Side effects of clozapine.

In addition to the low risk of agranulocytosis, several more frequent side effects are associated with clozapine therapy. We tried to estimate the incidence of these side effects. We analysed 391 treatments in 315 inpatients, who received clozapine alone or combined with other neuroleptic and antidepressant drugs. Two thirds were combined treatments, one third were treatments with clozapine alone (i.e., no other neuroleptic, antidepressant or anticonvulsive drugs were allowed). The numbers in brackets show the incidence based on the analysis of the treatments with clozapine alone. In 49% (61%) of the treatments a rise in the liver enzyme values was observed. However, counting only the cases in which a two-fold increase over the normal values was observed, the incidence was reduced to 20% (31%). Increase in temperature was observed in 4% (6%) and leukopenia (leukocyte count under 3500/microliters) was recorded in 2% (2%). Hypotensive dysregulation (systolic blood pressure under 90 mm Hg) was observed in 25% of all treatments and pharmacogenic delirium in 8%. No cases of agranulocytosis were observed. Mean treatment duration was 56 days, mean daily dosage 257 mg. The mean age of the patients was 34 years. In the overall evaluation 71% of the treatments were classified as successful; clozapine therapy was continued after discharge in 68% of the treatments. Adverse reactions (delirium, rise in temperature, hypotension, fatigue, rise in liver enzymes) necessitated a change of medication in 17% of the treatments. Changeover to another neuroleptic drug due to ineffectiveness of clozapine was necessary in 7% of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose kinetics of the neuroleptic drug perazine in psychotic patients.

Eight male and two female unmedicated psychotic patients received 100 mg perazine orally and seven blood samples were taken within 25 h. Plasma levels of perazine and its demethylated metabolite were analyzed by HPLC with electrochemical detection. They exhibited large interindividual variations, with maximal concentrations as well as AUC values of perazine differing more than 10-fold. From the decay of plasma levels during the last 12-18 h half-lives were estimated to be between 7.5 and 10 h; they did not correlate with AUC. There was a significant positive correlation between AUC and age. Desmethylperazine was consistently present at lower concentrations than the parent drug during the first 12 h.

Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy?

Twenty-nine inpatients with primary affective disorder were treated with 150 mg amitriptyline (AT) daily for 28 days. Pretreatment urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in two or three 24-h urine samples. Plasma levels of AT and nortriptyline (NT) were determined after 14, 21, and 28 days of treatment. MHPG excretion was significantly correlated with clinical response to treatment. Responders defined by two different methods showed higher pretreatment MHPG excretion than nonresponders. Correspondingly, high MHPG excretors (median split) showed significantly more improvement than low excretors. These relationships were even more apparent when possibly incomplete urine samples (creatinine excretion below 1000 mg/24h) were excluded. The high and low MHPG subgroups did not significantly differ from each other in their plasma levels of AT, NT, or AT plus NT. A significant rank correlation between clinical response and plasma levels of AT and/or NT did not exist, but there was a trend towards lower levels in responders.

Antidepressive effect and pharmacokinetics of amitriptyline with consideration of unbound drug and 10-hydroxynortriptyline plasma levels.

In 27 inpatients with primary affective disorder the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured prior to a 4-week treatment with 150 mg amitriptyline (AT)/day. Ratings according to the Hamilton depression scale were performed before therapy and repeated after 2 and 4 weeks. Plasma levels of AT, nortriptyline (NT), and E-10-hydroxynortriptyline (OHNT) were assayed weekly, and binding of AT to plasma proteins was determined in one sample. Better therapeutic results were obtained at intermediate, as compared to low and high concentrations of AT or AT plus NT. Independent evaluation of AT and metabolite levels revealed that patients with AT of 50--125 ng/ml responded particularly well when NT did not exceed 95 ng/ml or when NT plus OHNT was below 150 ng/ml. Outside this "therapeutic window' the outcome was markedly poorer. Interindividual variation of AT binding was much smaller than variation of total concentrations. Evaluation of free, instead of total levels did not help to clarify the relationship between clinical and pharmacokinetic variables. Plasma levels within the optimal ranges were found in more patients with high than with low MHPG excretion. The free fraction of OHNT in plasma of healthy subjects was about 35%.

Efficacy of simultaneous determination of bone alkaline phosphatase mass concentration in serum and urinary excretion of pyridinium cross-links for detection of bone metastases.

OBJECTIVES: To examine the diagnostic validity of bone alkaline phosphatase (BAP) in serum (a marker of bone formation) and of urinary excretion of pyridinium cross-links (PYR) (a marker of bone resorption) for detection of bone metastases. DESIGN AND METHODS: Two heterogeneous immunoassays were employed for determination of BAP mass concentrations (Tandem-R Ostase) in serum and the urinary excretion of PYR (Collagen Crosslinks) in a consecutive series of 89 tumor patients examined by bone scintigraphy (with 99mTc-methylene diphosphonate). RESULTS: The discrimination power (as determined by Z score analysis) and the accuracy (as assessed by the area under the receiver-operating characteristic curve) was higher for BAP (0.84) than for PYR (0.76). Combination of both markers yielded a further increase of accuracy (0.89). There was a correlation (r = +0.422; p < 0.001) between the urinary excretion of pyridinium cross-links and bone alkaline phosphatase mass concentrations in the whole of 89 patients examined. In 14 (16%) of 89 patients bone alkaline phosphatase values were within the reference interval in spite of total alkaline phosphatase activity being increased; this indicates a higher diagnostic specificity of bone alkaline phosphatase (compared with total alkaline phosphatase) with respect to detection of bone metastases. CONCLUSION: Simultaneous assessment of bone formation by BAP and of bone resorption by PYR provides a suitable tool for detection of bone metastases.

Tolerability and antidepressive effect of brofaromine, a short-acting reversible MAO inhibitor--an open study.

The tolerability and antidepressive effect of brofaromine, a selective MAO-A inhibitor was tested in 14 depressive patients. None of the patients showed blood pressure or pulse frequency changes after ingesting tyramine-enriched meals. Four instances of agitation were observed as side effects. In two of these cases, the appearance of paranoid thinking and suicidal tendencies led to premature termination of the study. In 3 cases sleep disturbances, in particular difficulties in falling asleep, were observed. In the test of antidepressive effectiveness (measured on the HAMD-scale) significant improvement was observed from day 14 onwards.

Integrating electrophysiology and neuroimaging of spatial selective attention to simple isolated visual stimuli.

Visual-spatial attention involves modulations of activity in human visual cortex as indexed by electrophysiological and functional neuroimaging measures. Prior studies investigating the time course and functional anatomy of spatial attention mechanisms in visual cortex have used higher-order discrimination tasks with complex stimuli (e.g. symbol matching in bilateral stimulus arrays, or letter discrimination), or simple detection tasks but in the presence of complex distracting information (e.g. luminance detection with superimposed symbols as distractors). Here we tested the hypothesis that short-latency modulations of incoming sensory signals in extrastriate visual cortex reflect an early spatially specific attentional mechanism. We sought evidence of attentional modulations of sensory input processing for simple, isolated stimuli requiring only an elementary discrimination (i.e. size discrimination). As in prior studies using complex symbols, we observed attention-related changes in regional cerebral blood flow in extrastriate visual cortex that were associated with changes in event-related potentials at a specific latency range. These findings support the idea that early in cortical processing, spatially-specific attentional selection mechanisms can modulate incoming sensory signals based on their spatial location and perhaps independently of higher-order stimulus form.

Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking.

Plasma norharman and harman levels were measured by solvent extraction and HPLC with fluorescence detection in alcohol-dependent patients undergoing in-patient abstinence treatment and in control subjects. In both groups, randomly collected samples from smokers contained higher mean norharman levels than those from non-smokers. In three volunteers norharman concentrations rose sharply after smoking of one or two cigarettes and declined to near-basal levels within one hour after one cigarette. When 12 patients kept a smoking-free interval of at least 6 h, they had similarly low plasma norharman concentrations (20 +/- 8 pg/ml) as 18 non-smoking control subjects (17 +/- 8 pg/ml) or as 13 smoking controls who had abstained from smoking (20 +/- 6 pg/ml). Ten of the patients smoked one cigarette and within 5-10 min attained norharman levels of 177 +/- 147 pg/ml plasma. The high prevalence of smokers among chronic alcoholics probably explains the previous finding of elevated norharman plasma levels in these patients.

Plasma levels, psychophysiological variables, and clinical response to amitriptyline.

Hamilton depression scale ratings and physiological measurements were made for 37 patients with primary depression before treatment with amitriptyline (150 mg/day) and again after 2 and 4 weeks of treatment; plasma drug levels were determined weekly. Improvement was maximal at mean amitriptyline + nortriptyline concentrations of 125-200 ng/ml (14 patients), while at lower levels the outcome was significantly poorer (12 patients). Highly variable results were seen in 11 patients with levels between 200 and 301 ng/ml, with lesser improvement occurring in those patients who exhibited poor habituation of the skin resistance response before treatment. Other psychophysiological variables showed significant changes during treatment, but no correlation with clinical results or drug levels.

Decomposing memory: functional assignments and brain traffic in paired word associate learning.

The recent covariance structural equation model for word-pair associate encoding and retrieval (Krause, Horwitz, Taylor, Schmidt, Mottaghy, Halsband et al., 1998; Krause, Horwitz, Taylor, Schmidt, Mottaghy, Herzog et al., 1999) is analysed to deduce possible functional assignments of the various brain modules used by subjects in solving the task. Specific processing aspects are considered, in particular, that of long-term working memory sites and how they are coupled to buffer working memory sites to enable deposition and manipulation of remembered associates. The new concept of 'brain traffic' is introduced as an aid to the assessment of how important are various brain modules. A set of functional assignments is produced for the relevant modules.

Increased activity and stability of poly(ethylene glycol)-modified trypsin.

The reaction of trypsin with activated monomethoxypoly(ethylene glycol) with various molecular masses led to the development of a series of poly(ethylene glycol)-modified trypsins (PEG-trypsins). On determining the catalytic properties of PEG-trypsin using N-benzoyl-L-arginine p-nitroanilide as a substrate, a three- to fourfold increase in the maximal velocity of hydrolysis was found to occur, whatever the size of the PEG moiety used. PEG-trypsin with higher molecular mass moieties showed lower Michaelis constant values. The activation of trypsin was neither reversed by nucleophiles such as hydroxylamine, nor prevented when modification was carried out in the presence of benzamidine or in the presence of the polypeptidic soybean trypsin inhibitor. Chemical modification of about 80% of the free amino groups with PEG chains significantly improved the resistance to heat and detergents. This might result from the formation of a highly hydrogen-bonded structure around the enzyme.

Prostacyclin in patients with peptic gastric ulcers--a placebo controlled study.

A double-blind study on prostacyclin (5 ng/kg/min infused i.v. for 5 hrs per day during 6 consecutive days) for the treatment of peptic gastric ulcers was carried out in thirty patients (15 prostacyclin, 15 placebo). Gastroscopy and its scoring was performed 1-2 days before the treatment, as well as a day and a week after the course of treatment was completed. Basal acid output (BAO) and pentagastrin stimulated release of gastric acid (maximum acid output MAO; peak acid output PAO) were measured before the treatment, during the third infusion, and one day after all the infusions had been completed. At the same time the basal release of bicarbonate into gastric juice was determined. Prostacyclin significantly accelerated healing of the ulcers at the end point of the study. Simultaneously, in the prostacyclin-treated patients an increase in bicarbonate release into gastric juice was noted, although the acidity of gastric juice was not changed. Our study shows a cytoprotective action of prostacyclin on a damaged human gastric mucosa.

Ectopic submandibular thyroid tissue with a coexisting active and normally located thyroid gland: case report and review of literature.

Ectopic thyroid tissue in the submandibular space with the thyroid gland in its normal location is an extremely rare phenomenon. We present a case of a 75-year-old woman who had painless swelling in the left submandibular space and was referred to our hospital with the suspicion of having a malignant tumor originating from the submandibular gland. Histologic examination showed normal follicular thyroid tissue without any sign of malignancy. In general there are 3 explanations for the presence of ectopic thyroid tissue found in the submandibular region: (1) displacement during the course of embryonal development, (2) spread of tissue during surgery on a normally located thyroid gland, and (3) metastasis of a highly differentiated papillary thyroid carcinoma. We reviewed the literature with respect to the embryological background and the clinical management of such cases.

[History of the Cracow Brothers of Mercy Hospital]. / Historia krakowskiego szpitala braci milosierdzia.

The oldest of existing Cracow hospitals was founded in 1609. The paper discusses the origins, development and decay of the hospital-cloister in its first seat at St. John's and St. Mark's streets. Later the author describes the fate of the hospital-cloister from 1812 after its translocation to the second residence at the Krakowska street. In 1906 the third seat became a new buildings' complex at the Trynitarska street. The work remembers the role of the hospital during several epidemies, Ist and IInd World War and its activity during peace times. The author emphasizes the great merits of Brothers of Mercy for Cracow medicine and hospital system in bringing medical and charitable help to sick and poor.

[Physician-patient relations: sympathy or empathy?]. / Relacja lekarz i pacjent: sympatia czy empatia?

At the beginning the author presents the definitions of antipathy, sympathy, empathy and syntony as different types of human interrelations. Then he recalls the kinds of physician-patient relations and discusses the antipathy, especially sympathy and empathy appearing in those relations. At the end the author proves the superiority of empathy over sympathy in the solution of problems of medical practice to the advantage of both the patients and the physicians.

[Health care of the rural population in the Cracow region during 1985-1989]. / Opieka zdrowotna nad ludnoscia wiejska województwa krakowskiego w latach 1985-1989.

The paper presents the structure and effects of the rural public health service in the Cracow region during the period of 1985-1989 with a short description of its demographic situation. The numbers and indexes concerning medical workers (especially general practitioners, stomatologists, pediatricians and gynecologists) as well as their services demonstrate a deterioration in the efficiency of the regional rural health service. This deterioration depends on the negative changes in the general condition of the country and Cracow region, of the population and public health service. The regional data are compared with the data of the whole of Poland and its other rural regions. The authors indicate principal directions in the reform of the public health service.

[Blood-group systems ABO and RH in the Kenyan population]. / Grupy krwi ukladu ABO i Rh u ludnosci Kenii.

The retrospective study was carried out in 38,898 healthy adult blood donors of both sexes, recruited mainly from Nairobi area in Kenya. The percentage proportions of blood groups were: group 0-47.4, group A-26.2, group B-22.0 and group AB-4.4. In all the samples, there were 96.1% Rh (D) positive blood donors. Among these were 0.75% subjects with Rh (D) variant antigen Du positive. Rh (D) negative was only 3.9% among the blood donors. There is a real preponderance of the blood group 0 over the blood groups A, B and especially AB as well as Rh (D) positive over Rh (D) negative. The authors found following frequencies of genes: p(A)0.168, q(B)0.142, r(0)0.690, D positive 0.804, D negative 0.196 and compare their own results with the data of other investigators concerning other Kenyan and African populations.

[Results of internal-medical examinations of the population from the region of a rural health center in Wielka Wies-BiaLy KoscióL]. / Wyniki internistycznych badan mieszkanców z rejonu wiejskiego osrodka zdrowia we Wielkiej Wsi-Bialym Kosciele.

Among 250 adults (120 male farmers-workers and 130 female farmers) belonging to the population of a village near Krakow, 153 (61%) were recognized sick (67 men--56% and 86 women--66%). Most frequent diseases concerned: the circulation (30% arterial hypertension), digestion (18%, peptic ulcer 14%), respiration (14% mainly bronchial chronic inflammations and asthma), locomotion (11% degenerative joint changes), neuroses (10%) and urogenital system (8.4%). Some cases of neoplasms (3.2%), parasitism (2.8%) and bone fractures caused by professional traumas (2.8%) were registered. The diseases of digestion and respiration were more frequent in men, arterial hypertension, neuroses, urogenital and locomotion diseases more common in women. Arterial hypertension and peptic ulcer afflicted persons over 30, the degenerative joint changes the individuals over 45 years of age.

[Double skin cancer coexisting with chronic myeloid leukemia]. / Dwukrotny rak skóry i przewlekla bialaczka szpikowa.

In a 71-year-old man chronic myeloid leukaemia was diagnosed 4--5 years after cure of pulmonary tuberculosis and removed auricular cancer and 2 years after nasal cancer cured by means of local radiotherapy.