PubMed Health⌕ Search

Biomedical subjects

J J Sramek

Publications and source records attributed to J J Sramek.

At least 55 records · Page 3Linked to original sources
PubMed1996

Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study.

Lesopitron, a 5-hydroxytryptamine 1A agonist, is a new potential anxiolytic of the azapirone class. It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone. Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers. Forty-two patients with generalized anxiety disorder (GAD) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron (20, 25, 30, 40, 45, 50, and 60 mg two times a day) over a 6 1/2-day inpatient administration period. Each of the seven panels included six patients (four drug/two placebo). One patient in the 25-mg, two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms. One patient experienced severe orthostatic hypotension at 60 mg two times a day, and moderate to severe adverse events (dizziness, lightheadedness, nausea, headache) occurred in two other patients at this dosage. The most commonly reported adverse events in all the panels were headache, dizziness, and nausea. Lesopitron is rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour, and its elimination half-life ranged from 1.1 to 5.6 hours. Peak plasma concentrations showed high interindividual variability for lesopitron, but increased linearly with dose for the main metabolite, 5-hydroxylesopitron. We defined the maximum tolerated dose in GAD patients as 50 mg two times a day, twice as high as the highest dose tested in healthy volunteers.

Adolescent↗
PubMed1996

Assessing the neuropsychological profile of stable schizophrenic outpatients.

In an administration of the Computerized Neuropsychological Test Battery (CNTB), stable schizophrenic outpatients (n = 26) showed significant impairment (P < 0.05) relative to normal control subjects (n = 28) in overall function and measures of verbal learning. Except on tests of motor speed, the performance profile of schizophrenic patients was similar to that of elderly normal control subjects (n = 33). This profile of deficits is consistent with findings of other investigators in similar patient populations. In addition to displaying sensitivity to the mild impairments found in outpatients, the CNTB showed high test-retest reliability (r = 0.76, P < 0.0001). It should be useful for evaluating cognitive impairment in clinical trials of prospective treatments.

Adult↗
PubMed1996

Effect of the ACE inhibitor ceronapril on cerebral blood flow in hypertensive patients.

OBJECTIVE: To assess the effect of the angiotensin-converting enzyme inhibitor ceronapril on cerebral blood flow (CBF) in patients with moderate hypertension. DESIGN: Patients received chlorthalidone 25 mg for 4 weeks, and if diastolic blood pressure remained in the range of 100-115 mm Hg, they were given titrated doses of ceronapril (10-40 mg/d based on blood pressure response) in addition to chlorthalidone for 9 weeks. SETTING: Outpatient research clinic. SUBJECTS: Eligible patients had moderate essential hypertension (diastolic blood pressure 100-115 mm Hg) assessed when the patients were receiving no medications. Thirteen patients were entered into the study; 1 withdrew for reasons unrelated to the study drug. Twelve patients (11 men, 1 woman; mean age 52 y) completed the study. INTERVENTION: Ceronapril, given with chlorthalidone. MAIN OUTCOME MEASURES: CBF measurements were taken at the start and end of ceronapril therapy using intravenous 133Xe; blood pressures were determined weekly. RESULTS: Mean arterial blood pressure decreased from 130 +/- 4 to 120 +/- 7 mm Hg after 4 weeks of chlorthalidone administration, and fell further to 108 +/- 8 mm Hg after an additional 9 weeks of combined chlorthalidone-ceronapril therapy (p < 0.05). CBF fell from 44 +/- 15 to 34 +/- 5 mL/min/100 g during the 9 weeks of combined therapy (p = 0.05). No adverse effects consistent with decreased CBF were observed. The decrease in CBF was not linearly correlated with the change in systemic blood pressure, but was strongly correlated (r = -0.937; p < 0.001) with the initial CBF. CONCLUSIONS: The decrease in mean arterial blood pressure was not associated with a decrease in CBF. Patients with high CBF may be predisposed to a decrease in CBF when treated with ceronapril and chlorthalidone.

Aged↗
PubMed1996

Placebo response in anxiety disorders.

OBJECTIVE: To review literature on placebo response in anxiety, to discuss sources and levels of placebo response in various anxiety disorders, and to suggest methods to prevent high placebo response rates in clinical research trials. DATA SOURCE: Data from scientific literature were identified using a MEDLINE search, and were extracted and summarized for this review. STUDY SELECTION: Representative findings were selected from clinical and epidemiologic studies, review articles, letters to the editor, book chapters, and proceedings. DATA EXTRACTION: Data from English-language reports of studies on humans were included. Only the most representative conclusions drawn from review articles were used. DATA SYNTHESIS: Anxiety disorders in general are thought to be extremely susceptible to a variety of influences, including patient characteristics and environmental variables. Reported placebo response levels in clinical studies of anxiolytics for generalized anxiety disorder and panic disorder vary widely, with a tendency to be rather high, although studies in social phobia and obsessive compulsive disorder appear to have consistently low placebo response rates. Comparisons of anxiety studies with studies of other indications, such as depression, show similar overall placebo response rates. To determine efficacy, drug response rates and placebo response rates must be clearly differentiated. CONCLUSIONS: Examination of the literature suggests that placebo response rates in studies of anxiolytics are influences by a number of factors, including both endogenous and exogenous variables. High placebo response rates may mask true drug response rates and may result from poor study design or lack of procedural standardization. The use of certain design methods may help to prevent high placebo response rates in anxiolytic clinical trials.

Anxiety Disorders↗
PubMed1996

Efficacy and safety of BMY 21,502 in Alzheimer disease.

OBJECTIVE: To assess the efficacy and safety of BMY 21,502, a nootropic agent, in patients with mild-to-moderate Alzheimer disease. DESIGN AND PARTICIPANTS: Sixty-nine patients with Alzheimer disease (28 men, 41 women, mean age 72 y, range 54-92, mean Mini-Mental State Examination (MMSE) score 23.5) were randomized to receive either BMY 21,502 (n = 34) or placebo (n = 35) for 12 weeks of double-blind treatment followed by a 4-week placebo washout period. SETTING: Outpatient research facility. MEASUREMENTS: Primary efficacy assessments were the Alzheimer's Disease Assessment Scale (ADAS) and the Clinical Global Impressions Scale. The Computerized Neurological Test Battery and MMSE were performed as secondary efficacy measurements. RESULTS: Although overall effects were not statistically significant (p > 0.05), patients taking BMY 21,502 showed a mean change in the ADAS cognitive score of -1.5 points at week 12, compared with -0.5 in patients who received placebo. Patients with moderate dementia (MMSE < or = 20) showed a greater change at week 12 with BMY 21,502 (-2.7 points) compared with placebo (+0.3 points), but the difference was not statistically significant. Although BMY 21,502 was well tolerated in general, patients treated with BMY 21,502 experienced higher rates of abnormal liver enzyme concentrations and nausea than did those in the placebo group. There was also a higher rate of discontinuations in the BMY 21,502 group, with 12 of 34 (35%) patients in the BMY 21,502 group discontinuing, compared with 3 of 35 (9%) in the placebo group (p < 0.05). CONCLUSIONS: In this pilot study, BMY 21,502 was not found to be significantly superior to placebo during the treatment period. The compound was generally well tolerated, although 8 of 34 (24%) patients discontinued active drug treatment. Further evaluation of BMY 21,502 in a larger study population may be warranted.

Aged↗
PubMed1996

Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms.

BACKGROUND: This study was designed to evaluate the anxiolytic efficacy of buspirone in patients with a diagnosis of generalized anxiety disorder (GAD) with coexisting mild depressive symptoms. METHOD: Patients who participated in this multicenter study scored >/= 18 on the Hamilton Rating Scale for Anxiety (HAM-A) and between 12 and 17 on the Hamilton Rating Scale for Depression (HAM-D). Following a 7- to 10-day placebo lead-in phase, patients who continued to qualify were randomly assigned to receive either buspirone titrated from 15 to 45 mg/day (N = 80) or placebo (N = 82) for the next 6 weeks. 121 patients completed 6 weeks of treatment. The primary efficacy measure was the HAM-A, taken weekly during the study. RESULTS: Buspirone-treated patients averaged a 12.4-point reduction from their baseline total HAM-A score of 24.9, while their counterparts on placebo averaged a 9.5-point reduction from their mean baseline total HAM-A score of 25.6. This 2.9-point difference in HAM-A reductions between treatment groups was significantly different (p < .03). Buspirone patients decreased their HAM-D scores by an average 5.7 points from their mean baseline total HAM-D score of 15.8, while placebo patients decreased their HAM-D scores by an average 3.5 points from their mean baseline score of 16.3 (p < .05). Overall, the incidence of adverse events was similar for both treatment groups, but buspirone-treated patients reported significantly more nausea, dizziness, somnolence, and sweating than placebo patients. CONCLUSION: Buspirone is superior to placebo in improving anxiety and depressive symptoms in GAD patients who have coexisting depressive symptoms.

Adult↗
PubMed1995

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

Adult↗
PubMed1995

The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease.

Xanomeline tartrate (active ingredient xanomeline) is a muscarinic agonist that has demonstrated specificity for the M1 receptor in preclinical studies and has been well tolerated at dosages up to 50 mg three times a day in healthy elderly subjects. To define the maximum tolerated dose (MTD) of xanomeline tartrate in patients with Alzheimer's disease, 48 patients (20 men, 28 women) with probable Alzheimer's disease were enrolled in a double-blind, placebo-controlled inpatient study to determine the safety and tolerability of 8 fixed dosages of xanomeline tartrate (25, 35, 50, 60, 75, 90, 100, and 115 mg, all three times a day) given for 7 days. For each dosage the treatment panel consisted of six patients (four taking xanomeline tartrate and two taking placebo). With the discontinuation of two patients because of severe intolerable adverse events, a minimum intolerated dose was reached at 115 mg three times a day, and 100 mg three times a day was defined as the MTD. This MTD in patients was two-fold greater than the MTD previously determined in healthy elderly volunteers.

Aged↗
PubMed1995

Scientific and ethical concerns in clinical trials in Alzheimer's patients: the bridging study.

This paper reviews the scientific and ethical issues surrounding the conduct of bridging studies in patients with Alzheimer's disease (AD). Bridging studies, so called because they facilitate the transition from phase I to phase II development, are late phase I safety/tolerance studies which determine the maximum tolerated dose (MTD) in patients before initiating phase II efficacy studies. Determining the MTD in patients is important because we have found that AD patients appear to respond to cholinergic compounds differently from normal volunteers, reaching a different MTD. Preliminary evidence of dose-related efficacy with two cholinergic compounds lends support to our contention that determination of the highest tolerated dose maximizes the potential to detect efficacy. We will review the early clinical development of several cholinergic compounds and make recommendations for the design and conduct of bridging studies based on our experience. A fixed-dose panel design with dosages based on the MTD determined in normal volunteers is recommended. In order to minimize risk to the patients, ensuring that scientific benefits outweigh the risks, a bridging study must be supported by detailed preclinical toxicology, by a clinical research unit that is prepared to handle unexpected contingencies, and by the oversight of a competent, multi-disciplinary review board. Patients should be in good physical health (excluding AD), and a comprehensive informed consent procedure must be instituted. Carefully planned and well run bridging studies represent a scientifically and ethically sound approach to drug development in the Alzheimer's population.

Alzheimer Disease↗
PubMed1995

Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.

OBJECTIVE: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. METHODS: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. RESULTS: A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml). CONCLUSIONS: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.

Acetophenones↗
PubMed1995

A multiple-dose safety trial of eptastigmine in Alzheimer's disease, with pharmacodynamic observations of red blood cell cholinesterase.

A placebo-controlled multiple dose study was conducted to evaluate the safety, tolerability, and pharmacodynamics of multiple dose levels of eptastigmine in 25 patients with probable Alzheimer's disease (AD). Twenty patients (12 M, 8 F; mean age 74, range 57-84) were randomized to receive 12mg (N = 3), 20mg (N = 6), 28mg (N = 6) or placebo (N = 5) tid on a double-blind basis for 14 days, followed by seven days of single blind placebo, in successively rising dose groups. All patients completed the study without intolerable or severe adverse events. All doses significantly (p < 0.001) reduced peak and trough RBC cholinesterase (AChE) activity as compared to baseline. Percent inhibition for Day 14 peak and trough RBC AChE peak and trough values, respectively, appeared proportional to dose: 18% and 21% (12mg); 36% and 35% (20mg); 40% and 44% (28mg). In order to determine the maximum tolerated dose of eptastigmine, an additional single-blind study was performed in five patients (2 M, 3 F; mean age 78, range 72-80) utilizing a rising dose schedule of eptastigmine (N = 4) or placebo (N = 1), starting with the previously tolerated 28mg tid dose and increasing by 4mg tid up to a potential maximum of 56mg tid. Dose-limiting adverse events occurred requiring discontinuation of medication in one patient at 48mg tid and two patients at 52mg tid; RBC AChE inhibition was proportional to dose, with peak values up to 70% inhibition at 48mg tid. The maximum tolerated dose of 48mg tid was identified as a basis for potential Phase II multicenter efficacy trials.

Acetylcholinesterase↗
PubMed1995

Safety and tolerability of CI-979 in patients with Alzheimer's disease.

CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride), a novel muscarinic agonist, is being investigated as a potential treatment for Alzheimer's disease (AD). The objective of the present study was to determine the safety and tolerance of multiple, rising, oral doses of CI-979 in patients with AD. Ten male patients aged 59 to 74 years (mean 65 years) who met NINCDS criteria for AD were randomized to receive either CI-979 (eight patients) or placebo (two patients) according to a double-blind, parallel-group, rising-dose design. Doses were 0.5-mg q6h, 1-mg q12h, 1-mg q6h, 2-mg q12h, 2-mg q6h, 2.5-mg q6h, and 3-mg q6h. All doses were to be administered sequentially for 3 days each with the exception of the 2.5-mg q6h dose, which was to be administered for 1.5 days. Five patients receiving CI-979 discontinued study medication because of adverse events; two after receiving 2-mg q6h (10 doses), two after 2.5-mg q6h (5 doses), and one after 3-mg q6h (4 doses). The study was terminated following administration of the fourth 3-mg dose due to the nature and intensity of adverse events. Cholinergic symptoms including diaphoresis, hypersalivation, nausea, diarrhea, hypotension, chills, headache, flatulence, and urinary frequency and signs suggestive of parkinsonism (cogwheeling, tremor, pillrolling, posturing, and shuffling gait) were dose-limiting. The frequency and intensity of adverse events increased with increasing CI-979 dose. No other clinically significant CI-979-related changes occurred in physical examinations, clinical laboratory measurements, electrocardiograms, or ophthalmologic examinations. Steady-state trough plasma CI-979 concentrations increased in proportion to dose. In summary, CI-979 doses of 1-mg q6h were well tolerated by all patients; 2-mg q6h was tolerated by most patients, and 2.5-mg and 3-mg doses were poorly tolerated, Dose titration to a maximum of 2-mg q6h will therefore be used in initial efficacy trials of CI-979 in patients with AD.

Aged↗
PubMed1995

A "bridging" (safety/tolerance) study of besipirdine hydrochloride in patients with Alzheimer's disease.

Besipirdine hydrochloride is a novel compound with cholinergic and adrenergic activity being investigated as a treatment for Alzheimer's disease (AD). The pharmacodynamics of some anti-dementia drugs are known to differ in patients with AD as compared with elderly normals. The present study was designed to determine the maximum tolerated dose (MTD) of multiple oral doses of besipirdine in AD patients. Twelve AD patients (NINCDS/ADRDA criteria; 7M, 5F, ages 58-75, mean age 65) were randomized to besipirdine (n = 9) or placebo (n = 3) in a double-blind, parallel-group, rising-dose design. Doses were 10, 20, 30, and 40 mg bid for 2 days each, followed by 50 and 60 mg bid for 5 days each. The most common adverse events were asymptomatic postural hypotension and asymptomatic bradycardia. Two patients on active drug developed severe adverse events: 1 after 3 days at 50 mg bid (nausea and vomiting); 1 after 3 days at 60 mg bid (angina). Due to the anginal episode, the study was terminated on Day 17. Plasma concentrations increased linearly with dose for besipirdine and its major metabolite. The two patients who developed severe adverse events had the highest plasma concentrations measured. Besipirdine 50 mg bid was considered the maximum tolerated dose (MTD).

Aged↗
PubMed1995

The utility of salivary amylase as an evaluation of M3 muscarinic agonist activity in Alzheimer's disease.

1. In this double-blind, placebo-controlled phase I study of the safety/tolerance of two doses of xanomeline tartrate (100 mg and 115 mg tid) given to 12 AD patients, the authors measured serum amylase, fractionated into pancreatic and salivary isoenzymes, as a potential marker for M3 activity associated with maximally tolerated dose (MTD). 2. MTD of xanomeline was determined to be 100 mg tid based on intolerable adverse events at 115 mg tid. One patient at the 115 mg tid level presented with moderate hypersalivation and salivary amylase levels 400% of baseline. 3. Overall amylase results were not significant, however a trend in the results for salivary amylase in the 115 mg panel suggests that salivary amylase may be a useful marker for M3 activity.

Aged↗
PubMed1995

Pramipexole in patients with early Parkinson's disease.

We evaluated the efficacy, safety, tolerability, and pharmacokinetics of pramipexole, a novel dopamine D2 receptor agonist, in early Parkinson's disease (PD). The study design was a parallel, placebo-controlled trial using an ascending dose of 4.5 mg/day pramipexole maximum. All subjects received selegiline (10 mg/day) but were not treated with levodopa. Of the 55 subjects who received at least one dose of the study medication, all but one, in the placebo group, completed the trial, which was 9 weeks in duration. The primary efficacy endpoints were changes in scores from baseline to final measurement on the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. The pramipexole group had a significantly greater improvement (p = 0.002) than the placebo group on UPDRS Part II (Activities of Daily Living). The change in score from baseline to final measurement on UPDRS Part III (Motor Examination) was not significantly different (p = 0.10) between the pramipexole and placebo groups, although the trend favoured the pramipexole group. All subjects in both the pramipexole and the placebo groups experienced one or more episodes of asymptomatic orthostatic hypotension; there was no significant difference between the pramipexole and the placebo groups in the number of subjects experiencing symptomatic orthostatic hypotension. The adverse events profile of pramipexole was similar, in general, to that of other dopamine receptor agonists. Plasma pramipexole levels increased linearly with dose. Pramipexole appears to be promising agent in the treatment of early PD.

Adult↗
PubMed1995

Efficacy trial of the 5-HT2 antagonist MDL 11,939 in patients with generalized anxiety disorder.

The purpose of this study was to assess the anxiolytic effect of MDL 11,939, a selective 5-HT2 receptor antagonist, in patients with generalized anxiety disorder. After a 1-week placebo lead-in period, 72 healthy male outpatients meeting DSM-III-R criteria for generalized anxiety disorder were randomized to MDL 11,939, 32 mg thrice daily (N = 37), or placebo (N = 35) for 6 weeks. At the end of treatment, MDL 11,939 showed a 7.2-point (30%) decrease in Hamilton Rating Scale for Anxiety scores compared with a 5.7-point (23%) decrease with placebo, but the difference was not significant (p > 0.05). The incidence of adverse events between treatments was similar. MDL 11,939 was well tolerated but did not demonstrate significant anxiolytic effects in this pilot study.

Adult↗
PubMed1995

Effects of the cholinomimetic SDZ ENS-163 on scopolamine-induced cognitive impairment in humans.

Scopolamine-induced cognitive impairment was used in healthy men to evaluate the central nervous system activity of the new cholinomimetic SDZ ENS-163. Eighteen subjects were treated in a crossover design with oral placebo/intravenous saline, 50 mg of oral SDZ ENS-163/intravenous saline, oral placebo/0.4 mg of intravenous scopolamine, and 50 mg of oral SDZ ENS-163/0.4 mg of intravenous scopolamine. The administration of placebo with scopolamine caused significant cognitive impairment, as assessed by the Computerized Neuropsychological Test Battery (CNTB), and also decreased salivation and heart rate. In contrast, SDZ ENS-163 with saline had no effect on CNTB scores, increased salivation, and increased heart rate. Despite the observed cholinomimetic effects of SDZ ENS-163 when administered with saline, the changes in CNTB scores, heart rate, and salivation were indistinguishable between placebo/scopolamine and SDZ ENS-163/scopolamine. Thus, 50 mg of oral SDZ ENS-163 has cholinomimetic activity in normal men, but this dose is insufficient to reverse the muscarinic effects of 0.4 mg of intravenous scopolamine.

Adult↗