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PubMed1978

Disturbances of liver function of long acting neuroleptic drugs.

In a study in 97 patients on the occurrence of disturbances of liver functions by use of long acting neuroleptic drugs (fluphenazine decanoate, flupenthixol decanoate and fluspirilene) no indications were found that these agents, even in relatively high dosages, are hepatotoxic. Furthermore, in 40% of the patients slight disturbances were found, which nevertheless, were not specific in nature, and mostly concerned the turbidity tests. In spite of these findings a regular control (for instances, once a year) of the liver functions in patients with long acting neuroleptic drugs seems to be called for.

Adolescent↗
PubMed2003

Prospective echocardiographic assessment of androgenic-anabolic steroids effects on cardiac structure and function in strength athletes.

Since the abuse of androgenic-anabolic steroids (AAS) has been associated with the occurrence of serious cardiovascular disease in young athletes, we performed two studies to investigate the effects of short-term AAS administration on heart structure and function in experienced male strength athletes, with special reference to dose and duration of drug abuse. In Study 1 the effects of AAS were assessed in 17 experienced male strength athletes (age 31 +/- 7 y) who self-administered AAS for 8 or 12 - 16 weeks and in 15 non-using strength athletes (age 33 +/- 5 y) in a non-blinded design. In Study 2 the effects of administration of nandrolone decanoate (200 mg/wk i. m.) for eight weeks were investigated in 16 bodybuilders in a randomised double blind, placebo controlled design. In all subjects M-mode and two-dimensional Doppler-echocardiography were performed at baseline and after 8 weeks AAS administration. In the athletes of Study 1 who used AAS for 12 - 16 weeks a third echocardiogram was also made at the end of the AAS administration period. Echocardiographic examinations included the determination of the aortic diameter (AD), left atrium diameter (LA), left ventricular end diastolic diameter (LVEDD), interventricular septum thickness (IVS), posterior wall end diastolic wall thickness (PWEDWT), left ventricular mass (LVM), left ventricular mass index (LVMI), ejection fraction (EF) and right ventricular diameter (RVD). For assessment of the diastolic function measurements of E and A peak velocities and calculation of E/A ratio were used. In addition, acceleration and deceleration times of the E-top (ATM and DT, respectively) were determined. For evaluation of factors associated with stroke volume the aorta peak flow (AV) and left ventricular ejection times (LVET) were determined. In Study 1 eight weeks AAS self-administration did not result in changes of blood pressure or cardiac size and function. Additionally, duration of AAS self-administration did not have any impact on these parameters. Study 2 revealed that eight weeks administration of nandrolone decanoate did not induce significant alterations in blood pressure and heart morphology and function. Short-term administration of AAS for periods up to 16 weeks did not lead to detectable echocardiographic alterations of heart morphology and systolic and diastolic function in experienced strength athletes. The administration regimen used nor the length of AAS abuse did influence the results. Moreover, it is concluded that echocardiographic evaluation may provide incomplete assessment of the actual cardiac condition in AAS users since it is not sensitive enough to detect alterations at the cellular level. Nevertheless, from the present study no conclusions can be drawn of the cardiotoxic effects of long term AAS abuse.

Adult↗
PubMed1991

Influence of anabolic steroids on body composition, blood pressure, lipid profile and liver functions in body builders.

The effects of anabolic steroids on body composition, blood pressure, lipid profile and liver functions were studied in male body builders who received a weekly i.m. injection of nandrolone-decanoate (100 mg) or placebo for 8 weeks in a double blind way. In addition, 5 body builders received the same dosage of nandrolone-decanoate or placebo, in a double blind cross-over design during two 8-week periods, interspersed by 12 weeks. Anabolic steroids induced a 25-27% decrease in HDL-cholesterol, which was virtually reversed 6 weeks after cessation of drug use. In the SAD group an increase in diastolic blood pressure was observed, which returned to pre-anabolic values approximately 6 weeks after cessation of drug administration. No deleterious effects of anabolic drugs on plasma activity of liver enzymes were found. Increases in lean body mass were found in all groups, though the increase in the subjects who received anabolic steroids was superior to that in the placebo-treated subjects. The increase in lean body mass suggests increases in muscle mass.

Adult↗
PubMed1978

Transport of long-chain fatty acids by Escherichia coli: mapping and characterization of mutants in the fadL gene.

A new locus (fadL) that is required for the utilization of long-chain fatty acids has been mapped and partially characterized in an Escherichia coli mutant. The fadL locus has been mapped at 50 min on the chromosome. A mutant bearing a defect in this locus cannot utilize long-chain fatty acids as a sole carbon source. Derivatives of this mutant that can grow on decanoate (termed fadR) are capable of growth on medium-chain but not long-chain fatty acids. It is believed that the fadL mutants is defective in the transport of long-chain fatty acids into the cell for the following reasons: (i) fadR fadL strains can oxidize in vivo decanoate but not oleate; (ii) neither fadL nor fadR fadL strains can incorporate oleate into their membrane lipids; (iii) the activity of the acyl-CoA synthetase (EC 6.2.1.3) in fadR fadL strains is comparable to the acyl-CoA synthetase activity in fadR fadL+ strains; and (iv) in vitro extracts from fadR fadL+ strains. If the above hypothesis is correct, the uptake of long-chain fatty acids by E. coli requires at least two gene products.

Biological Transport↗
PubMed1987

Depot neuroleptic medication and serum levels by radioreceptor assay: prolactin concentration, electrocardiogram abnormalities and six-month outcome.

Twenty-six chronic schizophrenic patients on well-established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, 10 on flupenthixol decanoate) had serum neuroleptic levels measured by radioreceptor assay (RRA) and were followed for six months. The serum prolactin (PRL) concentration and resting electrocardiogram (ECG) were also taken at the beginning of the study period. Correlations had previously been noted between RRA measured neuroleptic levels and outcome in both acute and chronic patients on oral medication. However, in this study of depot medication no significant correlations were found between serum neuroleptic concentration, serum prolactin concentration and the clinical state or outcome. The prevalence (33%) and type of ECG abnormality observed was similar to that previously reported.

Adult↗
PubMed1998

Human rectal absorption of short- and medium-chain C2-C10 fatty acids.

BACKGROUND: Current knowledge on the colonorectal absorption of medium-chain fatty acids is limited. The purpose of the present study was to evaluate and compare the human rectal absorption of short- and medium-chain C2-C10 fatty acids in healthy volunteers. METHODS: Dialysis bags containing 20 mmol x l(-1) of the fatty acids acetate, butyrate, hexanoate, octanoate, or decanoate in a phosphate-buffered (pH neutral) isoosmotic electrolyte solution were placed in the rectum for 30 min in 14 healthy volunteers. Absorption rates were calculated for all fatty acids, sodium, potassium, and water. RESULTS: Absorption rates of the fatty acids acetate, butyrate, hexanoate, octanoate or decanoate were the same (1.9 +/- 0.1 = 2.5 +/- 0.2 = 1.7 +/- 0.2 = 1.9 +/- 0.2 = 2.2 +/- 0.1 micromol x cm(-2) x h(-1) (mean +/- standard error of the mean), respectively; P = 0.24). CONCLUSIONS: Medium-chain fatty acids were absorbed in the human rectum at a rate similar to that for short-chain fatty acids. If results can be applied to the human colon, colonic absorption of medium-chain fatty acids could possibly become an important secondary site of absorption in abnormal intestinal conditions such as massive small-intestinal resection or malabsorption syndromes.

Administration, Rectal↗
PubMed2002

Antipsychotic prescribing practices in Connecticut's public mental health system: rates of changing medications and prescribing styles.

We characterized prescribing in Connecticut's State public mental health system to assess the feasibility of implementing an evidence-based medication algorithm. Medication records for a random sample of outpatients with diagnoses of schizophrenia spectrum disorders showed prescribing patterns similar to the entire United States. The base rate of changing antipsychotic medications was moderate. Over half of patients received decanoate medications, polypharmacy was nontrivial, and there was variability in prescribing patterns across physicians. Caucasian patients were more likely to receive an atypical antipsychotic and less likely to have a decanoate medication, and Latino patients were less likely to change medications. Because the base rate of changing medications was moderate and a considerable proportion of patients were prescribed newer antipsychotic medications, introducing a research-derived medication algorithm with newer atypical antipsychotics as first line agents may fit well with current practice. Further, implementing such an algorithm may reduce racial and ethnic disparities in prescribing patterns.

Adult↗
PubMed1981

Effects of a six-week drug holiday on symptom status, relapse, and tardive dyskinesia in chronic schizophrenics.

We have conducted a 6-wk drug withdrawal study in a group of chronic schizophrenic outpatients who had been maintained on injectable fluphenazine decanoate for at least 2 yr prior to the study. After two baseline assessments, patients were randomly assigned to two groups. The first group (holiday) received a placebo injection from a nurse who was not involved in the assessment (N = 17). The second group continued on their regular medication (N = 14). The assessment was done in a double-blind fashion at 3 and 6 wk using the Schedule for Affective Disorders and Schizophrenia (SADS) and the Global Assessment Scale (GAS) inventories to assess symptom status. Tardive dyskinesia was measured using the Abnormal Involuntary Movement Scale (AIMS). Community adjustment was assessed by means of the self-rated Weissman Social Adjustment Scale. We found that there were no relapses of any kind in either group of patients using the instruments mentioned above. The prevalence of tardive dyskinesia as measured by the AIMS was low, with only one patient having severe tardive dyskinesia. There was no significant worsening of the tardive dyskinesia during the drug holiday. Our study concludes that a 6-wk drug holiday was safe in this group of chronic schizophrenic patients maintained on fluphenazine decanoate. In contrast to other studies, no cases of covert tardive dyskinesia were detected during the drug holiday.

Adult↗
PubMed1999

Structured diagnostic assessment and depot fluphenazine treatment of multiple suicide attempters in the emergency department.

The aim of this study was to compare the efficacy of two doses of monthly intramuscular (i.m.) injections of fluphenazine decanoate in reducing self-harm behaviours in outpatients with histories of multiple suicide attempts. Fifty-eight patients who presented to a psychiatric emergency service after an attempted suicide and who had histories of multiple suicide attempts, were randomized to receive monthly i.m. injections of fluphenazine decanoate. Thirty patients received monthly 12.5 mg ('low' dose), and 28 patients received monthly 1.5 mg ('ultra low' dose) under double-blind conditions. DSM-III-R diagnoses were obtained on all patients using the Structured Clinical Interview for DSM-III-R-Patient Version (SCID-P) and SCID for DSM-III-R Personality Disorders (SCID-II). Outcomes were assessed by the Parasuicide History Inventory and the Abnormal Involuntary Movement Scale, collected monthly for 6 months. Patients had an average of six current Axis I and 2.6 Axis II diagnoses, with borderline personality (85%) and alcohol dependence (58%) occurring most frequently in the sample. Both the low dose and ultra-low dose groups showed a marked reduction in self-harm behaviours. For 'serious' self-harm behaviours, there was a trend for a greater effect of the low dose over the ultra-low dose group, however, the differences did not reach statistical significance. A survival analysis indicated that the presence of 'acute' stressors at baseline and female sex were risk factors for continuing (post-randomization) 'serious' self-harm behaviours, while younger age and the absence of concurrent general medical conditions were risk factors for all self-harm behaviours.

Adult↗
PubMed2004

Haloperidol half-life after chronic dosing.

In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration.

Adult↗
PubMed2003

Degradation of alkanes and highly chlorinated benzenes, and production of biosurfactants, by a psychrophilic Rhodococcus sp. and genetic characterization of its chlorobenzene dioxygenase.

Rhodococcus sp. strain MS11 was isolated from a mixed culture. It displays a diverse range of metabolic capabilities. During growth on 1,2,4-trichlorobenzene, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TeCB) and 3-chlorobenzoate stoichiometric amounts of chloride were released. It also utilized all three isomeric dichlorobenzenes and 1,2,3-trichlorobenzene as the sole carbon and energy source. Furthermore, the bacterium grew well on a great number of n-alkanes ranging from n-heptane to n-triacontane and on the branched alkane 2,6,10,14-tetramethylpentadecane (pristane) and slowly on n-hexane and n-pentatriacontane. It was able to grow at temperatures from 5 to 30 degrees C, with optimal growth at 20 degrees C, and could tolerate 6 % NaCl in mineral salts medium. Genes encoding the initial chlorobenzene dioxygenase were detected by using a primer pair that was designed against the alpha-subunit (TecA1) of the chlorobenzene dioxygenase of Ralstonia (formerly Burkholderia) sp. strain PS12. The amino acid sequence of the amplified part of the alpha-subunit of the chlorobenzene dioxygenase of Rhodococcus sp. strain MS11 showed >99 % identity to the alpha-subunit of the chlorobenzene dioxygenase from Ralstonia sp. strain PS12 and the parts of both alpha-subunits responsible for substrate specificity were identical. The subsequent enzymes dihydrodiol dehydrogenase and chlorocatechol 1,2-dioxygenase were induced in cells grown on 1,2,4,5-TeCB. During cultivation on medium-chain-length n-alkanes ranging from n-decane to n-heptadecane, including 1-hexadecene, and on the branched alkane pristane, strain MS11 produced biosurfactants lowering the surface tension of the cultures from 72 to </=29 mN m(-1). Glycolipids were extracted from the supernatant of a culture grown on n-hexadecane and characterized by (1)H- and (13)C-NMR-spectroscopy and mass spectrometry. The two major components consisted of alpha,alpha-trehalose esterified at C-2 or C-4 with a succinic acid and at C-2' with a decanoic acid. They differed from one another in that one 2,3,4,2'-trehalosetetraester, found in higher concentration, was esterified at C-2, C-3 or C-4 with one octanoic and one decanoic acid and the other one, of lower concentration, with two octanoic acids. The results demonstrate that Rhodococcus sp. strain MS11 may be well suited for bioremediation of soils and sediments contaminated for a long time with di-, tri- and tetrachlorobenzenes as well as alkanes.

Alkanes↗
PubMed1995

Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli.

Defined mutations of acrA or acrB (formerly acrE) genes increased the susceptibility of Escherichia coli to a range of small inhibitor molecules. Deletion of acrAB increased susceptibility to cephalothin and cephaloridine, but the permeability of these beta-lactams across the outer membrane was not increased. This finding is inconsistent with the earlier hypothesis that acrAB mutations increase drug susceptibility by increasing the permeability of the outer membrane, and supports our model that acrAB codes for a multi-drug efflux pump. The natural environment of an enteric bacterium such as E. coli is enriched in bile salts and fatty acids. An acrAB deletion mutant was found to be hypersusceptible to bile salts and to decanoate. In addition, acrAB expression was elevated by growth in 5 mM decanoate. These results suggest that one major physiological function of AcrAB is to protect E. coli against these and other hydrophobic inhibitors. Transcription of acrAB is increased by other stress conditions including 4% ethanol, 0.5 M NaCl, and stationary phase in Luria-Bertani medium. Finally, acrAB expression was shown to be increased in mar (multiple-antibiotic-resistant) mutants.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Synthesis of poly(3-hydroxyalkanoates) in Escherichia coli expressing the PHA synthase gene phaC2 from Pseudomonas aeruginosa: comparison of PhaC1 and PhaC2.

In order to obtain functional expression of PHA synthase gene phaC2 from Pseudomonas aeruginosa in Escherichia coli, the coding region of phaC2 was subcloned, including the ribosomal binding site, into pBluescript SK- collinear to the lac promoter. This plasmid pBHR71-C2 enabled functional expression of phaC2 in E. coli LS1298 (fadB) under lac promoter control, leading to PHA accumulation, when grown in LB medium containing 0.5% (w/v) of various fatty acids (C8-C14). The strongest accumulation of PHA was observed, when dodecanoate was provided as carbon source, and PHA contributed to 15% of cell dry weight, which was composed of 35 mol% 3-hydroxydodecanoate, 60 mol% 3-hydroxydecanoate and 5 mol% 3-hydroxyoctanoate. Plasmid pBHR78, which contained both genes phaC1 and phaC2 from P. aeruginosa under lac promoter control in pBluescript SK- led in E. coli LS1298 to PHA accumulation, which contributed to 13% of cell dry weight, when cells were grown on decanoate. Only slight differences in PHA composition compared with either PhaC1 or PhaC2 were obtained. The weight average molecular masses of PHA purified from decanoate-grown cells of E. coli LS1298 expressing PhaC1 or PhaC2 alone or both PHA synthases, were 106 x 10(3), 70 x 10(3) or 67 x 10(3), respectively. This study clearly demonstrated that both PHA synthases from P. aeruginosa exhibit very similar properties resulting in similar extent of PHA accumulation, similar composition and molecular mass, when expressed in E. coli and that fatty acid beta-oxidation provides substrates for both PHA synthases.

Acyltransferases↗
PubMed2002

Metabolic engineering of Escherichia coli for the production of medium-chain-length polyhydroxyalkanoates rich in specific monomers.

The Escherichia coli fabG(Ec) gene and the Pseudomonas aeruginosa rhlG(Pa) gene, which encode 3-ketoacyl-acyl carrier protein reductase, were expressed in E. coli W3110 and its fadA mutant strain WA101 to examine their roles in medium-chain-length (MCL) polyhydroxyalkanoate (PHA) biosynthesis from fatty acids. When one of these 3-ketoacyl-acyl carrier protein reductase genes was co-expressed with the Pseudomonas sp. 61-3 PHA synthase gene (phaC2(Ps)) in E. coli W3110, MCL-PHA composed mainly of 3-hydroxyoctanoate and 3-hydroxydecanoate was synthesized from sodium decanoate. When the fabG(Ec) gene and the phaC2(Ps) gene were co-expressed in the fadA mutant E. coli strain WA101, MCL-PHA rich in 3-hydroxydecanoate monomer up to 93 mol% was accumulated from sodium decanoate. This was possible by efficiently redirecting 3-ketoacyl-coenzymes A from the beta-oxidation pathway to the PHA biosynthesis pathway without losing two carbon units, the strategy of which can be extended for the production of MCL-PHAs rich in other specific monomers.

3-Oxoacyl-(Acyl-Carrier-Protein) Reductase↗
PubMed1979

Increase in weight after treatment with depot neuroleptics.

A trial has been performed investigating changes in weight in 99 female patients who have been treated with clopenthixol decanoate or perpehnazine enanthate after prior treatment with different oral neuroleptics. We found a significantly higher mean weight after the oral treatment period and a slight, but not statistically significant, further weight increase after the following depot period. In addition the rate of increase in weight was significantly lower during the depot treatment period. These increases might be due to achievement of a steady-state in weight during the first treatment period with oral intake. We found no difference between clopenthixol decanoate and perphenazine enanthate as regards change in weight or rate of change in weight.

Administration, Oral↗
PubMed1980

Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels.

Serum concentrations of clopenthixol and flupenthixol have been determined during a four weeks dosage interval in patients treated with intramuscular injections of clopenthixol decanoate or flupenthixol palmitate in Viscoleo. Maximal drug levels were attained by the end of the first week after injection of either preparation. A period of exponential decline was then recorded. The half-lives were estimated to 19 days for clopenthixol and 17 days for flupenthixol. These half-lives most likely refer to the rate of release from the oil depot and not to elimination of drug. The mean ratio between maximal and minimal drug levels was 2.5 for clopenthixol and 3.7 for flupenthixol. Systemic clearance was estimated to about 0.7 l/min and 0.5 l/min, respectively. Significant correlation was found between the administered doses and recorded serum levels, between doses and estimated areas under the serum concentration curves, and also between areas and drug levels. The data indicate more limited individual variability than that seen with other psychotropic drugs, given orally. The study clearly demonstrates, that significant serum levels of active drug is maintained throughout the dosage interval by intramuscular injection of clopenthixol decanoate or flupenthixol palmitate in Viscoleo every fourth week.

Ambulatory Care↗
PubMed1985

Pharmacokinetic implications of different oil vehicles used in depot neuroleptic treatment.

On separate occasions two male schizophrenic inpatients were given intramuscular injections of equal amounts of perphenazine decanoate dissolved in sesame oil and Viscoleo, respectively. Substantially more even, but also lower perphenazine plasma concentrations were found within the dose intervals following the injections of perphenazine decanoate dissolved in sesame oil compared to the intervals following the Viscoleo-preparation. The occurrence of extrapyramidal side effects were consistent with the magnitude of the perphenazine plasma concentrations. The results support the importance of selecting an appropriate oil vehicle in a depot neuroleptic.

Adult↗
PubMed1987

Partitioning of polar fatty acids into lymph and portal vein after intestinal absorption in the rat.

We tested the hypothesis that fatty acids destined for the portal vein after intestinal absorption would be diverted into lymph when infused along with a saturated long-chain fatty acid. Thoracic fistula rats were infused intraduodenally with either linolenic (18:3), lauric (12:0), or decanoic (10:0) acid, or with each fatty acid in combination with 5 mM palmitic acid (16:0), in micellar solutions of taurocholate (10 mM) and 2-mono-oleoylglycerol. Lymphatic transport of linolenic acid was enhanced by co-absorption with palmitic acid: when 0.1 mM linolenic acid was infused alone, 32 +/- 8% of that absorbed and transported beyond the mesentery was carried in lymph. The addition of palmitic acid to the infusate increased the percentage transported in lymph to 56 +/- 10% (P less than 0.005). The increment was due to enhanced intracellular re-esterification of linolenate into triacylglycerol. When 5 mM linolenic acid was infused, the comparable figures for lymphatic transport were 55 +/- 2% for linolenate infused alone and 66 +/- 6% for linolenate infused with palmitate (P less than 0.005). In contrast, the predominantly portal venous transport of lauric and decanoic acids was unaffected by co-absorption with palmitate. We conclude that the partitioning of long-chain fatty acids between portal blood and lymph is dependent on the luminal milieu, in addition to polarity of the fatty acid and the rate of absorption. Unsaturated long-chain fatty acids have a substantial portal transport under conditions which simulate normal food ingestion.

Animals↗