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Biomedical subjects

N R Cutler

Publications and source records attributed to N R Cutler.

At least 91 records · Page 5Linked to original sources
PubMed1994

A phase II multicenter dose-finding, efficacy and safety trial of ipsapirone in outpatients with generalized anxiety disorder.

Benzodiazepines have been prescribed for the treatment of Generalized Anxiety Disorder (GAD) for nearly three decades due to their proven anxiolytic efficacy, despite a considerable side effect and abuse liability profile. A new class of compounds, the azapirones, have been developed as an alternative to benzodiazepine treatment. Ipsapirone is a novel anxiolytic azapirone which has high specificity for the 5-HT1A receptor and which has the potential for offering certain advantages over buspirone. The present 5-week study investigated three doses of ipsapirone (2.5mg, 5.0mg and 7.5mg tid) versus placebo in 267 GAD outpatients. Efficacy was evaluated using the Hamilton Anxiety Rating Scale (HAM-A), Zung Anxiety Scale (Zung-A), and Clinical Global Impression (CGI). The study design consisted of a 1-week placebo run-in, a 4-week double-blind treatment period, and a 1-week placebo washout. The 5.0mg group demonstrated consistently superior improvement in all efficacy variables during the treatment period, with significant differences (p < 0.05) from placebo and, at times, the 2.5mg and 7.5mg groups. Incidence of adverse events, primarily dizziness, nausea, sedation, and asthenia, was found to be dose proportional, with significant increase in the 7.5mg group, which may account for the diminished effectiveness seen with this dose. Our results suggest that ipsapirone may represent a viable treatment for GAD.

Adult↗
PubMed1994

An evaluation of the anxiolytic SC 48,274 in generalized anxiety disorder (GAD)

1. The present study evaluated the safety and efficacy of two dosages of SC 48,274 (1mg and 25mg) as compared to placebo in subjects with Generalized Anxiety Disorder (GAD). 2. This was a randomized, double-blind, placebo-controlled, parallel-group study which was part of one of three large multicenter trials which evaluated a total of 5 doses of SC 48,274 (.25, 1, 5, 25, and 100mg bid). Following a 7-day placebo baseline period, patients entered 4 weeks of double-blind treatment and a 7-day placebo follow-up period. 3. Efficacy was assessed weekly throughout the study with the Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impression (CGI), and at treatment endpoint with the Covi Anxiety Scale, Raskin Depression Scale and Hamilton Depression Rating Scale (HAM-D). A diagnosis of GAD according to DSM-III-R criteria (with the exception that a GAD minimum duration of 3 months was allowed), a HAM-A score > or = 20 (anxious mood and tension items > or = 2), HAM-D less than HAM-A, Covi Anxiety Score > or = 8, Raskin Depression Scale less than the Covi Anxiety, and age of 18 to 65 years were necessary for inclusion in the study. 4. Patients received one of two dosages of SC 48,274, either 1mg (n = 28), 25mg (n = 9), or placebo (n = 28) bid, during the 4-week randomized portion of the trial. 5. Mean changes from baseline in HAM-A scores for the 1mg, 25mg, and placebo groups after 4 weeks treatment were -5.1, -4.2, and -1.9, respectively. Changes were significant for the 1mg group vs. placebo (F = 8.93, p = 0.004), but not for the 25mg group (F = 2.26, p = 0.138). 6. CGI severity of illness scores were also significant for the 1mg group versus placebo at the end of treatment (X2 = 3.8, p = 0.05), but not for the 25mg group (X2 = 0.90, p = 0.343). Neither group showed significant CGI improvement scores by end of treatment. 7. The most frequent adverse events associated with the study drug (n = 37) were headache (n = 7), nausea (n = 3), palpitations (n = 4) and chest pains (n = 2). There was, however, no apparent pattern of adverse events distinguishing SC 48,274 from placebo.

Adult↗
PubMed1994

Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients.

The pharmacokinetics of single and co-administered didanosine and stavudine were evaluated in 10 HIV-seropositive subjects in an open, within subject design in which each subject received each of three treatments. Single doses of didanosine 100 mg were alternated randomly with single doses of stavudine 40 mg on days 1 and 2. Beginning on day 3, subjects received the same doses of both drugs simultaneously every 12 h for nine doses. Serial blood and urine samples were obtained on single dose days 1 and 2, first simultaneous dose day 3, and last simultaneous dose day 7. The average maximum plasma concentrations of didanosine and stavudine before and after simultaneous administration were 422 +/- 184 (s.d.) ng ml-1 and 603 +/- 160 (s.d.) ng ml-1, and 419 +/- 153 (s.d.) ng ml-1 and 726 +/- 188 (s.d.) ng ml-1, respectively. Didanosine and stavudine AUC values before and after simultaneous administration were 615 +/- 170 (s.d.) ng ml-1 h and 1246 +/- 230 (s.d.) ng ml-1 h, 637 +/- 155 (s.d.) ng ml-1 h and 1326 +/- 267 (s.d.) ng ml-1 h, respectively. No significant changes in maximum plasma concentration, AUC elimination half-life, or renal clearance of didanosine and stavudine were observed when the drugs were administered simultaneously. Co-administration of didanosine 100 mg and stavudine 40 mg is well tolerated and the drugs do not interact pharmacokinetically.

Adult↗
PubMed1994

Safety and tolerance of intravenous nimodipine.

OBJECTIVE: To evaluate the safety and tolerance of intravenous nimodipine administered via a peripheral vein in healthy male volunteers. DESIGN: Double-blind, placebo- and vehicle-controlled trial with three fixed-dose panels. SETTING: Inpatient infusion and observation periods. SUBJECTS: 61 healthy male volunteers, aged 18-40 years. METHODS: Subjects in panel 1 received nimodipine 0.4 mg/h, vehicle 2 mL/h, or placebo 2 mL/h; subjects in panel 2 received nimodipine 1 mg/h, vehicle 5 mL/h, or placebo 5 mL/h; subjects in panel 3 received nimodipine 2 mg/h, vehicle 10 mL/h, or placebo 10 mL/h. All infusions were administered intravenously for 48 hours and volunteers were observed for 48 hours after cessation of the infusion. In addition to standard safety assessments (physical examination, electrocardiogram, laboratory studies, and adverse event reporting), supine and standing blood pressures and pulse rates were measured frequently. Plasma samples were also analyzed for nimodipine and its two demethylated metabolites. RESULTS: Of 61 subjects, 55 completed the 48-hour infusion and 6 discontinued the study because of adverse events. Intravenous nimodipine was well tolerated at 0.4 and 1 mg/h. However, all six subjects who received nimodipine 2 mg/h experienced moderate-to-severe adverse events, and one subject was discontinued because of dizziness, diaphoresis, and postural hypotension. The matched vehicle (10 mL/h) also was not well tolerated, with three subjects who discontinued because of phlebitis. Two subjects who received placebo were also discontinued during the study. Small (2 mm Hg) decreases in mean supine diastolic blood pressure were observed in the 0.4- and 1-mg/h nimodipine groups, but the 2-mg/h group showed a slight (5 mm Hg) increase in blood pressure. These changes were not clinically significant. Clearance and half-life of nimodipine and its metabolites were similar at all three dosages. CONCLUSIONS: Using peripheral vein administration, nimodipine 2 mg/h and matched vehicle at 10 mL/h were not well tolerated in this healthy normal population. The maximum tolerated dose of nimodipine was found to be 1 mg/h.

Adolescent↗
PubMed1993

The use of the Computerized Neuropsychological Test Battery (CNTB) in an efficacy and safety trial of BMY 21,502 in Alzheimer's disease.

BMY 21,502 is a nootropic which protects memory and enhances long-term potentiation according to preclinical findings. Alzheimer's disease (AD) patients who were diagnosed by DSM-III-R and NINCDS-ADRDA criteria were enrolled in a 12-week double-blind investigation of BMY 21,502 vs. placebo at 300 mg tid. The study design included a 1-week placebo lead-in and a 4-week placebo washout in addition to the 12-week double-blind treatment period. Efficacy was assessed with the Alzheimer's Disease Assessment Scale (ADAS) and the Computerized Neuropsychological Test Battery (CNTB) at weeks 4, 8, 12, and 16. Clinical Global Impression (CGI) assessments were also performed biweekly. Sixty-nine patients (28M, 41F; mean age 72 years, range 54 to 92 years) were enrolled in the study. Baseline Mini-Mental Status Examination (MMSE) scores ranged from 16 to 26 (mean 23.5) in patients on active drug (n = 34), and from 15 to 26 (mean 22.5) in placebo patients (n = 35). Baseline efficacy scores were comparable for drug and placebo patients (p > 0.05). Twelve (35%) patients who received BMY 21,502 withdrew from the study, 8 (24%) due to adverse events. Three (9%) patients who received placebo withdrew from the study, all due to adverse events. Patients on active drug who were valid for analysis of efficacy (n = 22) showed a mean decrease in ADAS of -1.5 at week 12, vs. a mean change of -0.5 in patients who received placebo (n = 32), although there was no significant difference between the two (p > 0.05). Correlations between the CNTB summary scores and ADAS cognitive subscores were, nevertheless, highly significant at baseline (r = -0.83, p = 0.0001) and week 12 (r = -0.83, p = 0.0001). Correlations between the word list learning, spatial, and naming subtests of the ADAS and CNTB were also highly significant (p = 0.0001). Although modest, the findings for active drug vs. placebo response in this study suggest that BMY 21,502 should be further investigated, with a larger study population, in order to fully determine the compound's potential efficacy.

Aged↗
PubMed1993

Psychomotor and memory effects of two adinazolam formulations assessed by a computerized neuropsychological test battery.

The memory effects of adinazolam were assessed using the computerized neuropsychological test battery (CNTB). In a single-blind crossover study, 12 volunteers received 2 x 20 mg adinazolam mesylate immediate-release (CT) tablets, 2 x 30 mg sustained-release (SR) tablets, and placebo. Plasma adinazolam and N-desmethyladinozolam (NDMAD) were determined by high-pressure liquid chromatography. Choice reaction time and word-list-learning/delayed-recall CNTB modules were administered at 0, 1, 3 and 6 hours after dosing. Adinazolam and NDMAD maximum peak plasma concentration were lower after SR tablets. Immediate-release tablets significantly prolonged reaction time compared with placebo and SR tablets; reaction time after SR tablets did not differ from placebo. Differences between SR and CT tablets in memory were significant only at 1 hour, but memory scores tended to be higher after SR tablet administration than after the CT tablet. At all times, memory scores were significantly lower than placebo for active treatments. Results suggest that memory is more impaired at lower NDMAD concentrations than is psychomotor function.

Anti-Anxiety Agents↗
PubMed1993

A pilot clinical trial of the angiotensin-converting enzyme inhibitor ceranapril in Alzheimer disease.

This pilot clinical trial was a 15-week, double-blind, controlled, three-way crossover study evaluating cognitive effects of ceranapril in subjects with dementia of the Alzheimer type (age range 50-75 years). Computerized (CNTB) and noncomputerized cognitive test batteries revealed no significant results (p > 0.05). On further analysis of the data, however, a study of longer duration and/or higher dosages may be warranted.

Aged↗
PubMed1993

The safety and efficacy of ipsapirone vs. lorazepam in outpatients with generalized anxiety disorder (GAD): single site findings from a multicenter trial.

We report the findings of a randomized, double-blind, placebo-controlled, parallel, generalized anxiety disorder (GAD) outpatient study. The purpose of the study was to compare the efficacy, safety, and tolerability of ipsapirone, an azapirone and 5-HT1A agonist, given at a total daily dose of 10 mg to 30 mg, with a total daily dose of 2 mg to 6 mg of lorazepam or placebo in 90 outpatients with GAD of moderate or greater severity. At baseline, all patients had a Hamilton Anxiety Scale (HAM-A) score of > or = 18 and Covi anxiety score of > or = 8. After a 1-week single-blind washout, patients entered a 4-week double-blind period with an optional extension for another 4 weeks, followed by a 2-week single-blind placebo washout. Ipsapirone and lorazepam ratings on the HAM-A and Clinical Global Impressions (CGI) were significantly (p < .05) superior to placebo at the end of the acute and maintenance periods of the trial, with a 50 percent HAM-A reduction on active drugs vs. 20 percent on placebo. The anxiety of patients receiving lorazepam, but not ipsapirone, rebounded during the final placebo washout.

Adult↗
PubMed1993

A double-blind, placebo-controlled study comparing the efficacy and safety of ipsapirone versus lorazepam in patients with generalized anxiety disorder: a prospective multicenter trial.

This multicenter, double-blind, placebo-controlled, randomized study compared the efficacy, safety, and tolerability of ipsapirone (an azapirone anxiolytic) at daily dose levels of 10.0 to 30.0 mg with a daily dose of 2.0 to 6.0 mg of lorazepam (a benzodiazepine) or placebo when given to outpatients with generalized anxiety disorder (GAD) of moderate or greater severity. A total of 317 outpatients with a primary diagnosis of GAD according to DSM-III criteria (at least 1 month's duration) were randomized. Study entry criteria at the time of screening and at baseline included a Hamilton Rating Scale for Anxiety (HAM-A) score of 18 or more, a Covi Anxiety Scale score of 8 or more, and a Raskin Depression Scale score of 7 or less. The study design consisted of a 1-week, single-blind placebo evaluation, a 4-week, double-blind acute treatment period, and a 4-week extension period, followed by a 2-week, single-blind placebo withdrawal period. Efficacy was measured by changes in the HAM-A and Clinical Global Impression Scale and by evaluations of the Hamilton Rating Scale for Depression and Zung-Anxiety Self-Rating scale. The Raskin and Covi scales were performed at screening and baseline only. Withdrawal reactions were assessed during the withdrawal period by the Physician Withdrawal Checklist and by a patient self-rating checklist. Two-hundred sixty-three patients were valid for the analysis of efficacy in the ipsapirone (N = 87), lorazepam (N = 89), and placebo (N = 87) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Comparison of quantitative methodologies to define chronic pressure ulcer measurements.

The objective of this study was to evaluate and compare various methodologies of measuring the characteristics of pressure ulcers. This prospective, four-week, follow-up study consisted of 20 patients, of whom 17 completed the study. Each patient had at least one full-thickness pressure ulcer (surface area between 1.2 and 61.6 cm2) that had been present for at least four weeks. The ulcers were assessed weekly for four weeks using the following techniques: direct measurement (length, width, and depth), tracing of the ulcer outline onto transparent material, standard photography, and volume measurement. Computer-assisted planimetry from the tracings and photographs, and calculations from the direct measurements determined ulcer areas. Each technique estimating ulcer area gave similar results; however, the areas obtained from the direct measurements slightly over-estimated the areas when compared with the areas obtained by computer-assisted planimetry (mean difference of about 1.5 cm2). Areas obtained from the photographs were more variable than the other measurement techniques. Volumes calculated from bedside measurements were consistently larger than those calculated by jeltrate impression (mean difference of 4.0 cm3). While all the measurement methodologies gave similar and reproducible results, the areas obtained from the photographs were more variable than the areas obtained from the other measurement techniques. The photographic measurements could be improved either by tracing the ulcer outline at the bedside onto the photograph shortly after being taken, or by drawing an outline of the ulcer margin directly on the patient's skin just before taking the photograph.

Aged↗
PubMed1992

A dose-response trial of once-daily diltiazem.

This trial was performed to determine the safe and effective dosage range of once daily diltiazem (diltiazem CD) capsules for treatment of essential hypertension. Patients with essential hypertension having supine diastolic blood pressure values greater than or equal to 95 mm Hg and less than or equal to 110 mm Hg were randomly assigned to receive placebo or one of four doses of diltiazem CD: 90, 180, 360, or 540 mg. Blood pressure was measured at trough, 24 hours after the dose, and at the time of peak effect, 10 hours after the dose. Diltiazem CD lowered both supine diastolic and systolic blood pressure. A linear dose response was seen with changes in diastolic and systolic blood pressure and heart rate for trough and peak measurements. Trough/peak ratios for the 180, 360, and 540 mg doses were all greater than 0.50. Adverse effects were dose related; those most commonly reported were headache (8.6%), bradycardia (8.1%), and edema (7%), with bradycardia and edema possibly dose related. It is therefore concluded that diltiazem CD is a safe and effective antihypertensive agent.

Adolescent↗
PubMed1992

A comparison of circulating hormone levels in postmenopausal women receiving hormone replacement therapy.

Seventeen postmenopausal subjects were randomized into this comparative study of esterified estrogen 0.625 mg (Estratab), esterified estrogen 0.625 mg plus 1.25 mg methyltestosterone (Estratest H.S.), or conjugated estrogen 0.625 mg (Premarin). Sixteen subjects completed the study in which plasma hormone concentrations of estrone and estradiol were assessed at various time points. There were no significant differences among the treatment groups.

Adult↗
PubMed1992

Detection of benzodiazepines in human hair by radioimmunoassay.

OBJECTIVE: In this preliminary investigation, we sought to determine whether a standard benzodiazepine radioimmunoassay (RIA) could detect three benzodiazepines in human hair. DESIGN: Hair samples of 20-50 strands (minimum 10 mg) were cut from eight patients receiving diazepam, two patients receiving alprazolam, three patients receiving lorazepam, and two negative controls. Samples were treated with ethanol and phosphate buffer washes at 37 degrees C to remove external contamination. The protein hair matrix was destroyed using proprietary procedures, then analyzed with Abuscreen RIA designed to detect various benzodiazepines and their metabolites, using oxazepam as a reference standard. SETTING: Patients were hospitalized in a locked psychiatric facility. PATIENTS: Twelve patients with chronic psychiatric conditions who had received therapeutic dosages of benzodiazepines for 1-11 months were included in the sample. One outpatient who reported heavy prior diazepam use was also included. MAIN OUTCOME MEASURE: Detection of benzodiazepines was well above a 1.5 ng/10 mg cutoff level with the Abuscreen assay. RESULTS: Diazepam was readily detected, but alprazolam and lorazepam were not detected. CONCLUSIONS: There is no test that can currently determine duration and extent of prior benzodiazepine use. Hair analysis for diazepam offers a potential, new clinical and research tool for characterizing prior level and extent of usage.

Adult↗
PubMed1992

Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer's disease.

OBJECTIVE: Velnacrine testing for tolerance and safety in both normal elderly subjects and patients with Alzheimer's disease (AD) is reviewed to illustrate the importance of Phase I trials in the target group as more predictive of safety and tolerance for subsequent multicenter trials than those conducted in healthy elderly subjects. DESIGN: Both a single-dose and a randomized, double-blind, placebo-controlled, ascending, multiple-dose study were performed with healthy, elderly men. In the multiple-dose study, the subjects were randomized to four groups of 14, with 10 subjects receiving velnacrine and 4 receiving placebo. The doses were velnacrine 25 (group 1), 50 (group 2), and 100 mg (group 3), respectively, administered twice daily; group 4 received 100 mg three times daily for 28 days. Blood and urine were collected serially for the pharmacokinetic assessment. With AD patients, 24 subjects were randomly assigned to receive either placebo or velnacrine for 10 days in a double-blind, sequential escalation study in a hospital setting. There were three groups of 8 subjects. Six patients in each group received velnacrine and 2 placebo. The three groups received respective dosages of 450, 300, and 225 mg/d three times daily. Adverse events were closely monitored and recorded. PATIENTS/PARTICIPANTS: The multiple-dose test in healthy elderly men included 56 men, aged 60-74 years. Rigorous screening for any potential complications that could affect absorption, distribution, metabolism, or excretion preceded patient entry in the AD patient study. Patients with a history of major psychiatric, neurologic, and cardiovascular disorders were excluded. The patients ranged in age from 56 to 89 years, and were equally distributed between gender. INTERVENTION: Velnacrine was administered in various doses. MAIN OUTCOME MEASURES: We emphasize the extreme adverse effects encountered in the AD patient group compared with the healthy group. Plasma concentrations of velnacrine over time in both groups are given, as well as the drug's half-life and excretion rates. RESULTS: The tolerable dosage predicted by studies performed in healthy elderly subjects was 300 mg/d. This dosage was not tolerable among the AD patients. A dosage as high as 450 mg/d resulted in a tonic seizure in one patient. The predicted dosage of 300 mg/d produced an adverse effect profile in AD patients that included dizziness, nausea and/or vomiting, headaches, and severe diarrhea. AD patients tolerated a dosage of 225 mg/d. CONCLUSIONS: A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.

Aged↗