[The psychosomatic correlations in bronchial asthma]. / Psikhosomaticheskie sootnosheniia pri bronkhial'noi astme.

Combination of somatic symptoms with neurotic manifestations and personality's disturbances in clinical picture of bronchial asthma was established during clinical and psychological observation of 89 patients with bronchial asthma. It was shown that increase of the number of frustrating situations (when psychical vulnerability was elevated), strengthening of both anxiety and emotional tension, as well as rigidity of negative emotions, hypochondriac and anxious-depressive tendencies composed the whole correlational system with alterations in functions of external respiration, changes in blood immunoglobulins levels just as with clinical indices of bronchial asthma. This system represented different levels of psychosomatic correlations' regulation. The complex psychophysiological factor of frustration and emotional tension was described, moreover the increase of its value was accompanied by strengthening of both psychical alterations and somatic disorders which were quite characteristic for prevalence of either trophotropic activation or ergotropic one when beta-adrenoceptors were blocked.

Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.

Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.

Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent.

Oral oltipraz, as a single-dose treatment, was evaluated as a chemopreventive agent in 31 normal subjects. In a subset of subjects, the relationship between plasma oltipraz concentrations and the induction of lymphocyte glutathione (GSH) and glutathione S-transferase (GST) enzyme levels was evaluated. Pharmacokinetic analysis revealed nonlinear disposition of oltipraz with disproportionate 40-fold increase and 9.5-fold decrease in peak plasma concentrations (Cmax) and p.o. clearance, respectively, over the dose range of 100-500 mg. There was no correlation between the oltipraz dose and the absorption rate or the time to reach Cmax. Since oltipraz undergoes extensive metabolism, saturable first-pass elimination could be one of the sources of nonlinearity. Pharmacodynamic evaluation was conducted based on the percentage of elevation of GSH and GST levels over baseline in lymphocytes of subjects receiving 100 mg and 125 mg oltipraz. Induction was observed in both dose groups with a time lag between the maximum concentrations of oltipraz and that of GSH or GST. We also observed a linear correlation between oltipraz Cmax and the corresponding GSH and GST elevations. Subjects with higher Cmax values showed a greater increase over baseline in the GSH and GST levels. Mild toxicities were observed at all dose levels. The most common were flatulence, hunger, fatigue, and headache. These preliminary results indicate that oltipraz may be effective in inducing GSH and GST, an enzyme capable of carcinogen elimination.

Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456).

Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v. bolus for 5 consecutive days repeated every 28 days. Thirty-one patients with advanced cancer refractory to standard therapy received a total of 65 cycles of therapy at 7 sequential PZDH dose levels: 18, 36, 45, 56, 75, 100, and 133 mg/m2/day. At the maximally tolerated dose (133 mg/m2/day x 5), all 4 patients experienced grade 3-4 thrombocytopenia, and 3 of 4 had grade 3-4 neutropenia. At the recommended phase II dose (100 mg/m2/day x 5), the median WBC nadir following the first cycle was 2.5 x 10(3)/microliters (range, 0.6-7.6) occurring on day 36, and the median platelet nadir was 87 x 10(3)/microliters (range, 9-155) occurring on day 26. Nausea and vomiting occurred at all dose levels, but were well controlled with ondansetron. No evidence of hepatic, renal, pulmonary, cardiac, venous, dermatological, or neurological toxicity was observed. Pharmacokinetic evaluations were performed on 28 of the 31 patients using an analytical method including derivatization of the parent drug to 2-chloropyrazine. We report the total 2-chloropyrazine, which represents PZDH converted per method plus PZDH converted in vivo. Although the assay quantitation limit is 10 ng/ml, PZDH could only be detected at the first dose level for 30-90 min after the i.v. bolus. Compartmental modeling of the first 4 dose levels was most consistent with a 2-compartment model. Subsequent dose levels revealed a third phase to the plasma decay curve. The area under the plasma drug concentration-time curve increased proportionally with dose; there was no evidence for dose-dependent pharmacokinetics. Pharmacokinetic parameters for 12 patients analyzed by the 3-compartment model revealed an alpha-half-life (t1/2 alpha) of 2.83 +/- 1.57 (mean +/- SD), a t1/2 beta of 11.9 +/- 4.42, and a t1/2 gamma of 161 +/- 47.1 min, with a mean clearance of 1.86 +/- 0.91 liters/min. At the 100- and 133-mg/m2 dose levels, the mean areas under the plasma drug concentration-time curve were 105 and 169 micrograms min/ml, respectively. There was a moderate correlation between body surface area and clearance (r = 0.45, P = 0.015) but a better correlation between weight and clearance (r = 0.53, P = 0.004).(ABSTRACT TRUNCATED AT 400 WORDS)

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.

BACKGROUND: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). PATIENTS AND METHODS: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. RESULTS: Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml. CONCLUSIONS: The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.

Phase I study of amonafide dosing based on acetylator phenotype.

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m2 (daily for 5 days) and had a median WBC nadir of 1600/microliters. Fast acetylators were treated at both 200 and 250 mg/m2, resulting in median WBC nadirs of 5300 and 2000/microliter, respectively. Two patients were not typeable, and two patients appear to have been misphenotyped, one in each phenotype category. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, gender, and pretreatment WBC. We recommend doses of 250 and 375 mg/m2 (for 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.

Paradoxical relationship between acetylator phenotype and amonafide toxicity.

Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration-time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.

Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity.

We have previously demonstrated that individualized dosing of etoposide (VP16) by 72-hour infusion is feasible and that the extent of leukopenia is a function of plasma concentration, pretreatment WBC (WBCp), albumin (ALB), performance status (PS), and bone marrow function (based on transfusion requirements). In the current study, 45 patients were randomized between a fixed dose of VP16 (125 mg/m2/d) versus individualized dosing to a target WBC nadir (WBCN) of 1,700/microL. The total dose was increased by an average of 22% in the latter patients (459 +/- 130 mg/m2 v 375 mg/m2, P = .002). This was associated with a decrease in both the mean WBCN (1,510 +/- 950 v 2,500 +/- 1,420/microL, P = .013) and in the variability of the WBCN (P = .039). The VP16 clearance (mL/min) was not correlated with body surface area. Partial responses were observed in one patient each with hepatoma and non-Hodgkin's lymphoma. We conclude that pharmacologically based dosing may be a means of increasing dose intensity without increasing the incidence of life-threatening toxicity due to a decrease in variability around a target WBC.

[Biochemical polymorphic systems and psychological characteristics in residents of the Soviet North-East]. / Biokhimicheskie polimorfnye sistemy i psikhologicheskie osobennosti u zhitelei severo-vostoka SSSR.

15 biochemical polymorphic systems (AcP, PGM, GPT, GLO-1, EsD, PGP, Pp, AK, Gc, Hp, Tf, BO, MN, Le, P) were comparatively studied which possess psychodiagnostic features investigated by means of all-round personality study and 16-factors Kettle personality inventory in 340 healthy residents of Magadan. With the aid of computer cluster analysis, psychodiagnostic features were revealed which authentically differentiate clusters consisting of 5 combined polymorphic systems, three of them being different. Frequency of particular loci participation in differentiation of persons for psychodiagnostic tests is well-coordinated with a degree of their participation in genotype differentiation in those who left and remained in the region. Interrelations between psychological personality features and individual heterozygosis for 12 loci with codominant inheritance are determined. Authentic differences between low- and highly-heterozygous individuals are revealed using the same psychodiagnostic parameters as those in the cluster analysis.

[Psychophysiological correlations in paroxysmal forms of cardiac rhythm disorders]. / Psikhofiziologicheskie sootnosheniia pri paroksizmal'nykh formakh narushenii serdechnogo ritma.

Fifty-two patients with paroxysmal disorders of cardiac rhythm were under observation for periods of 6 months to 3 years. Paroxysmal supraventricular tachycardia was registered in 16, ventricular tachycardia in one, paroxysmal cardiac fibrillation in 35. The method of comprehensive examination of personality (modified MMPI test, Cattell's and Hekhausen's tests) made it possible to reveal certain characteristic features of the personality and the actual psychic condition of all patients. Treatment with modern psychotropic agents (predominantly tranquilizers) improved the course of arrhythmia considerably in most patients; a tendency to normalization of the psychic condition was noted simultaneously. The possible mechanisms of the effect of psychotropic agents on the course of arrhythmias are discussed.

[Clinical pharmacokinetics of azabutyron, a new short-term action neuroleptic]. / Klinicheskaia farmakokinetika azabutirona--novogo neiroleptika kratkovremennogo deistviia.

Pharmacokinetics of azabutyron--a new Soviet-made neuroleptic was studied clinically without anesthesia and also during surgery against the background of deep and surface fluorothan anesthesia in conjunction with artificial nitrous oxide and oxygen ventilation of the lungs (2:1). After intravenous administration of the drug in a dose of 4 mg/kg its maximum concentration (about 8 gamma/ml) was recorded in 5 minutes and the amount eliminated during 2 hours of observation comprised 1--2 per cent of the dose introduced. In practically healthy individuals with no anesthesia the pharmacokinetics of azabutyron lies within the limits of a bicompartment pharmacokinetics model, while surface anesthesia, blood loss changes the pharmacokinetics of the drug to such an extent that is has to be described from the standpoint of the unicompartment model system.