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Biomedical subjects

J J Sramek

Publications and source records attributed to J J Sramek.

At least 37 records · Page 2Linked to original sources
PubMed1998

Monitoring of acute migraine attacks: placebo response and safety data.

In the course of evaluating the safety and efficacy of an investigational compound for acute migraine headaches, a large number of patients received placebo at a single site, offering the opportunity to characterize subjective and clinical physiologic responses of migraine patients to placebo in a controlled environment. In a single-site, double-blind, placebo-controlled study, 67 patients reported to the clinic while suffering a moderate to severe acute migraine headache and received oral placebo. For 6 hours after treatment, a continuous electrocardiogram (ECG) was performed, and headache severity, adverse events, and vital signs were recorded. Patients returned and repeated the procedure when free from pain. A headache was considered to be improved if its severity dropped to "mild" or "none." Twenty-five patients (37%; 95% CI: 26% to 50%) experienced headache improvement within 2 hours of receiving placebo, and 32 patients (48%: 36% to 60%) improved within 4 hours. There were no clinically important ECG changes during the migraine visit, and there were no clinically relevant differences in vital signs between the migraine and pain-free visits. Thus, a substantial placebo response occurs in migraine headache. Hemodynamic and ECG parameters are unchanged between migraine and pain-free states.

Acute Disease↗
PubMed1998

Pharmacokinetics and pharmacodynamics of avitriptan in patients with migraine after oral dosing.

Avitriptan (BMS-180048) is a 5-HT1-like receptor agonist for the treatment of migraine. This double-blind, placebo-controlled, randomized, parallel-group study evaluated the pharmacokinetics, safety, and preliminary efficacy of avitriptan in patients with migraine during migrainous and pain-free states. Patients met the IHS criteria for migraine with or without aura and suffered one to six migraines per month for at least 1 year. Patients in a clinic experiencing a migraine headache received avitriptan 75 mg, 150 mg, or 200 mg or matching placebo capsules. Blood samples were obtained before and 0.25, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after dosing. Headache intensity was rated before and up to 6 hours after dosing. Seven to 30 days after the inclinic treatment, patients returned in a pain-free state for the same study medication. All pharmacokinetic and safety measures were repeated. Forty-eight patients (9 men and 39 women) participated. Peak plasma concentrations of avitriptan were achieved 1 to 2 hours following dosing in migraine and pain-free states for all doses. The pharmacokinetics of avitriptan were proportional to dose during a migraine attack over the 75- to 200-mg dose range. The 150- and 200-mg doses of avitriptan demonstrated a greater decrease in headache intensity scores at 2 hours postdose. The most common adverse event was paresthesia. Thus, avitriptan was rapidly absorbed, well tolerated, and demonstrated preliminary efficacy in this population.

Administration, Oral↗
PubMed1998

Guidelines for conducting bridging studies in Alzheimer disease.

This report provides guidelines for conducting bridging studies in patients with Alzheimer disease (AD). Bridging studies are late phase I safety/tolerance studies that determine the maximum tolerated dose (MTD) in patients before phase II efficacy studies are initiated, facilitating the transition from phase I to phase II development. Determining the MTD in patients maximizes the potential to detect efficacy by permitting the use of the highest tolerated doses in phase II while providing a good understanding of potential adverse events. Bridging studies should be double-blind, placebo-controlled, inpatient studies conducted in acute-care facilities by clinical personnel who are equipped to handle unexpected contingencies under the oversight of a competent, multidisciplinary review board. Patients should be in good physical health (excluding AD), and a comprehensive informed consent procedure must be instituted. We recommend initially using a fixed-dose panel design with a dose schedule based on the MTD in normal volunteers and later establishing the dose titration MTD.

Alzheimer Disease↗
PubMed1998

Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB).

The cognitive efficacy of the M1-selective muscarinic agonist xanomeline in mild-to-moderate Alzheimer disease (AD) was measured using the Computerized Neuropsychological Test Battery (CNTB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) in this 17-center, double-blind, placebo-controlled study. Three hundred forty-three patients were randomly assigned to receive 25, 50, or 75 mg xanomeline tartrate or placebo three times daily (t.i.d.) for 24 weeks, followed by placebo for 4 weeks in a single-blind washout phase. Cognitive function was assessed at randomization and after 4, 8, 12, 24, and 28 weeks. Three hundred nineteen patients were included in an intent-to-treat (ITT) analysis; 209 completers had evaluable data at week 24. ITT analysis showed a significant (p < or = 0.05) dose-response trend and a significant (p < or = 0.05) between-group comparison favoring 75 mg t.i.d. over placebo for the CNTB summary score but not for the ADAS-cog. In the completer analysis, however, the ADAS-cog showed a significant (p < or = 0.05) dose-response trend and between-group comparison, whereas the CNTB Summary Score did not. The ADAS-cog was less sensitive to treatment effects in mildly impaired patients (ADAS-cog < 21) than in moderately impaired patients (ADAS-cog > or = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (p < or = 0.05) beneficial treatment effects were seen in measures of simple reaction time and delayed verbal recall, which are included in the CNTB but not in the ADAS-cog. During the single-blind placebo washout period, the ADAS-cog score of the placebo group worsened dramatically (change of 2.63 points; p < or = 0.001), whereas the CNTB score remained stable (change of 1.04 points; p=0.694). Thus, the CNTB appears to be more objective than the ADAS-cog.

Aged↗
PubMed1998

Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease.

INTRODUCTION: This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters. METHODS: Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713. RESULTS: Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose. CONCLUSION: Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.

Administration, Oral↗
PubMed1998

A bridging study of fananserin in schizophrenic patients.

Fananserin is a potential antipsychotic compound with high affinity for both D4 and 5-HT2A receptors, and negligible affinity for D2 receptors. Because the tolerance for antipsychotic compounds often differs between schizophrenic patients and healthy subjects, this bridging study was designed to evaluate the tolerability of fananserin, to define the slow titration maximum tolerated dose in the target population, and to identify the most rapid well-tolerated rate of titration for this compound. Three rates of titration regimens were examined in a total of 26 schizophrenic patients in a parallel group design, following a 3-day placebo washout period from previous antipsychotic medication. The slow rate of titration (reaching the maximum dose of 600 mg/day in 16 days with 100-mg increases every 3 days) was well tolerated, but a rapid titration schedule (reaching 600 mg/day in 8 days with 200-mg increases every 3 days) resulted in hypotension in 3 of 6 patients and termination of the group on Day 10. An intermediate rate of titration (reaching 600 mg/day in 10 days with 100-mg increases every 2 days) was then examined and was well tolerated, with transient episodes of mild hypotension reported in 2 of 10 patients. Thus, although hypotension was identified as the dose-limiting adverse event in this study, a reduction in the titration rate was effective in reducing the incidence and severity of this side effect. In this study, schizophrenic patients administered multiple doses of fananserin tolerated doses 400 percent greater than the maximum tolerated single dose in healthy volunteers.

Adolescent↗
PubMed1998

Initial safety, tolerability pharmacodynamics, and pharmacokinetics of CI-1007 in patients with schizophrenia.

CI-1007 is a novel dopamine autoreceptor agonist and partial dopamine D2/D3 agonist that is currently under development for the treatment of schizophrenia. This single-blind, rising, multiple-dose, inpatient bridging study was designed to evaluate the safety and tolerability of CI-1007 in consecutive panels of patients with schizophrenia. Following a 4-day placebo washout period, 16 patients (4 per panel) were assigned to receive one of four fixed-dosage regimens of CI-1007 (5, 10, 15, or 20 mg q12h for 9 doses). CI-1007 was generally well tolerated over the dose range evaluated. Adverse events, including mild to moderate sporadic orthostatic hypotension and/or nausea and vomiting, were most commonly observed after the initial drug dose and decreased after repeated dosing. Serum concentrations of growth hormone (GH) increased following the administration of CI-1007, confirming its central dopamine agonist activity. Changes in serum prolactin were not related to dose. The pharmacokinetics of CI-1007 and its active metabolite appear linearly related to dose. The results of this study suggest that patients with schizophrenia tolerate slightly higher initial doses of CI-1007 than do healthy subjects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Exploratory studies: implications for drug development in Alzheimer's disease.

The process of drug development involves cycles of learning and confirming. In the learning phase of the cycle, data from studies are used to generate hypotheses; later studies are designed specifically to confirm these hypotheses. There is a growing realization that exploratory studies early in drug development are critical for the design of large confimatory clinical trials. For example, patients often differ from healthy volunteers in their tolerance of CNS compounds, so investigators should determine the maximum tolerated dose (MTD) in the patient population though a "bridging study" prior to designing Phase II efficacy trials. By performing well-controlled safety/tolerability studies with a small number of patients on an inpatient basis, researchers can avoid exposing large numbers of study participants to the wrong dose. Bridging studies also provide information on the approximate frequencies of various types of adverse events, which is very helpful in designing outpatient trials to confirm the safety profile. A second type of exploratory study, a "dynabridge study", is an early pharmacokinetic/pharmacodynamic (PK/PD) study in patients to measure drug concentrations and activities in the central compartment (assessed by sampling the CSF). Dynabridge studies can be used to optimize the dosing regimen, to confirm that the drug is affecting the targeted receptor, and to measure correlations between drug activity and proposed surrogate markers.

Alzheimer Disease↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1996

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↗