Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.

RATIONALE AND OBJECTIVES: To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS: The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1. RESULTS: Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+. CONCLUSIONS: Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

Alcohol dependence and abuse diagnoses: validity in community sample heavy drinkers.

Despite the widespread influence of the alcohol dependence syndrome concept on the major nosological classification systems, little work has been done to test the validity of the alcohol dependence syndrome in community samples. In addition, numerous questions have been asked about the validity of current definitions of alcohol abuse. We examined the cross-sectional validity of DSM-IV alcohol dependence and abuse in 936 household residents randomly selected and screened for elevated drinking. We investigated validity by testing the association of a set of seven "criterion" variables, external to the alcohol diagnostic criteria, with dependence and abuse diagnoses. Results indicated that dependence diagnoses were significantly associated with all criterion variables when compared to those with no diagnosis, even though all subjects had elevated drinking and the cases of alcohol dependence were mild. In contrast, abuse diagnoses did not show a pattern of association with the criterion variables when compared to no diagnosis. When associations were tested comparing dependence cases to those with abuse only, results were mixed. This study is one in a series of investigations in this sample of household residents screened for elevated drinking levels.

The alcohol use disorder and associated disabilities interview schedule (AUDADIS): reliability of alcohol and drug modules in a clinical sample.

The alcohol use disorder and associated disabilities interview schedule (AUDADIS), was designed for use in the general population, and was previously shown to have good reliability in a sample of household residents. However, measurement problems are different in clinical samples. Thus, a test-retest study was conducted of the AUDADIS in a clinical sample of 296 substance-using patients from substance- and psychiatrically-identified treatment settings. Reliability for current drug-specific AUDADIS dependence diagnoses was good to excellent for high-prevalence as well as low-prevalence drug categories. Reliability for abuse diagnoses was not as good, although this was due to the hierarchical nature of the abuse diagnosis itself, rather than its defining criteria. Demographic and other factors were investigated for their potential effects on the reliability of alcohol and cocaine diagnoses; low severity was the only consistent predictor of unreliability for both of these categories. Reliability of consumption variables was generally good, with a few notable exceptions. Results suggest that the AUDADIS can be used in research comparing treated to community samples of individuals with alcohol and drug diagnoses.

Differentiating DSM-IV alcohol dependence and abuse by course: community heavy drinkers.

The purpose of this study was to investigate the differences in short-term course between DSM-IV alcohol abuse and alcohol dependence in a community sample of men and women. Eight hundred seventy-six individuals were given a baseline interview that included DSM-IV criteria for alcohol use disorders, and were followed up with a similar interview approximately one year later. Group differences were compared with chi-square tests. Multinomial logistic regression analyses were used to test group differences controlling for potential confounders. The course of alcohol abuse and dependence differed significantly from each other, and from individuals with no alcohol diagnosis at baseline. Chronicity was the most common outcome for dependence but not for abuse. Most subjects with baseline diagnoses of abuse received the diagnosis with only one symptom, repeated drunk driving. While the validity of the alcohol dependence diagnosis was supported in this community sample, the results concerning alcohol abuse remain equivocal.

Agreement between DSM-III, DSM-III-R, DSM-IV and ICD-10 alcohol diagnoses in US community-sample heavy drinkers.

DSM-III-R, DSM-IV and ICD-10 definitions of alcohol dependence were all developed from the concept of the Alcohol Dependence Syndrome, and thus have a common theoretical link. This link is not shared by DSM-III, and no link exists between definitions of abuse in the different classification systems. The level of agreement on diagnoses produced by the different systems has practical as well as theoretical implications. We tested this agreement in 962 US household residents randomly sampled and screened for heavier than average drinking in the last 12 months. Agreement for most comparisons involving diagnoses of current dependence ranged from good to excellent, with no clear pattern of lower agreement for DSM-III. However, agreement on past dependence was sharply lower for comparisons involving DSM-III than those involving the other classification systems. This appeared to be due to the DSM-III requirement for physiological dependence and the apparently emerging nature of the disorder in this relatively young, non-treatment sample. Comparisons for abuse were generally poor for current as well as past diagnoses. Implications of the findings are discussed.

Cross-system agreement among demographic subgroups: DSM-III, DSM-III-R, DSM-IV and ICD-10 diagnoses of alcohol use disorders.

Increasing importance is being placed on the appropriateness of methodologies for different population subgroups, such as women as well as men, non-Whites as well as Whites, and older and younger individuals. In the alcohol field, this applies to a number of areas, including the agreement between diagnoses of alcohol use disorders by different sets of diagnostic criteria. We tested the agreement between DSM-III, DSM-III-R, DSM-IV and ICD-10 criteria for alcohol dependence and abuse in demographic subgroups of a sample of 962 community residents screened for heavy drinking in the previous 12 months. Good to excellent agreement was found for current diagnoses of dependence across all subgroups and classification systems. For past diagnoses, agreement was good across all subgroups for comparisons that did not involve DSM-III, and quite low for comparisons of DSM-III to other classification systems across subgroups. With few exceptions, cross-system agreement for diagnoses of alcohol abuse was poor. This result was also consistent across demographic subgroups. Results suggest that studies can be compared equally well for diagnoses of alcohol dependence subsequent to DSM-III for males and females. Whites and non-Whites, and older and younger respondents. Abuse remains a problematic category psychometrically across all demographic categories, even in this sample of largely untreated household residents.

Tissue plasminogen activator (tPA) as a reporter gene in transient gene expression.

Using the gene coding for tissue plasminogen activator (tPA) as a reporter gene, a transient gene expression system has been established. Vectors containing the full-length cDNA of tPA with its signal sequences were introduced into mammalian recipient cells by a modified gene transfer procedure. Thirty hours after transfection, the secreted tPA was found in serum-free medium and measured by a fibrin-agarose plate assay (FAPA). In this assay, tPA converts plasminogen into plasmin which then degrades high-Mr fibrin to produce cleared zones. The sizes of these zones correspond to quantities of tPA. The combination of transient tPA expression system and the FAPA provides a quick, sensitive, quantitative and non-destructive method to examine the strength of eukaryotic regulatory elements in tissue-culture cells.

Discrepancy between the antibacterial activities and the inhibitory effects on Micrococcus luteus DNA gyrase of 13 quinolones.

Thirteen quinolone antibacterial agents were investigated as to their ability to inhibit Micrococcus luteus DNA gyrase and cell growth, and compared to those of novobiocin and coumermycin. Among the quinolones tested, the most active were found to be CI-934 and ciprofloxacin, which inhibited gyrase full supercoiling activity at concentrations of 100 and 200 micrograms/ml, respectively, while inhibiting cell growth at a concentration of 1 microgram/ml. However, both novobiocin and coumermycin inhibited gyrase full supercoiling activity at concentrations of 0.5 and 1.0 microgram/ml, respectively, which were comparable to those concentrations causing inhibition of cell growth.

Inhibitory activity of cefpiramide on beta-lactamase.

The beta-lactamase stability and inhibitory activity of cefpiramide were investigated. Cefpiramide was found to be stable to hydrolysis and inhibited beta-lactamase produced by Citrobacter freundii, Enterobacter cloacae, Morganella morganii, and Escherichia coli. Kinetic studies showed that cefpiramide is a competitive inhibitor of cephaloridine hydrolysis by E. cloacae beta-lactamase.

Experimental efficacy and pharmacokinetic properties of cefpiramide, a new cephalosporin.

The in vivo therapeutic efficacy of cefpiramide was investigated and compared with that of cefoperazone. Cefpiramide was more potent than cefoperazone against infections produced by both beta-lactamase-producing and non-beta-lactamase-producing S. aureus. The protective activity of cefpiramide against experimental infections with selected members of Enterobacteriaceae was lower than that of cefoperazone. Against carbenicillin-resistant P. aeruginosa infections, cefpiramide was as active as gentamicin and aztreonam and three times more potent than cefoperazone, cefotaxime and piperacillin. The pharmacokinetic properties of cefpiramide in mice and rats were superior to those of cefotaxime and cefoperazone. The peak serum concentrations of cefpiramide, administered subcutaneously at a dose of 50 mg/kg, were 76 micrograms/ml in mice and 174 micrograms/ml in rats and the corresponding serum half-lives of cefpiramide were 87 min and 49 min in mice and rats respectively.