration of PEG-GHRH. Antibodies to GHRH were not observed. CONCLUSIONS: PEG-GHRH offers the possibility of less frequent dosing compared with GHRH. This possibility deserves further clinical testing.

Bioequivalence of liquid and freeze-dried recombinant human follicle-stimulating hormone.

OBJECTIVE: The bioequivalence and tolerability of freeze-dried and liquid formulations of recombinant human follicle-stimulating hormone (r-hFSH) filled-by-mass were assessed in a crossover, open-label, randomised, single-centre, phase I bioequivalence study. METHODS: Following pituitary down-regulation with the gonadotrophin-releasing hormone agonist goserelin, healthy adult volunteers (18years-45years of age) received single subcutaneous injections of r-hFSH , 300 IU, from freeze-dried and liquid formulations in random order, separated by a 7-day washout period. Blood was obtained over 144 h for pharmacokinetic analysis. MAIN OUTCOME MEASURES: These were peak serum FSH concentrations (Cmax,), time to peak concentration (Tmax) and area under the concentration-time curve from zero to the last measurable concentration (AUCJ), local and systemic tolerability. RESULTS: Of 44 volunteers who underwent down-regulation, 39 (18 men, 21 women) completed the study. Cmax and AUClast were similar with the freeze-dried (mean 9.51 IU/L and 844 IU.h/L, respectively) and liquid (mean 8.99 IU/L and 841 IUh/L, respectively) formulations, whereas T was significantly higher with the liquid formulation (median 12h vs 15h, p = 0.0183). The 90% confidence intervals for the ratio of the treatment means for Cnw and AUC,=, were within the pre-defined bioequivalence range of 0.8-1.25. CONCLUSION: Both formulations were well tolerated with regard to both systemic and local adverse events. The freeze-dried and liquid formulations of r-hFSH are bioequivalent and show no significant differences in tolerability. Thus, the liquid formulation is expected to provide comparable efficacy and tolerability to the freeze-dried formulation in clinical use.

The bioequivalence of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin.

OBJECTIVE: To compare the bioavailability and tolerability of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin (r-hCG). SUBJECTS AND METHODS: In an open-label, randomised, single-centre, Phase I study, healthy adult volunteers (18-50 years of age) received single injections of r-hCG 250 microg from reconstituted freeze-dried (1.0 mL of 250 microg/mL) and liquid (0.5 mL of 250 microg/0.5 mL) formulations in random order, separated by a 10-day wash-out period. Pharmacokinetics (C(max), AUC, AUC(last), t(max)) and local and systemic tolerability were assessed. RESULTS: Pharmacokinetic properties of the two formulations were very similar, with mean C(max) 125 mIU/mL (liquid formulation) vs 129 mIU/mL (freeze-dried formulation), mean AUC 10,350 mIU.h/mL vs 10,480 mIU(.)h/mL, mean AUC(last) 10,050 mIU.h/mL vs 10,210 mIU.h/mL, and median t(max) 20 vs 24h. The 90% confidence intervals of the ratios of the treatment means for C(max), AUC and AUC(last) all fell within the pre-defined FDA acceptance range of 0.8-1.25, demonstrating the bioequivalence of the two formulations. Both formulations were equally well tolerated; the most frequent adverse events were headache and nausea. CONCLUSION: The liquid formulation of r-hCG was shown to be bioequivalent to the freeze-dried formulation, with no clinically significant differences in tolerability. The liquid formulation of r-hCG can be expected to provide the same efficacy and tolerability as the freeze-dried formulation when used to trigger final follicular maturation in women undergoing therapies for assisted reproduction, together with a greater convenience of use.

A two-item screening test for alcohol and other drug problems.

BACKGROUND: Although nonmedical use of illicit and prescription drugs is not uncommon among American adults, the currently recommended screening tests for substance use disorders (SUDs) focus only on alcohol. This study reports on the criterion validity of a two-item conjoint screening (TICS) test for alcohol and other drug abuse or dependence for a primary care sample. METHODS: A random sample of 434 primary care patients aged 18 to 59 years responded to nine screening items, which emanated from a focus group process. The DSM-III-R criteria for SUDs, as operationalized by the Composite International Diagnostic Interview-Substance Abuse Module, served as the criterion standard. RESULTS: At least one positive response to the TICS ("In the last year, have you ever drank or used drugs more than you meant to?" and "Have you felt you wanted or needed to cut down on your drinking or drug use in the last year?") discriminated current SUDs with approximately 81% sensitivity and specificity. The TICS was particularly sensitive to polysubstance use disorders. Respondents with zero positive responses had a 7.4% chance of a current SUD; one positive response, 45.0%; and two positive responses, 75.0%. CONCLUSIONS: More than 80% of young and middle-aged patients with current alcohol or other drug problems may be recognized by the TICS, which is easily integrated into a clinical interview.

Substance abuse among patients with chronic back pain.

BACKGROUND: Little is known about substance use and substance use disorders among primary care patients with chronic back pain. This study compared groups of patients with and without chronic back pain for the prevalence of substance use and substance use disorders. It also assessed the temporal relationship between the onset of chronic back pain and that of substance use disorders. METHODS: Adult patients aged 18 to 59 years who made three or more visits for back pain to a family practice clinic were eligible for the pain group. The comparison group consisted of a random sample of patients of the same ages who made appointments with the same clinic. A validated diagnostic interview about substance use disorders and other issues related to substance use was administered. RESULTS: Ninety-two percent of the patients in the chronic pain group reported severe pain, high disability, and severe to moderate limitation of activity. Two thirds (67%) of this group reported having continuous pain, and 21% experienced at least one episode of pain daily. Forty-four percent said their pain continously interfered with their activities, and 31% reported daily disruption of activity. There was little difference, however, in the adjusted rates of lifetime and current substance use disorders between the chronic pain and comparison groups. Lifetime prevalence rates were 54% for the pain group and 52% for the comparison group; current prevalence rates were 23% for both the pain and comparison groups. Substance abuse preceded the onset of pain by as much as 20 years for 77% of patients with chronic pain who had current substance use disorders and 63% of those who had lifetime substance use disorders. CONCLUSIONS: Chronic back pain did not connote special risk for current substance use disorders.

Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus.

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 x 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept-BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicept's biological activity was compatible with its presumed mechanism of action. Bioavailability was approximately 30-40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies.

Bioequivalence of recombinant human FSH and recombinant human LH in a fixed 2:1 combination: two phase I, randomised, crossover studies.

OBJECTIVES: To assess bioequivalence of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) and recombinant human luteinising hormone (r-hLH, lutropin alfa) in a fixed 2:1 combination (Pergoveris) compared with injection of each of the hormones separately. RESEARCH DESIGN AND METHODS: Two, two-way crossover, phase I studies in healthy female volunteers after gonadotrophin-releasing hormone agonist down-regulation. Volunteers were randomised to the order in which they received subcutaneous injections. In the r-hFSH study, volunteers received one injection of r-hFSH (300 IU) and one of r-hFSH (300 IU)/r-hLH (150 IU) > or = 7 days apart; in the r-hLH study they received r-hLH (450 IU) and r-hFSH (900 IU)/r-hLH (450 IU) > 21 days apart. MAIN OUTCOME MEASURES: The serum concentration-time profiles of FSH in the r-hFSH study and LH in the r-hLH study from zero to the last measurable concentration (AUC(0-last)) and the peak FSH/LH serum concentrations (C(max)) were assessed by non-compartmental analysis. The pre-defined range for bioequivalence was 0.8-1.25 for 90% confidence intervals (CI) of the ratio (fixed combination/single gonadotrophin) of the mean for each pharmacokinetic parameter. RESULTS: Bioequivalence criteria were met for the r-hFSH study (n = 34) for C(max) (ratio of means 1.0024, 90% confidence interval (CI) 0.9611-1.0454) and AUC(0-last) (ratio of means 1.0167, 90% CI 0.9933-1.0407), and for the r-hLH study (n = 63) for C(max) (ratio of means 0.9687, 90% CI 0.9194-1.0207) and AUC(0-last) (ratio of means 0.9753, 90% CI 0.8990-1.0581). In the r-hFSH study, 20 adverse events (AEs) were reported after injection of r-hFSH and 20 after r-hLH/r-hFSH. In the r-hLH study, 179 AEs were reported after injection of r-hLH and 193 after the fixed-dose combination. Across both studies, headache was the most commonly reported AE. No serious AEs occurred. CONCLUSIONS: These studies demonstrated bioequivalence between r-hFSH and r-hLH administered alone or in fixed 2:1 combination. The 2:1 combination of follitropin alfa and lutropin alfa allows administration of both recombinant gonadotrophins in a single injection.

A two-item conjoint screen for alcohol and other drug problems.

BACKGROUND: Although nonmedical use of illicit and prescription drugs is not uncommon among American adults, the currently recommended screens for substance use disorders focus only on alcohol. This study reports on the criterion validity of a two-item conjoint screen (TICS) for alcohol and other drug abuse or dependence for a split sample of primary care patients. METHODS: Two random samples of primary care patients aged 18 to 59 years responded to several screening items that emanated from a focus group process. The DSM-III-R criteria for substance use disorders, as codified by the Composite International Diagnostic Interview-Substance Abuse Module, served as the criterion standard. RESULTS: At least one positive response to the TICS (In the last year, have you ever drunk or used drugs more than you meant to? and Have you felt you wanted or needed to cut down on your drinking or drug use in the last year?) detected current substance use disorders with nearly 80% sensitivity and specificity. The TICS was particularly sensitive to polysubstance use disorders. Respondents who gave 0, 1, and 2 positive responses had a 7.3%, 36.5%, and 72.4% chance of a current substance use disorder, respectively; likelihood ratios were 0.27, 1.93, and 8.77. The results were consistent across split samples of 434 and 702 participants. CONCLUSIONS: Current alcohol or other drug problems can be detected in nearly 80% of young and middle-aged patients by asking two questions that are easily integrated into a clinical interview.

Physicians' decisions to prescribe benzodiazepines for nervousness and insomnia.

OBJECTIVE: To assess the effects of particular clinical cues on decisions about prescribing benzodiazepines. DESIGN: A factorial survey based on social judgment theory. SETTING: A midwestern U.S. medical school. PARTICIPANTS: Physicians (n = 115) recruited from the staff by invitation and interview. MEASUREMENTS AND MAIN RESULTS: Physicians indicated their level of agreement with prescribing a benzodiazepine for 24 hypothetical cases of nervousness and insomnia. The cases stemmed from the same scenario but varied systematically with regard to psychiatric diagnosis, recent ability to work, and long-term social stability. A fourth cue, called "health status," covertly depicted the presence or absence of three common alcohol-related medical problems. One fourth of the physicians agreed with prescribing for 15 or more cases, and 15% disagreed for all of them. Agreement was cumulative and least common for major depression, more common for adjustment disorder, and most common for generalized anxiety. Agreement with prescribing for cases with alcohol-related medical problems was 14% less than that for cases without them. Over half the physicians agreed with prescribing for 4 or more of the 12 cases with alcohol-related medical problems. CONCLUSIONS: Prescribing decisions varied widely. Some physicians avoided benzodiazepines unnecessarily for some cases, while others agreed with prescribing for patients with a high probability of alcohol abuse. Blanket calls for more or less prescribing are overly simplistic; physicians should be able to recognize substance use disorders among anxious patients and make prescribing decisions based on relevant literature and clinical cues.

The prevalence and detection of substance use disorders among inpatients ages 18 to 49: an opportunity for prevention.

BACKGROUND: Previous studies have found that substance use disorders are prevalent among inpatients of general medical hospitals. These studies were limited in the validity of their measures, their failure to distinguish between current and lifetime disorders, or their lack of attention to drugs other than alcohol. METHODS: The current study used validate diagnostic instruments to measure current and lifetime alcohol and other drugs abuse and dependence among patients ages 18 through 49. Additionally, this study assessed the sensitivity and specificity of four substance abuse screening questions. Patients were recruited from the general medical, general surgery, and orthopedics services of a university hospital in Madison, Wisconsin. The sample included 363 patients, or 86.4% of those recruited. RESULTS: The current and lifetime prevalence rates of substance use disorders were 21.8 and 49.6%, respectively. The prevalence rates of current problems were 16.3%, alcohol only; 2.5%, other drugs only; and 3.0%, alcohol and other drugs. Males had nearly a 30% current prevalence of current substance use disorders. The CAGE Questions Adapted to Include Drugs exhibited 70.9% sensitivity and 75.7% specificity. CONCLUSIONS: At one hospital, and perhaps at others, an alcohol and drug screening, assessment, and intervention program may have the potential to prevent future health and social problems.

Pronounced cytoplasmic pH gradients are not required for tip growth in plant and fungal cells.

The existence of pronounced cytoplasmic pH gradients within the apices of tip-growing cells, and the role of cytoplasmic pH in regulating tip growth, were investigated in three different cell types: vegetative hyphae of Neurospora crassa; pollen tubes of Agapanthus umbellatus; and rhizoids of Dryopteris affinis gametophytes. Examination of cytoplasmic pH in growing cells was performed by simultaneous, dual emission confocal ratio imaging of the pH-sensitive probe carboxy SNARF-1. Considerable attention was paid to the fine tuning of dye loading and imaging parameters to minimise cellular perturbation and assess the extent of dye partitioning into organelles. With optimal conditions, cytoplasmic pH was measured routinely with a precision of between +/-0.03 and +/-0.06 of a pH unit and a spatial resolution of 2.3 microm2. Based on in vitro calibration, estimated values of mean cytoplasmic pH for cells loaded with dye-ester were between 7.15 and 7.25 for the three cell types. After pressure injecting Neurospora hyphae with dextran-conjugated dye, however, the mean cytoplasmic pH was estimated to be 7.57. Dextran dyes are believed to give a better estimate of cytoplasmic pH because of their superior localisation and retention within the cytosol. No significant cytoplasmic pH gradient (delta pH of >0.1 unit) was observed within the apical 50 microm in growing cells of any of the three cell types. Acidification or alkalinisation of the cytoplasm in Neurospora hyphae, using a cell permeant weak acid (propionic acid at pH 7.0) or weak base (trimethylamine at pH 8.0), slowed down but did not abolish growth. However, similar manipulation of the cytoplasmic pH of Agapanthus pollen tubes and Dryopteris rhizoids completely inhibited growth. Modification of external pH affected the growth pattern of all cell types. In hyphae and pollen tubes, changes in external pH were found to have a small transient effect on cytoplasmic pH but the cells rapidly readjusted towards their original pH. Our results suggest that pronounced longitudinal gradients in cytoplasmic pH are not essential for the regulation of tip growth.