[Dexamethasone suppression test in endogenous depression and schizophrenia in male and female patients]. / Test hamowania deksametazonem w depresji endogennej i schizofrenii u mezczyzn i kobiet.

Dexamethasone Suppression Test was performed during an acute phase in 81 patients with endogenous depression and 105 schizophrenic patients. The lack of suppression of cortisol was found in 1/3 if those ill with depression and 1/3 of those ill with schizophrenia. A relationship between those results and age was shown in female schizophrenic patients. In both groups a yearly rhythm was observed, however female patients differed from male patients.

Changes in carbamazepine plasma concentrations in psychiatric patients during treatment.

Plasma concentrations of carbamazepine (CBZ) were studied in 24 psychiatric patients who were given 400 mg of CBZ every 12 h. The assays were performed on the 1st, 3rd, 8th, 15th, 22th and 29th day of the therapy. The highest minimum 12h plasma CBZ concentrations occurred on the 3rd day of therapy, then decreased up to the 15th day and remained stable thereafter. The CBZ half-time values also diminished up to the 15th day of therapy and then stabilized. This may suggest that the enzymatic autoinduction of CBZ is completed within the first 1-2 weeks of therapy. CBZ plasma levels were slightly but insignificantly higher in patients taking CBZ alone than in patients in which CBZ was added to other psychotropic drugs. A significant correlation was found between the minimum CBZ plasma concentration after the first dose and that at steady state. A dosing schedule for CBZ administration has been proposed with administration of 75% of the maintenance dose during the first week and the full CBZ maintenance dose from the beginning of the second week of CBZ therapy.

[Dexamethasone suppression test and the positive and negative symptoms of schizophrenia]. / Test hamowania deksametazonem, a objawy pozytywne i negatywne schizofrenii.

40 patients (26 males, 14 females), aged 18-50 years, with diagnosis of schizophrenia were studied before the treatment for recurrence of acute schizophrenic symptom was started. All patients had dexamethasone suppression test (DST) and BPRS and Hamilton Depression Scale tests. Initial cortisol plasma concentration correlated positively with the intensity of productive symptoms measured by BPRS. The cortisol plasma level measured 17 hour after dexamethasone administration correlated negatively with the global symptom intensity in the BPRS. Pathological DST results were observed in 14 patients (35%). These patients presented lower intensity of psychopathological symptoms in the BPRS as compared to the remaining patients. The intensity of depression measured by Hamilton Scale did not show correlation with DST results. We conclude that in the schizophrenic patients during acute phase of the disease, the intensity of psychopathologic symptoms (mainly productive symptoms) is related to increased activity of the hypothalamo-hypophyseal-suprarenal axis which manifests itself with increased basal levels of plasma cortisol. Reactivity of this axis, with good suppression in the DST results seems to be normal. The intensity of depressive symptoms did not show significant relation to activity of the axis judging from DST results.

[Monitoring of the treatment of endogenous depression with imipramine and amitriptyline (preliminary report)]. / Monitorowane leczenie depresji endogennej imipramina i amitryptylina (doniesienie wstepne).

Monitored treatment of a depressed phase of unipolar affective disorder was conducted in 11 female patients receiving imipramine and in 12 females taking amitriptyline. Patients were randomly assigned to one of the drug and in 6 patients the drugs were switched because of the lack of response to the first used compound. In the imipramine treated group a satisfactory response after 4 weeks of management (less than 6 points on Hamilton's depression scale) was observed in 6 patients and in amitriptyline treated group in 5 patients. Patients displaying a satisfactory response to amitryptyline had significantly higher--as compared to remaining patients in the group--plasma levels of the drug after two and four weeks of treatment. Such an association was not observed in patients treated wtih imipramine. Severity of depression and motor retardation before the treatment was similar both in patients with satisfactory and with poor response to imipramine as well as to amitriptyline. However the intensity of anxiety symptoms was higher in patients exhibiting poor response to treatment with amitriptyline and imipramine as well.

Effect of selenium supplementation on glutathione peroxidase synthesis and element accumulation in sheep erythrocytes.

For three months four groups of sheep were fed either a basal diet (group A) containing 0.082 ppm selenium (Se), or this diet plus mineral mixture with Se (as selenite) so that the total diet contained 0.25, 0.41 and 0.58 ppm Se (groups B, C, and D, respectively). The Se concentration and GSH-Px activity in red cells were determined at the commencement of the study and at monthly intervals. While in the control group the Se level and GSH-Px activity did not differ throughout the study, in the experimental groups both Se accumulation and GSH-Px activity were elevated. In group B the increase in Se concentration was linear throughout, while in groups C and D great accumulation was observed in the first month and lower in the subsequent period. In all Se-supplemented groups, the red cell GSH-Px increased linearly throughout the study, but no significant differences were found between groups B, C and D. The mean elevations of the enzyme activities were: 58 +/- 8%, 142 +/- 5% and 192 +/- 7% of the initial values after 1, 2 and 3 months of the study, respectively. These data show that the amount of 0.25 ppm Se in the sheep diet satisfy the requirement of the erythropoietic systems to synthesize the enzyme.

Pharmacokinetics of carbamazepine in psychiatric patients.

Plasma levels of carbamazepine (CBZ) were studied in 10 patients with psychiatric illnesses who were given the drug every 12 hours for 28 days. No correlation has been found between the daily dose of carbamazepine (calculated for body weight) and the steady-state level of the drug. In most patients taking CBZ as the only drug, a 10-20% fall in plasma drug level occurred between the first and second week of treatment, suggesting autoinduction process. A significant correlation was obtained between the plasma level of CBZ measured after the first dose of the drug and the subsequent steady state concentration. This makes possible to predict the steady-state CBZ concentration early in the treatment.

Studies of lithium pharmacokinetics in patients with affective illness.

Lithium pharmacokinetics after a single dose and pharmacokinetic prediction of optimal lithium carbonate dose in steady-state, were investigated in 15 patients with affective illness. In nine patients the course of plasma concentration after a single dose was characteristic for two-compartment and in six patients for one-compartment model. Patients fitting the two-compartment model required higher daily lithium dose to achieve steady-state therapeutic lithium level than patients fitting the one-compartment model. A significant correlation was found between plasma lithium level 12 and 24 h after a single dose and the daily dose required for achieving optimal lithium level in the course of subsequent lithium administration.

Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking.

The effects of tobacco and oral contraceptive (OC) use (Ovral) on the pharmacokinetics of levonorgestrel (0.25 mg) and ethinyl estradiol (50 micrograms) were examined. Young women (n = 27) were grouped as follows: I: non-OC users/nonsmokers; II: OC users/nonsmokers; III: non-OC users/smokers; and IV: OC users/smokers. The apparent clearance of levonorgestrel in group I was 80.9 +/- 15.6 ml/hr/kg and the half-life was 19.3 hours. A significant decrease in levonorgestrel clearance was seen in the chronic OC users (groups II and IV). The apparent oral clearance of ethinyl estradiol was 1002 +/- 398 ml/hr/kg in group I and the half-life averaged 7.7 hours. Groups II and III showed decreased (not significant) clearance of ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Although chronic OC use did not affect ethinyl estradiol clearance, a joint effect of tobacco/OC use on enhancing clearance of ethinyl estradiol appeared to occur. A linear relationship was found between 24-hour trough serum concentrations and AUC values of both steroids that may facilitate population monitoring studies of OC exposure.

PIP: The effects of combined cigarette smoking and oral contraceptive (OC) use on the pharmacokinetics of the pill's major components were examined in 27 white female volunteers grouped as follows: Group 1, non-OC user, nonsmoker; Group 2, OC user, nonsmoker; Group 3, non-OC user, smoker; Group 4, OC user, smoker. The 11 OC users in the study had been taking the pill for over 6 months; 5 were taking Ovral (50 mcg of ethinyl estradiol, 0.5 mg of norgestrel) and the remaining 6 switched to Ovral for the 1-month cycle before the study period. The non-OC users took 1 study dose of Ovral. The clearance of levonorgestrel was significantly lower in chronic OC users (mean elimination half-life of 30 hours) than in single-dose subjects (mean elimination half-life of 23 hours). The mean elimination half-life of ethinyl estradiol was approximately 12 hours for both chronic and acute OC use, although there was a nonsignificant tendency for lower ethinyl estradiol clearances in chronic OC users. Chronic tobacco use as a single factor did not influence the pharmacokinetics of levonorgestrel; however, a joint effect from chronic OC use and tobacco use was seen for ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Finally, a linear relationship was found between 24-hour trough serum concentrations and area-under-curve values of both steroids that may facilitate population monitoring studies of OC exposure.

Effects of tobacco smoking and oral contraceptive use on theophylline disposition.

The independent as well as interactive effects of chronic (greater than 6 months) oral contraceptive (OC) use and cigarette smoking on single-dose (4 mg/kg) theophylline disposition were assessed in 49 young, healthy women. Significant elevations (40%) in theophylline plasma clearance were found in women who smoked. OC use resulted in decreases in clearance of a similar magnitude (28%). These factors do not appear to interact with respect to theophylline disposition. The combination of main effects tended to cancel one another (clearance of 49.1 ml h-1 kg-1 ideal body weight for OC non-user, non-smoker, vs 49.7 ml h-1 kg-1 for OC user-smoker). Single dose exposure to OC in non-users did not significantly alter theophylline pharmacokinetics for the group as a whole. However, in the subgroup of smoking subjects, significant decreases in clearance were evident (P less than 0.05). Analogous results were found for half-life. Volume of distribution was slightly diminished in smokers, but was unaffected in OC users. Areas under the serum concentration-time (AUC) profiles of norgestrel and ethinyloestradiol were examined in 27 women as indices of OC exposure. The smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. Appropriate statistical analyses of data which are influenced by multiple factors are discussed. Special concern is needed when the factor partitioning process yields subgroups of unequal sizes.

PIP: The independent and interactive effects of smoking and oral contraceptive (OC) use on theophylline disposition were examined in 49 healthy women aged 19-30 years. 16 subjects had used OCs for longer than 6 months, and 27 reported daily tobacco use. Subjects were subdivided into 4 groups based on their tobacco and OC use or nonuse. A single dose of theophylline (4 mg/kg) was administered orally and venous blood samples were collected 0, 0.5, 1, 2, 3, 5, 7, 11, and 23 hours later. For 27 subjects, a single Ovral tablet was given 1 hour before the test dose of aminophylline. For 16 subjects, this treatment represented a single dose exposure, whereas for 11 the tablet was their routine daily OC. A 4-way analysis of covariance was performed, with the main effects defined as cigarette smoking, OC use, marijuana use, and acute exposure to contraceptive steroids. Cigarette smoking, chronic OC ingestion, and daily caffeine intake significantly altered theophylline clearance processes, while casual marijuana use and acute OC exposure failed to induce significant changes in this parameter. A 40% elevation in theophylline clearance was observed in women who smoked, while OC use resulted in a 28% decrease in clearance. These factors did not appear to interact with respect to theophylline disposition, and the combination of main effects tended to cancel one another. When areas under the serum concentration-time (AUC) profiles of norgestrel and ethinylestradiol were examined in the 27 women with experimental OC exposure, the smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. Data suggest that OC use exerts a significant inhibitory effect on theophylline clearance, while cigarette smoking markedly enhances theophylline's hepatic metabolism. The most likely explanation for the inhibitory effect of OC use is that chronic exposure to steroidal agents reduces the nonconjugative activities of the liver. A limitation of the study is that partitioning of the study group by mulitple factors resulted in subgroups of unequal size.

Effect of chronic oral contraceptive steroids on theophylline disposition.

The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female non-OC users and to 8 healthy women who were chronic (greater than 6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OC (35.1 +/- 5.6 vs. 53.1 +/- 14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79 +/- 1.43 vs. 7.34 +/- 1.75 h) while the volume of distribution was similar between the 2 groups. The serum ethinylestradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent clearance of EE and the plasma clearance of theophylline. The effects of OC are predominantly due to chronic use with decreased elimination of both theophylline and EE.

PIP: The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female nonusers and to 8 healthy women who were chronic (6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OCs (35.1 +or- 5.6 vs. 53.1 +or- 14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79 +or- 1.43 vs. 7.34 +or- 1.75 hours) while the volume of distribution was similar between the 2 groups. The serum ethinyl estradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent EE clearance and the plasma clearance of theophylline. The effects of OCs are predominantly due to chronic use with decreased elimination of both theophylline and EE.