Sequencing diet and exercise programs for African American women with diabetes.

PURPOSE: This study was designed to compare the effects of 2 programs that present diet and exercise components in a different sequence. METHODS: At an urban YMCA, African American women with type 2 diabetes, aged 30 to 65, were randomly assigned to either 10 weekly sessions about healthy eating followed by 6 weekly sessions about exercise or to the reverse sequence. Sessions consisted of small group discussions and physical activity or food tasting. Primary outcomes were attendance, percent of calories consumed from fat, fruit and vegetable intake, and minutes of exercise per week. Measures were taken at baseline, and 4 and 12 months after the program. RESULTS: The only group difference found at the 12-month follow-up was in diastolic blood pressure. Time effects for both groups combined included an increase in minutes of activity, an increase in vegetable intake, and a decrease in percent of calories consumed from fat. CONCLUSIONS: This study does not provide definitive evidence of which sequence may be best to bring about behavior change. The effects of sequencing difficult behavioral changes such as diet modification and establishing an exercise habit deserve further study.

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines.

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.

Design and synthesis of N-alkylated saccharins as selective alpha-1a adrenergic receptor antagonists.

Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.

Fear of hypoglycemia in the parents of children and adolescents with diabetes: maladaptive or healthy response?

Sixty-one parents of children with insulin-dependent diabetes mellitus completed modified versions of the Hypoglycemic Fear Survey (HFS) and the Diabetes Quality of Life (DQOL) scale. They also indicated their child's history of hypoglycemic-related seizures or loss of consciousness (SLC) events. Parental HFS scores were significantly greater if their child had ever experienced a SLC event or experienced a SLC event within the past year. Parental HFS scores were positively correlated with general parental worry about their child having diabetes. Adolescent children who experienced a SLC event during the past year reported greater HFS scores, greater general worry about diabetes, and a greater negative impact of having diabetes compared with adolescents with no such history. Despite the greater fear of hypoglycemia in parents and adolescents, there was no significant difference in HbA1 values between children with or without any history of SLC events or children with or without a SLC event within the past year.

Comparison of obese NIDDM and nondiabetic women: short- and long-term weight loss.

Previous research suggests that overweight patients with diabetes lose less weight than nondiabetics. We compared the response of obese women with NIDDM to nondiabetic controls, matched for age and weight, to a behavior weight loss program. Forty-three overweight women (20 NIDDM, 23 nondiabetic) participated in the study. NIDDM and nondiabetic subjects were treated together and received the same 16-week behavioral weight loss program. Dependent measures included weight, 3-day food records, physical activity, fasting plasma glucose, and questionnaires assessing eating behavior and depressive symptomatology. Weight loss of NIDDM and nondiabetic subjects at posttreatment was comparable (-7.4 +/- 5.3 kg vs. -6.4 +/- 3.8 kg, respectively). Changes in caloric intake, eating behavior, exercise and depressive symptomatology were also similar between the two groups. However, during the 1-year follow-up period, NIDDM subjects regained 5.4 +/- 6.1 kg compared to 1.0 +/- 6.7 kg for nondiabetics (p = .058). These data indicate that NIDDM subjects can lose as much weight as their nondiabetic peers during active treatment. Once treatment terminated, however, NIDDM subjects demonstrated poor weight loss maintenance. Thus the added motivation that comes from having diabetes and seeing improvements in glycemic control with weight loss were not sufficient to improve long term weight loss in diabetic subjects. A continuous care model of weight control may be particularly necessary for overweight patients with type II diabetes.

L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.

A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.

Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.

Lifetime prevalence of major depression and its effect on treatment outcome in obese type II diabetic patients.

OBJECTIVE: To assess the lifetime prevalence of major depression (MD) and its relation to glycemic control among a group of non-insulin-dependent (type II) diabetic subjects seeking obesity treatment and to determine whether a history of MD affected response to treatment. RESEARCH DESIGN AND METHODS: Sixty-six obese subjects with type II diabetes (22 men, 44 women) completed the Inventory to Diagnose Depression-Lifetime Version before a 52-wk behavioral weight-control program. Weight, glycosylated hemoglobin, fasting blood glucose, and mood were assessed at pre- and posttreatment. RESULTS: Thirty-two percent of the subjects reported a history of MD. Neither a history of MD nor current depressive symptoms were associated with pretreatment glycemic control. However, a history of MD was related to treatment attrition (52.4 vs. 22.2%, P = 0.03). Subjects with and without a history of MD showed comparable improvements in weight, glycemic control, and mood. CONCLUSIONS: A history of MD among type II diabetic patients seeking obesity treatment was not related to pretreatment glycemic control but was associated with higher rates of attrition from treatment. Individuals with a history of MD who completed the program did not differ from those with no history of MD in response to treatment.

The effect of weight loss on change in waist-to-hip ratio in patients with type II diabetes.

This study sought to determine whether weight loss would alter body fat distribution in obese men and women with type II diabetes. Subjects were 60 women and 33 men who participated in a year-long weight loss program. Weight losses of women and men, respectively, averaged 13.4 kg and 16.8 kg at six months and 11.2 kg and 13.1 kg at one year. WHR decreased significantly in both genders: for women, WHR decreased from 0.95 at baseline to 0.93 at six months and 0.94 at one year; for men WHR decreased from 0.99 at baseline to 0.96 at six months and 0.96 at one year. Subjects with greater upper body obesity at baseline did not lose more weight than subjects with less upper body obesity, but they did have greater reductions in WHR at six months in both genders and at one year in men. The magnitude of WHR reduction was strongly related to the amount of weight lost in men, but was not related to weight loss in women. Improvements in fasting glucose, fasting insulin, and HbA1 were significantly related to weight loss, but not to reductions in WHR. Thus, participation in a weight loss program had beneficial effects on body fat distribution in patients with type II diabetes, but these changes in WHR were not independently associated with improvements in glycemic control.

Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679.

A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.

A comparison of children with and without learning disabilities on social problem-solving skill, school behavior, and family background.

The study compared 86 children with learning disabilities (LD) with 86 matched children without learning disabilities (NLD) on three domains of variables: social problem-solving skill, teacher-rated school behavior and competence, and family background. The children with LD and the NLD group differed on variables in all three domains. More specifically, the children with LD were able to generate fewer alternatives for solving social problem situations, showed less tolerance for frustration and less adaptive assertiveness, and had more overall classroom behavior problems and less personal and social competence in a variety of areas as rated by teachers. Children having LD also showed more family background difficulties (e.g., lack of educational stimulation at home, economic difficulties). The findings suggest the need for greater attention to social and behavioral remediation for children with LD and greater involvement of their families, in addition to the cognitive and academic remediation emphasized in existing curricula for children with LD.

Analysis of changes in eating behavior and weight loss in type II diabetic patients. Which behaviors to change.

To identify the behavior-change strategies that are most clearly related to weight loss, 106 patients with type II (non-insulin-dependent) diabetes completed the Eating Behavior Inventory (EBI) before and after participating in a behavioral weight-loss program and at 1-yr follow-up. The EBI is a standardized questionnaire that assesses behavioral strategies typically taught in a behavioral weight-loss program. Pretreatment scores on the EBI were not related to weight-loss outcome, but changes on the EBI in the direction of more frequent use of appropriate strategies were related to weight loss at both posttreatment and 1-yr follow-up. Specific strategies related to weight loss at both times were 1) eating foods that help in losing weight, 2) recording foods eaten, 3) refusing food offered by others, and 4) being able to stop eating when appropriate. However, few patients maintained frequent use of these strategies at follow-up. It is concluded that weight-loss programs should focus on the strategies most strongly related to weight loss and try to improve long-term use of these techniques.

[3H]L-654,284 as a probe of the central alpha 2 adrenoceptor.

L-654,284 [2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide], a potent and selective antagonist of the alpha 2 adrenoceptor, was tritiated to high specific activity. Saturation binding to cell membrane suspensions obtained from calf cerebral cortex revealed a high affinity binding site (0.63 nM). Kinetics of association and dissociation were well represented by single exponential processes, and the equilibrium dissociation constant obtained from the ratio of rate constants agreed well with that found by saturation binding. A direct comparison of saturation binding revealed that the antagonist [3H]L-654,284 had roughly the same affinity for the alpha 2 adrenoceptor as the agonist [3H]clonidine and eight times the affinity of the antagonist [3H]rauwolscine. The maximum receptor densities of these radioligands were not significantly different. Competition assays with a series of compounds of known receptor affinity revealed that [3H]L-654,284 selectively binds to a site with all of the characteristics expected of the alpha 2 adrenoceptor.

Structure-affinity relationships of arylquinolizines at alpha-adrenoceptors.

Hexahydroaryl[a]quinolizines comprise a prominent structural element in several alpha 2-adrenoceptor antagonists. Eight hexahydroheteroarylquinolizines were prepared as minimal ligands to investigate the relationship between the nature of the aromatic ring and affinity of these molecules for alpha-adrenoceptors. Affinity for alpha 1-and alpha 2-adrenoceptors was assessed by displacement of [3H]prasozin and [3H]clonidine, respectively. Lipophilicity of the aryl portion of the molecules, reflected by their partition coefficient between octanol and pH 7.4 buffer, correlated well with affinity at both receptor subtypes. Although some compounds showed nanomolar affinity for alpha-adrenoceptors, no subtype selectivity was observed. These results suggest that the aromatic ring enhances binding at both receptors chiefly through hydrophobic interactions and contributes little to subtype selectivity.

Preventive intervention with latency-aged children of divorce: a replication study.

This replication study assessed the efficacy of a school-based preventive intervention for latency-aged children of divorce. The Children of Divorce Intervention Program (CODIP) emphasizes support, identifying and expressing divorce-related feelings, training situationally relevant communication, problem solving, and anger control skills, and enhancing self-esteem. Fifty-four children of divorce participated in the 11-session program conducted in small groups. Their adjustment was contrasted at pre and post with that of demographically matched peers (N = 78) from intact families on teacher, parent, self-report, and group leader measures. Children of divorce were less well adjusted than their peers before the intervention. They improved significantly after the intervention, approaching youngsters from intact families in adjustment status. The replication data support CODIP's efficacy as a preventive alternative for children of divorce. Needed future development and research steps are considered.