Propranolol in schizophrenia. Clinical, metabolic, and pharmacological findings.

Six schizophrenic patients received propranolol hydrochloride to evaluate pharmacological, endocrinological, and antipsychotic properties of the drug. They had previously been unsuccessfully treated with phenothiazines. After a drug-free period of two weeks, propranolol was administered in gradually increasing doses. After two to four weeks, a low dose of phenothiazines was added. The clinical effect was evaluated using the Comprehensive Psychopathological Rating Scale. Three of the six patients showed a definite improvement with propranolol therapy given as a sole treatment. Propranolol in plasma was positively correlated to dosage. The proportion of its major metabolite, 4-hydroxy-propranolol, decreased with increasing drug dose. Melatonin and prolactin levels in serum decreased noticeably with propranolol treatment. When phenothiazines were added, prolactin increased above drug-free levels. These results support the view that propranolol has an antipsychotic potential that needs further evaluation in clinical trials.

Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers.

The concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and glutamate were determined in cerebrospinal fluid (CSF) and serum in 10 healthy volunteers. The monoamine metabolites were measured by mass fragmentography and the glutamate by high-performance liquid chromatography. The level of glutamate in CSF was low (0.34 +/- 0.14 nmol/ml) in comparison with previously published values. The concentrations of monoamine metabolites in CSF were in close agreement with earlier findings. There were negative correlations between the concentrations of HVA (r = -0.82, p less than 0.01) and 5-HIAA (r = -0.77, p less than 0.01) and glutamate in CSF, but not in serum. The serum levels of HMPG and glutamate were negatively correlated (r = -0.95, p less than 0.001), but not the CSF levels. The HMPG levels in serum and CSF were positively correlated (r = 0.94, p less than 0.001), but not the HVA and the 5-HIAA levels. The serum and CSF levels of glutamate were positively correlated (r = 0.67, p less than 0.05). The results indicate relationships among the metabolism of dopamine, serotonin, and glutamate in the brain and between the metabolism of noradrenaline and glutamate in peripheral tissue.

Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment.

Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (starting with 400, 800 or 1200 mg) according to a double blind randomized administration schedule. The monoamine metabolites (MAM) homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before treatment and once a week during treatment. There were no significant differences between healthy controls and schizophrenic patients in serum levels of monoamine metabolites and amino acids before treatment. There was no dose-response effect of sulpiride on serum levels of the monoamine metabolites or the amino acids. The results are therefore based on the whole group of patients. During treatment the HMPG levels were reduced at all points in time. The serum level of HVA was significantly reduced after 6 weeks. The 5-HIAA and the amino acid levels were not changed during treatment. There were no significant correlations among the monoamine metabolites before treatment. During treatment, however, significant correlations were found among MAM and amino acids. Since the biochemical findings during the treatment were not related to the dose or the concentration of sulpiride the results may be related to secondary biochemical effects of sulpiride and/or to changes in the clinical state following treatment.

The presence of 7-hydroxychlorpromazine in CSF of chloropromazine-treated patients.

7-Hydroxychlorpromazine (7-OHCPZ) has been identified and quantified in CSF from chlorpromazine (CPZ)-treated schizophrenic patients. The level of the metabolite in CSF was similar to that of CPZ. In serum the amount of 7-OHCPZ was about 30% of CPZ. The concentration of 7-OHCPZ in csf was positively and significantly correlated to the serum level.

Concentrations of chlorpromazine and two of its active metabolites in plasma and cerebrospinal fluid of psychotic patients treated with fixed drug doses.

Efforts to find a correlation between serum levels of chlorpromazine (CPZ) and clinical effect have been rather unsuccessful, which could be due to fluctuations of CPZ and CPZ metabolite levels during treatment, the complicated metabolism of CPZ, or to varying degrees of protein binding. Using a mass fragmentographic analysis technique the variations of CPZ and two active metabolites nor1-CPZ and 7-OH-CPZ were studied in ten schizophrenic patients during the day at steady state and after withdrawal. There was a significant correlation between the area under curve (AUC) for CPZ in serum during 24-h treatment and serum concentration at different fixed times of the day. The half-life (T 1/2) for CPZ was found to be 8-33 h. 7-OH-CPZ and nor1-CPZ disappeared at about the same rate as the parent compound. The concentration of both metabolites was less than 10 ng/ml after 36 h. CPZ was administered to 43 schizophrenic patients in one of three fixed doses (200, 400, or 600 mg) according to a double-blind design. Plasma and cerebrospinal fluid (CSF) samples were analysed before and after both 2 and 4 weeks' treatment. The levels of the metabolites were considerably lower as compared to CPZ levels. The same levels were found after 2 and 4 weeks' treatment. There were no sex differences. The levels of CPZ and metabolites presented a weak positive correlation to daily dose but not to dose calculated by mg/kg body weight. Older patients tended to have higher CPZ and metabolite levels. The dose effects were very similar in plasma and CSF and there was a highly significant correlation between CPZ levels in serum and CSF. CSF/plasma ratio for CPZ seems to be an individual factor possibly related to variations in protein-binding in plasma and CSF.

Relationships between clinical effects and monoamine metabolites and amino acids in sulpiride-treated schizophrenic patients.

Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (400, 800 or 1200 mg) according to a double dummy blind randomized administration schedule. The psychopathology of the patients was rated by the Comprehensive Psychopathological Rating Scale (CPRS) and the Nurse's Observation Scale for Inpatient Evaluation (NOSIE). The monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before and once a week during sulpiride treatment. There were no significant correlations between the CPRS or the NOSIE morbidity scores and the biochemical measures before drug treatment. HVA levels were not correlated to rating scores during treatment, but after 6 weeks HVA had decreased significantly in the patients with a good response but not in the patients with a poor response. A negative relationship between 5-HIAA levels and depressive and negative symptoms was found. Non-responders according to the subscale for depression had low 5-HIAA levels throughout the treatment. An increase of tryptophan was correlated to improvement in the early part of treatment. High levels of glutamate or glutamine were found in non-responders before treatment. During treatment an increase of the glutamate level was correlated to improvement. Low levels of glutamine were related to improvement according to global and NOSIE (total) rating scores. Peripheral biochemical measures may be a valuable tool in the study of pathophysiological mechanisms and treatment effects in patients with schizophrenia.

A mass fragmentographic method for the determination of chlorpromazine and two of its active metabolites in human plasma and CSF.

A mass fragmentographic method for the quantitation of chlorpromazine (CPZ), mono-demethyl-chlorpromazine (nor1-CPZ), and 7-hydroxy-chlorpromazine (7-OH-CPZ) in plasma, cerebrospinal fluid, and tissues has been developed. The deuterated analogues of the compounds are used as internal standards. The high specificity was ascertained by multiple ion determination. The experimental error is below 10%. The sensitivity allows determination of sub ng quantities of CPZ per ml cerebrospinal fluid. The method has been applied to the analysis of drug concentrations in plasma and cerebrospinal fluid (CSF) of chlorpromazine-treated patients. The amount of CPZ in CSF was about 3% of the plasma level. The CPZ levels in plasma and CSF were significantly correlated.

Effects of sulpiride and chlorpromazine on autistic and positive psychotic symptoms in schizophrenic patients--relationship to drug concentrations.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chlorpromazine (CPZ) (400 mg/day) during a period of 8 weeks using a double-blind design. There were 25 patients in each group and all of them fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Autistic and psychotic symptoms were rated with subscales developed from the Comprehensive Psychopathological Rating Scale (CPRS). Autistic symptoms were also rated with a subscale of the Nurse's Observation Scale for Inpatient Evaluation (NOSIE). Sulpiride was superior to CPZ in reducing the autistic symptoms. Patients with low concentrations of sulpiride in serum had a better recovery rate from autistic symptoms than those with high concentrations. Both drugs reduced positive psychotic symptoms to the same degree.

Effects of sulpiride and chlorpromazine on depressive symptoms in schizophrenic patients--relationship to drug concentrations.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chlorpromazine (CPZ) (400 mg/day) over a period of 8 weeks using a double-blind design. There were 25 patients in each group and all the patients were in an acute phase of their disease. They all fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Depressive symptoms as rated according to the Comprehensive Psychopathological Rating Scale (CPRS) were present in the patients before treatment was started. The depressive and psychotic symptoms in both groups decreased in parallel during the whole period of treatment. Patients in the sulpiride group recovered more quickly from depressive symptoms than patients in the CPZ group. It was also found that patients with low concentrations of sulpiride or CPZ in serum recovered more completely from depressive symptoms and had fewer extrapyramidal side effects than patients with high drug concentrations.

Prolactin response following intravenous and oral sulpiride in healthy human subjects in relation to sulpiride concentrations.

Sulpiride (100 mg) was administered intravenously and orally to healthy human subjects. Serum concentrations of sulpiride and prolactin were followed for 36 h. Both routes of drug administration resulted in a pronounced and sustained increase in serum prolactin concentration. The prolactin response was positively correlated to the prolactin baseline value. The concentrations of prolactin remained at an elevated plateau for 9--36 h after drug treatment despite low drug concentrations. The level of this plateau was directly related to the normal circadian secretion of prolactin. The sustained prolactin elevation may be due to high affinity and strong binding of the compound to the regulating receptors or the formation of an active sulpiride metabolite. Prolactin and sulpiride concentrations were significantly correlated during the initial phase after intravenous sulpiride. Following intravenous and oral sulpiride the area under the concentration-time curve (AUC) for prolactin was similar despite a considerable difference in the sulpiride concentration.

Mass fragmentographic analysis of clomipramine and its mono-demethylated metabolite in human plasma.

A mass fragmentographic method for the quantification of clomipramine (CIM) and monodemethyl-clomipramine (DCIM) in human plasma was developed. The deuterium labelled analogues of the compounds were used as internal standards. The sensitivity of the method allows the determination of CIM and DCIM in plasma after oral doses with a standard deviation less than 7% at concentrations of 25 ng/ml. The method was applied to the analysis of drug concentrations in plasma of clomipramine treated healthy volunteers and depressed patients. After acute treatment the level of DCIM in plasma was low as compared to chronical treatment.

Purification and characterisation of a serine peptidase from the marine psychrophile strain PA-43.

An extracellular serine peptidase, purified from the culture supernatant of the sub-Arctic psychrophilic bacterium strain PA-43, is monomeric, with a relative molecular mass of 76000, and an unusually low pI of 3.8. The peptidase is active towards N-succinyl AAPF p-nitroanilide and N-succinyl AAPL p-nitroanilide, indicating a chymotrypsin-like substrate specificity. It is inhibited by the serine peptidase inactivator phenylmethylsulfonyl fluoride, but not by EDTA or EGTA, suggesting that added metal ions are not necessary for activity. The enzyme is most active at pH 8.3 and at 55-60 degrees C, although it is unstable at 60 degrees C. It is nevertheless remarkably stable for an enzyme from a psychrophilic microorganism, remaining active after 1 week at 20 degrees C and after five freeze-thaw cycles. Comparison of the N-terminal 40 amino acid residues with other archived sequences revealed highest similarity to the alkaline serine protease (aprx) from Bacillus subtilis.

A twin study of amino acid concentrations in cerebrospinal fluid.

The concentrations of amino acids in the cerebrospinal fluid (CSF) were measured in pairs of healthy mono- and dizygotic twins. Intraclass correlations were calculated. Genetic and cultural heritabilities were estimated using a path analytical model. CSF levels of glycine, tyrosine and arginine were shown to be influenced by genetic factors. Genetic variation was also shown for serine, alpha-aminobutyrate and leucine. The results were compared with results from a genetic analysis of the amino acids in serum.

A new biotyping scheme for Salmonella typhimurium and its phylogenetic significance.

A new, two-tier system for biotyping Salmonella typhimurium gives a finer and more reliable differentiation of strains than the Kristensen scheme and is capable of future extension by the addition of new types and new tests. Strains are allocated to a primary type (1-32) by their reactions in five primary tests with Bitter's xylose medium, meso-inositol, L-rhamnose, d-tartrate and m-tartrate. Subtypes are distinguished within the primary types by reactions in ten secondary tests, which include observations for flagella and type-1 (haemagglutinating) fimbriae. Full biotypes are designated by letters indicating the subtype reactions appended to the primary-type numbers. A series of 2030 strains of S. typhimurium collected from many different sources and countries during 53 years was classified into 19 of the 32 potential primary biotypes and into 144 full biotypes. Of the series, 14% (275) were non-fimbriate inositol-nonfermenting rhamnose-nonfermenting (FIRN) strain in primary biotypes 29-32. Most other strains were fimbriate and rhamnose fermenting. Observations on several series of cultures isolated from different human or animal sources in the same epidemic showed that the biotype characters of a strain were generally stable during its growth in the natural environment and in the unselective media used for isolation and storage. Most non-fermenting strains gave rise to fermenting mutants on prolonged incubation in the substrate-containing--and therefore selective--test medium, and false-positive results from this cause were avoided by making the definitive readings of tests after a short, carefully chosen period of incubation. A genealogical tree has been drawn to show how eighteen observed primary biotypes may have evolved from a presumed archetypal ancestor of biotype 1.

The distribution and metabolism of chlorpromazine in rats and the relationship to effects on cerebral monoamine metabolism.

Rats were injected with chlorpromazine (CPZ), 21 mumoles/kg (7.5 mg/kg) i.p., and killed after different time intervals up to 24 h. Mass fragmentographic methods were used to determine the levels of CPZ, monodemethyl-chlorpromazine (nor1-CPZ) and 7-hydroxy-chlorpromazine (7-OH-CPZ) in brain and blood and dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in the striatum. Significant correlations between the brain and blood concentrations of CPZ as well as its active metabolites and the levels of DOPAC and HVA were obtained at several time points. The similarity between the time curves for CPZ dominantly the unchanged drug in the brain which determines the acceleration of DA metabolism.

A polyphasic study on the taxonomic position of industrial sour dough yeasts.

The sour dough bread making process is extensively used to produce wholesome palatable rye bread. The process is traditionally done using a back-slopping procedure. Traditional sour doughs in Finland comprise of lactic acid bacteria and yeasts. The yeasts present in these doughs have been enriched in the doughs due to their metabolic activities, e.g. acid tolerance. We characterized the yeasts in five major sour bread bakeries in Finland. We found that most of the commercial sour doughs contained yeasts which were similar to Candida milleri on the basis of 18S rDNA and EF-3 PCR-RFLP patterns and metabolic activities. Some of the bakery yeasts exhibited extensive karyotype polymorphism. The minimum growth temperature was 8 degrees C for C. milleri and also for most of sour dough yeasts.

Protein binding of chlorpromazine in cerebrospinal fluid and serum.

The binding of chlorpromazine (CPZ) to proteins in human cerebrospinal fluid (CSF) was measured by equilibrium dialysis. In CSF from schizophrenic patients binding of CPZ was found to vary by between 19 and 72%. There was no correlation between the degree of binding and the total amount of protein in the CSF. When CPZ was equilibrated between CSF and serum in vitro almost the same distribution was found as obtained in vivo in drug-treated patients.

Stability of sulphonamide drugs in meat during storage.

Incurred samples from a pig treated with sulphamethazine and spiked samples of the same concentration were compared during frozen storage. The contents of sulphamethazine in the different types of samples decreased similarly to about 50% after 15 months. When the samples were heat treated before analysis the sulphamethazine concentration did not change over time. Samples of bovine and porcine muscle were spiked with five different sulphonamide drugs and stored frozen for 3 months. Twenty-four hours at room temperature or 1 week at -20 degrees C did not affect the drug levels but after 1 month of frozen storage the levels in bovine and porcine muscle had decreased significantly. After 3 months the average decrease was 35% in bovine and 55% in porcine muscle.

Distribution of Thermus spp. in Icelandic Hot Springs and a Thermal Gradient.

The growth range in nature of bacteria belonging to the genus Thermus was investigated by sampling 55 different hot springs in Iceland. The springs ranged in temperature from 32 to 99 degrees C, and in pH from 2.1 to 10.1. Viable counts of Thermus spp. ranging from 10 to 10 CFU/100 ml of spring water were found in 27 of the springs sampled. The temperature range for these bacteria was found to be 55 to 85 degrees C, and the pH range was from about 6.5 to above 10. Thermus spp. were found in springs containing up to 1 mM dissolved sulfide and having conductivity up to 2,000 muS/cm. The distribution of Thermus spp. in a hot spring thermal gradient was also investigated and found to agree well with the overall distribution in individual springs.