Defining the maximum tolerated dose: investigator, academic, industry and regulatory perspectives.
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Animals↗
Biomedical subjects
N R Cutler
Publications and source records attributed to N R Cutler.
Two rapid-dose titrations of sertindole in patients with schizophrenia.
The novel antipsychotic sertindole has demonstrated efficacy in psychosis with an extrapyramidal syndrome profile indistinguishable from placebo. Prior trials of sertindole have increased the dose by 4 mg every third day, whereas the present study evaluated the safety and tolerability of two, previously untested, more rapid dose escalation regimens. Sixteen schizophrenic inpatients entered a 4-day, single-blind placebo washout period in two consecutive groups. All patients received sertindole in 4-mg dose increments up to a maximum dose of 24 mg, which was maintained for 5 days. Dose increases were every other day for group 1 (N = 8) and daily for group 2 (N = 8). Adverse events, electrocardiograms, routine laboratory tests, and plasma sertindole concentrations were recorded. No patient was discontinued because of adverse events. The most frequent adverse events were tachycardia upon orthostatic challenge, nasal congestion, dry mouth, and headache; except for dry mouth, the incidence of these was greater in group 2. All cases of tachycardia were asymptomatic. No clinically significant laboratory abnormalities were detected in either group. In conclusion, 4-mg increases of sertindole every other day seems to be safe. Daily titration was, in general, not well tolerated.
Adult↗
Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin.
A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.
Adolescent↗
Ethnicity and antipsychotic response.
OBJECTIVE: To review the data generated by studies examining interethnic/racial differences in response to antipsychotics. DATA SOURCES: A MEDLINE search (1966-1996) identified all articles examining differences in antipsychotic response among Caucasians, Asians, Hispanics, and African-Americans, as well as articles evaluating postulated mechanisms for these differences. STUDY SELECTION: All abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Ethnic/racial differences in response to antipsychotic medications have been reported and may be due to genetics, kinetic variations, dietary or environmental factors, or variations in the prescribing practices of clinicians. Studies suggest that Asians may respond to lower doses of antipsychotics due to pharmacokinetic and pharmacodynamic differences. Research relevant to African-Americans is limited, but some studies suggest that differences in this group may be due to clinician biases and prescribing practices, rather than to pharmacokinetic or pharmacodynamic variability. CONCLUSIONS: Future research directed at validating the hypotheses that different ethnic/racial groups show variations in response to antipsychotics should focus on homogeneous ethnic groups, use recent advances in pharmacogenetic testing, and control for such variables as observer bias, gender, disease chronicity, dietary and environmental factors, and exposure to enzyme-inducing and -inhibiting agents. Clinicians should be aware that potential interethnic/racial differences in pharmacodynamics and pharmacokinetics may exist that can alter response to antipsychotics.
Antipsychotic Agents↗
The bridging concept: optimizing dose for phase II/III in Alzheimer's disease.
Our research has shown that the tolerance of Alzheimer's disease (AD) patients for anti-dementia compounds is frequently higher but occasionally lower than the tolerance of healthy young or elderly populations. Such differences can either pose safety problems in later efficacy studies if patients cannot tolerate the dosages previously deemed 'safe' in healthy populations, or interfere with determining efficacy if inadequate doses are employed. We recommend use of a 'bridging study', which optimizes dosage early in development by determining the maximum tolerated dose of a compound in patients. Consecutive panels of patients each receive higher doses of study drug until a minimum intolerated dose is reached. The dose immediately below this one is then considered the maximum tolerated dose. Careful subject selection, adequate facilities, and highly qualified, experienced personnel, are critical to the successful implementation of a bridging study. Correctly done, bridging can streamline the overall drug development process while making Phase II and III trials safer for patients, and has immense potential for accelerating the search for compounds that have efficacy in AD.
Alzheimer Disease↗
Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.
SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present study was designed to assess the safety and tolerability of higher doses of ENA 713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs, range 45-90) were assigned to a fixed, nine-week dose escalation schedule in which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20) or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose escalation for the bid and tid ENA 713 groups was identical, beginning with 2 mg/day on Days 1 to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses through 12 mg/day were well tolerated. Most adverse events were mild to moderate in severity and of limited duration, most commonly headache, nausea, dizziness, and diarrhea. Three of forty patients on ENA 713 discontinued, all due to adverse events. Two experienced nausea and vomiting; the third experienced an unrelated mild atrial fibrillation.
Aged↗
Pilot study of MK-462 in migraine.
MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post-menopausal female migraine patients aged 22-51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.
Adult↗
Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal.
Following the conduct of a 28-day inpatient bioequivalence study of clozapine in schizophrenia patients, withdrawal effects after abrupt discontinuation from clozapine were assessed. Thirty patients who met DSM-III-R criteria for schizophrenia, residual type, or schizophrenia in remission were enrolled in the study. Patients were evaluated for symptoms of withdrawal effects for 7 days after clozapine 200 mg/day was abruptly withdrawn. Of 28 patients who completed the study, 11 had no withdrawal symptoms; 12 had mild withdrawal adverse events of agitation, headache, or nausea; four patients experienced moderate withdrawal adverse events of nausea, vomiting, or diarrhea; and one patient experienced a rapid-onset psychotic episode requiring hospitalization. Cholinergic rebound is a likely explanation for the mild to moderate withdrawal symptoms and is easily treated with an anticholinergic agent. Mesolimbic supersensitivity, as well as specific properties of clozapine, are discussed as likely causes for rapidonset psychosis. Our findings are consistent with previous reports of withdrawal reactions associated with clozapine, further reminding clinicians to monitor patients closely following abrupt discontinuation of clozapine.
Adolescent↗
A treatment and withdrawal trial of besipirdine in Alzheimer disease.
Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg b.i.d.) in 275 patients with Alzheimer disease during 3 months of treatment and for 3 months after withdrawal of treatment. Assessment after withdrawal of treatment was used in an effort to distinguish persistent efficacy attributable to a neuroprotective mechanism from reversible symptomatic efficacy. Besipirdine was generally well tolerated. The level of performance on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) was sustained during 3 months of treatment with besipirdine, whereas some deterioration in the performance of patients treated with placebo was observed over the same period. The small difference between active and placebo treatment groups approached, but did not reach statistical significance in the primary intent-to-treat analysis (p = 0.067); analysis of patients who completed all assessments was supportive (p = 0.031). Global ratings using the Clinician Interview-Based Impression of Change did not detect a besipirdine treatment benefit, possibly because of an adverse effect on mood and behavior in some patients. A high ratio of adrenergic to cholinergic potency may have resulted in the adverse effects of besipirdine and hence its failure to support the hypothesis that multiple neurotransmitter treatment may be more efficacious than monotherapy. The efficacy apparent on the ADAS-Cog after 3 months of treatment did not persist 3 months after withdrawal of treatment, suggesting that the benefit was symptomatic. This study provides a practical example of the use of treatment withdrawal assessment to distinguish neuroprotective from symptomatic efficacy.
Aged↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
A placebo-controlled trial of L-365,260, a CCKB antagonist, in panic disorder.
The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.
Adult↗
The use of placebo controls.
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Antidepressive Agents↗