A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression.

Ipsapirone, an azapirone with 5-hydroxytryptamine (5-HT1A) partial agonist activity, has been shown in preliminary studies to be effective in the treatment of major depressive disorder. This 8-week, randomized, double-blind study compared the efficacy, safety, and tolerability of three fixed doses of controlled-release ipsapirone (10-, 30-, and 50-mg dose once daily) with placebo in 410 patients with moderate to severe major depression (Hamilton Rating Scale for Depression [HAM-D] score > or = 20). The 10-mg ipsapirone treatment arm was discontinued early in the study. A total of 390 patients were eligible for evaluation in the intent-to-treat sample. The primary efficacy variable was the change in HAM-D total score from baseline to visit 8. There was no significant difference in efficacy in the two treatment groups versus the placebo group. The overall treatment response, defined as a 50% decrease in the HAM-D total score from baseline, was 43% with ipsapirone 50 mg given once daily, 34% with ipsapirone 30 mg given once daily, and 35% with placebo. In subanalyses, ipsapirone 50 mg given once daily was superior to placebo according to the HAM-D Core Depression (mood, guilt, interest, psychomotor activity) subtotal (p = 0.0453) and Melancholic item (p = 0.0225). Ipsapirone 30 mg given once daily was superior to placebo only in patients with moderate depression (baseline HAM-D total score < or = 25; p = 0.0100). The most common adverse effect in all groups was headache. The only dose-dependent adverse effects were dizziness and nausea.

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.

The safety of mesalamine in human pregnancy: a prospective controlled cohort study.

BACKGROUND & AIMS: Mesalamine is a first-line drug in the treatment of inflammatory bowel disease. Information regarding human pregnancy experience with mesalamine has been scarce and uncontrolled despite its frequent use in women of childbearing age. The aim of this study was to examine the fetal safety of mesalamine. METHODS: The Motherisk Program prospectively enrolled and followed up 165 women exposed to mesalamine during pregnancy, 146 of whom had first trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in major malformations (1 of 127 [0.8%] for mesalamine vs. 5 of 131 [3.8%] for nonteratogenic controls; P = 0.23). There was an increase in the rate of preterm deliveries (13.0% for mesalamine vs. 4.7% for nonteratogenic controls; P = 0.02), a decrease in the mean maternal weight gain during pregnancy (13.1 +/- 6.3 kg for mesalamine vs. 15.6 +/- 6.0 kg for nonteratogenic controls; P = 0.0002), and a decrease in the mean birth weight (3253 +/- 546 g for mesalamine vs. 3461 +/- 542 g for nonteratogenic controls; P = 0.0005). There were no significant differences in the maternal obstetric history, rates of live births, miscarriages, pregnancy terminations, ectopic pregnancies, delivery method, or fetal distress between the groups. CONCLUSIONS: This study suggests that mesalamine does not represent a major teratogenic risk in humans when used in the recommended doses.

Inhibitory effects of BAY x 7195, a CYS leukotriene 1 receptor antagonist, on allergen-induced asthmatic responses.

BACKGROUND: Leukotriene antagonists may inhibit bronchoconstrictive responses to a variety of stimuli. OBJECTIVE: To evaluate the efficacy and safety of a new CYS LTI antagonist, BAY x 7195, given as a single oral dose of 500 mg, in prevention of allergen-induced asthmatic responses. METHODS: This is a randomized, double-blind crossover, placebo-controlled study in mildly asthmatic non-smoking subjects (n = 10), aged 20 to 32 years (mean 24.8). Following an initial baseline allergen challenge, the subjects came back for two other challenges separated by at least a 2-week period, during which placebo or BAY x 7195 was administered two hours before allergen inhalation. Allergen challenges were preceded and followed by a methacholine inhalation test (24 hours before and 30 hours after). RESULTS: For each subject, the same allergen and doses were used throughout the study. In the randomized (intent-to-treat) population (n = 10), after BAY x 7195, the allergen induced % fall in FEV1 was less than after placebo, with mean between-treatment differences of 31.8 +/- 18.0% during the early asthmatic response, P = .03, and of 54.4 +/- 23.2% during the late asthmatic response (P = .04). The allergen-induced increase in methacholine responsiveness was reduced after BAY x 7195, with a change of -0.45 doubling concentrations of methacholine as compared with -1.77 after placebo; however, the change did not achieve statistical significance, P = .08. CONCLUSION: BAY x 7195 shows suppressive effects on allergen-induced responses, suggesting that it may be useful in the treatment of asthma.

Course of pregnancy and fetal outcome following maternal exposure to carbamazepine and phenytoin: a prospective study.

This prospective study followed the pregnancy course of epileptic women at the Motherisk Program of The Hospital for Sick Children, Toronto. We compared fetal outcome of women treated with carbamazepine (CBZ), those treated with diphenylhydantoin (phenytoin, DPH), and a drug-free control group. Seizures were reported in 15 pregnancies; in a subgroup of 9 women without change in drug or schedule, an increase in seizure frequency was evident in 6, a decrease in 1, and no change in 2, regardless of the drug taken. Of 23 children exposed to CBZ in utero, one was born with a lumbar myelomeningocele and multiple congenital anomalies. Of 21 children exposed to DPH, there was one case of severe developmental delay and four with minor features of fetal hydantoin syndromes (FHS). The three groups did not differ in birth weights or gestational ages of the babies. Although much more experience is needed, as a result of this study and other similar reports, Motherisk now offers women treated with CBZ diagnostic tests to detect neural tube defects during the second trimester of pregnancy.

Pregnancy-induced changes in drug metabolism in epileptic women.

The pharmacokinetics of antiepileptic drugs may be altered during pregnancy, resulting in decline of serum concentrations and subsequent suboptimal control of seizures. We investigated changes which may occur during pregnancy in hepatic drug handling by comparing metabolic ratios of 15 pregnant epileptic women to 15 nonpregnant epileptic women, as well as 10 pregnant nonepileptic and 10 nonpregnant nonepileptic controls. We used the caffeine test to describe several enzyme activities: P450 1A2, xanthine oxidase, n-acetyltransferase and hydroxylation. For this end, ratios were calculated among a number of metabolites of the main demethylation pathway of caffeine. In addition, we measured D-glucaric acid excretion for specific characterization of antiepileptic drug metabolism. Paired comparison of epileptic women in late pregnancy and six to eight weeks post partum revealed statistically significant decreases in P450 1A2, xanthine oxidase and n-acetyltransferase activities, and a significantly increased hydroxylation activity during pregnancy. Twenty-one of the 30 epileptic women (70%) were found to be fast acetylators, whereas the normal distribution in the nonepileptic control groups was 50%. Excretion of D-glucaric acid was significantly increased in all epileptic patient groups as compared to the matched nonepileptic control groups. Importantly, it was also significantly increased in the pregnant nonepileptic control group as compared to the nonpregnant nonepileptic women. Overall, our results suggest that enzymatic pathways involved in antiepileptic drug metabolism tend to be increased during pregnancy as a potential cause for observed lower serum concentrations of these drugs.

Women's perception of teratogenic risk.

PIP: Administration of the Visual Analog Scale (VAS) to 80 women who presented to the Canadian organization, Motherisk, in 1986 revealed an exaggerated perception of risk of teratogenic effects among women exposed to drugs and chemicals in early pregnancy. The 69 exposed to nonteratogenic agents assigned a mean risk of 24% for major malformations in the initial interview; after counseling, however, the risk was perceived to be only 14.5%. On the other hand, the mean risk score assigned by the 11 women exposed to known teratogenic agents remained unchanged at 36% after counseling. There was no association between estimation of risk and the number of preparations consumed, age, parity, or socieconomic status. The misperceptions of risk documented in this survey reflect a tendency in the popular literature to assign risks to drugs such as aspirin that are not proven to have adverse effects on a developing fetus. This is an important area for counselors to address, given the impact of risk perception on the decision to continue or terminate pregnancy. A follow-up study of 78 Motherisk clients who had indicated at presentation (prior to counseling) a greater than 50% inclination to terminate their pregnancy revealed that 61 decided, on the basic of counseling, to continue with the pregnancy; 57 of these women delivered normal, healthy infants, while the remaining 4 miscarried.^ieng

Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester.

We assessed the perception of teratogenic risk by 80 women attending an antenatal consultation service for drug, chemical, and radiation exposure. Women exposed to agents not known to be teratogenic assigned themselves a risk of 24% +/- 2.8% for major malformation before the relevant medical literature was delivered to them and 14.5% +/- 3% thereafter. These women accurately estimated the risk for major malformation in the general population (5.6% +/- 1.3%). The tendency to terminate pregnancy when exposed to a nonteratogen significantly decreased after the consultation. Eleven patients exposed to drugs known to be teratogenic assigned a risk of 36.2% +/- 11.7% before the interview and did not change their perception thereafter (36.7% +/- 15.8%). Similarly, their tendency to continue or terminate pregnancy did not change; three of them eventually chose to terminate the pregnancy. Advising women about their teratogenic risk early in pregnancy may prevent unjustified termination of many pregnancies and may help to inform women exposed to proven teratogens about the known risk.