Biomedical subjects

N R Cutler

Publications and source records attributed to N R Cutler.

At least 73 records · Page 4Linked to original sources

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

Dose-ranging study of a new, once-daily diltiazem formulation for patients with stable angina.

A double-blind safety and efficacy dose-ranging study was conducted with a new, once-daily, extended-release (XR) diltiazem hydrochloride formulation (Dilacor XR, Rhône-Poulenc Rorer, Collegeville, PA) in 189 patients with chronic stable angina pectoris. After a 2-week placebo lead-in phase, the patients were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: placebo, XR diltiazem 120 mg, 240 mg, or 480 mg. Extended-release diltiazem, at 240-mg and 480-mg once-daily doses, significantly improved (P < .05) total exercise time during treadmill exercise tolerance testing after 2 weeks of treatment when assessed 24 hours after the previous dose. These increasing doses of XR diltiazem were associated with incremental improvements in exercise tolerance. Outpatient function, as assessed by frequency of anginal attacks, nitroglycerin use, and ambulatory electrocardiogram (Holter, Scole Engineering Culver City, CA) monitoring of ischemic events, was also improved by XR diltiazem. This extended-release diltiazem formulation can be clinically titrated within the 120- to 480-mg dosing range, permitting effective once-daily administration for treating chronic stable angina.

Adult↗

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↗

PubMed1995

A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder.

This multicenter, double-blind, placebo-controlled, parallel-group, randomized study assessed the efficacy, safety, and tolerability of a novel CCK-B antagonist CI-988 in the treatment of generalized anxiety disorder (GAD). Patients received placebo or CI-988 (300 mg/day, thrice daily) for 4 weeks. Patients with a primary diagnosis of GAD according to DSM-III-R criteria were randomized. The study design included a 1- to 2-week single-blind placebo baseline phase, followed by a 4-week double-blind treatment phase. Efficacy was measured weekly by Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impressions of Severity and Change, UCLA-Multi Dimensional Anxiety Scale, and Hamilton Rating Scale for Depression. Patients were also evaluated to determine whether they met criteria for irritable bowel syndrome (IBS) at screening and were evaluated with a gastrointestinal visual analog scale at each visit. Eighty-eight patients were randomized to CI-988 (N = 45) and placebo (N = 43) at three centers. CI-988 did not demonstrate an anxiolytic effect superior to placebo in this clinical trial. There was no significant difference in mean change in HAM-A total between placebo (-7.73) and CI-988 (-8.64). However, a significant treatment-by-center interaction and a highly variable placebo response rate among the three centers limit the interpretation of the results. CI-988 did not have an effect on symptoms of IBS other than diarrhea, which worsened in patients with IBS. Other than a higher incidence of some gastrointestinal symptoms (diarrhea, dyspepsia, flatulence, and nausea), CI-988 was well tolerated. Results suggest that testing higher oral doses of CI-988 may be warranted.

Adult↗

PubMed1995

Evaluation of cycloserine in the treatment of Alzheimer's disease.

This multicenter study evaluated the efficacy and safety of cycloserine and measured its effects on explicit and implicit memory tests in patients with Alzheimer's disease (AD). Four hundred ten patients with AD, aged 50 years or older, were enrolled in this parallel-group, double-blind, placebo-controlled, randomized trial of 5, 15, or 50 mg cycloserine or placebo twice daily, and 403 entered the double-blind treatment phase. Two hundred sixty-five patients completed the entire 26-week treatment phase. There were no baseline differences among the four treatment groups. Cognitive Drug Research (CDR) efficacy assessments showed no differences between active treatments and placebo from baseline to study weeks 2, 6, 14, or 26. Patients receiving 15 mg of cycloserine improved significantly on one section of an implicit memory test. No differences among treatments were observed for any other assessment scales evaluated. The incidence and severity of adverse events were similar across treatment groups. Cycloserine was well tolerated but did not demonstrate consistent evidence of efficacy during the course of therapy. Higher doses may be necessary to achieve efficacy in the AD population and do not appear to be precluded by the adverse event profile seen in this study.

Aged↗

PubMed1995

Oral sumatriptan in preventing headache recurrence after treatment of migraine attacks with subcutaneous sumatriptan.

Headache recurrence (HR) may occur within 24 hours in approximately 40% of migraine attacks initially treated successfully with 6 mg subcutaneous (SC) sumatriptan. This may be due to the short plasma half-life of sumatriptan. We studied whether an additional dose of 100 mg oral sumatriptan 4 hours after treatment of a migraine attack with 6 mg SC sumatriptan could prevent HR. Patients (n = 667) treated up to three migraine attacks in a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. For each attack, they initially took open-label 6 mg SC sumatriptan by autoinjector. Four hours later all patients took either 100 mg oral sumatriptan or matched placebo. Patients could take an additional optional oral dose of 100 mg sumatriptan to treat HR. The primary efficacy end point was the number of successfully treated patients without HR within 24 hours after the initial SC injection for the first study attack. Two hundred twenty-five patients were not assessable for HR, mainly because of protocol violations. Of 442 assessable patients, 82/212 in the sumatriptan-treated group (39%) and 89/230 in the placebo-treated group (39%) reported HR in attack 1. Median times to recurrence were 15.6 hours after sumatriptan and 10.3 hours after placebo (p = 0.006). One hundred mg oral sumatriptan taken 4 hours after 6 mg SC sumatriptan does not prevent HR but significantly delays time to recurrence.

Administration, Oral↗

PubMed1995

The target population in phase I clinical trials of cholinergic compounds in Alzheimer disease: the role of the "bridging study".

Our experience with studies investigating central nervous system active compounds in Alzheimer disease (AD) patients suggest that conducting a "bridging study," in which patients from the target population are included in Phase I, could expedite the drug development process in AD. With one acetylcholinesterase (AChE) inhibitor compound (velnacrine), we found that AD patients tolerated considerably lower dosages than young normals and healthy elderly subjects, whereas our findings were exactly the opposite with another AChE inhibitor (eptastigmine). In studies of a muscarinic agonist (CI-979), AD patients were able to tolerate dosages higher than those that were well tolerated in young normals. A possible explanation for differences in drug effect and tolerance in the target population may be the pathologic changes in both the brain and the peripheral nervous system that are associated with AD.

Alzheimer Disease↗

PubMed1995

Anti-hypertensive effects of intravenous compared with oral captopril.

Twenty mild to moderate hypertensive subjects (11 men, 9 women, mean age 54.3 years, range 39-65 years) were studied to determine whether an intravenous form of captopril could be as safe and efficacious as an oral form and to estimate the time course of anti-hypertensive action over a wide dose range (100-fold) of i.v. doses versus oral captopril and placebo. Each subject demonstrated supine diastolic blood pressure (DBP) < or = 90 mm Hg following prospective ACE inhibitor monotherapy, with return of supine DBP to within 95-110 mm Hg 4 weeks after ACE inhibitor discontinuation. These subjects were then admitted to an inpatient unit for six 24 h periods; an initial acclimation period followed by five single doses of i.v. captopril (1.25, 12.5 and 125 mg) or placebo given as a 20 min infusion and oral captopril (25 mg) or placebo in a double-blind, double-dummy crossover study. Each dose was separated by 48 h. All 20 patients completed the study with no clinically significant adverse events. Captopril at doses of 125 mg i.v., 12.5 mg i.v. and 25 mg orally produced similar BP reductions over the 12 h postdose interval, and were more effective in lowering BP than intravenous captopril 1.25 mg or placebo. The 125 mg intravenous captopril dose was no more effective overall in BP reduction than the 12.5 mg i.v. and 25 mg oral doses and was associated with a greater incidence of adverse events. Treatment with 12.5 mg i.v. captopril is safe and comparable to 25 mg oral therapy.

Administration, Oral↗

PubMed1995

Orthostasis in Alzheimer disease: a retrospective analysis.

Vitiello et al. (1993) recently reported statistically significant decreases in systolic blood pressure upon standing in patients with Alzheimer disease (AD) (n = 60) as compared with healthy elderly controls (n = 20), which would suggest a possible autonomic dysfunction associated with AD. To investigate this issue, we conducted a retrospective analysis of blood pressures and heart rates of 31 patients 55-85 years of age (mean 69.6) who met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable AD. The patients were selected from a pool of placebo-treated patients with AD in five inpatient phase I clinical trials. All patients met rigorous entrance criteria and thus were in excellent physical health except for AD. Blood pressure and pulse were assessed after 3-5 min of lying down and after 1-3 min of standing. Systolic and diastolic blood pressures showed decreases upon standing of 12 mm Hg (8.6%) and 6 mm Hg (8.2%), respectively, on day 1 and decreases of 10 mm Hg (7.6%) and 4 mm Hg (5.7%), respectively, on day 7 of hospitalization (p < 0.05). Pulse rates increased upon standing by 17% and 13% on days 1 and 7, respectively (p < 0.05). Our data support the finding of Vitiello et al. of significant postural decreases in systolic blood pressure in patients with AD. Well-controlled, prospective studies of orthostasis in AD and healthy elderly subjects should be conducted to determine its prevalence in both populations and to determine whether the orthostatic changes seen in AD differ from those in normal aging.

Aged↗

PubMed1994

A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers.

OBJECTIVE: To determine the efficacy of the daily topical application of recombinant platelet-derived growth factor-BB (rPDGF-BB), a recognized vulnerary agent, in the treatment of deep pressure ulcers. DESIGN: Prospective, randomized, double-blind trial. SETTING: Patients were treated in a nursing home or a hospital setting before transfer to a nursing home. PATIENTS: Eligibility criteria included a clean pressure ulcer that had been adequately debrided and the absence of severe cardiac, pulmonary, or renal conditions. The causes of the ulcers were not related to a venous or arterial vascular disorder. The patients were elderly (mean age, 68 to 74 years). INTERVENTIONS: After randomization, patients were given daily topical aqueous rPDGF-BB (dosage, 100 or 300 micrograms/mL) or placebo and saline gauze dressings were applied daily in addition to frequent turning. MAIN OUTCOME MEASURE: Serial volume measurements of the healing wounds were taken using alginate molds. RESULTS: The ulcers of 41 patients were analyzed. At the end of 28 days, median ulcer volumes had decreased to 83%, 29%, and 40% of the initial size in the groups receiving placebo, rPDGF-BB, 100 micrograms/dL, and rPDGF-BB, 300 micrograms/mL, respectively. When adjusted for initial volume, ulcer volume after 28 days of treatment was smaller in the rPDGF-BB-treated groups compared with the placebo group (analysis of covariance, P = .056). Ulcers in the two rPDGF-BB-treated groups were significantly smaller in volume compared with those in the placebo group, using a linear contrast procedure. CONCLUSIONS: Data from this small trial suggest that local application of rPDGF-BB may be of therapeutic benefit in accelerating the healing of chronic pressure ulcers.

Administration, Topical↗