Clinical experience with fluphenazine decanoate in the treatment of patients with long-standing chronic schizophrenia.
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Adolescent↗
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[Accidental intravenous administration of haloperidol decanoate].
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Adult↗
Fluphenazine decanoate causing atrioventricular block.
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Antipsychotic Agents↗
[Total illness costs of schizophrenia and monetary evaluation of prevention of recurrence exemplified by a standard depot neuroleptic (flupenthixol decanoate)].
Treatment of patients suffering from schizophrenia is very expensive. However, by consistently and methodically performed medical prophylaxis the disease can be controlled sufficiently well. Regular prophylactic treatment compared to repeated treatment of acute episodes has both medical advantages and reduces cost by reducing the rate of hospitalisation. Prophylactic treatment with Flupentixoldecanoat can save up to 68% of costs.
Adult↗
[Complications of the treatment with long-acting neuroleptic preparations. Brain disease due to fluphenazine decanoate].
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Adult↗
Clinical pharmacokinetics of the depot antipsychotics.
The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixol decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life ranging from 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit 'lumps' due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from less than 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug. Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day.(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗
The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients.
In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Neuroleptic serum levels measured by radioreceptor assay in patients receiving intramuscular depot neuroleptics. Some preliminary findings.
Twenty-six chronic schizophrenic patients on well established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, ten on flupenthixol decanoate) had serum neuroleptic levels measured by a radioreceptor assay (RRA) method. The assay was sufficiently sensitive to measure serum levels in all cases, with acceptable levels of inter-assay variation. Blood level measurements were repeated on two occasions, at the same time interval from the last injection, in 18 patients (11 on fluphenazine decanoate, seven on flupenthixol decanoate) and remained reasonably stable in most cases, although others showed a wider variation. Despite a wide range of doses (X 32 fluphenazine decanoate, X 21 flupenthixol decanoate) the serum levels fell in a remarkably narrow range (X 4, X 6). There was a significant correlation between dose and blood level for flupenthixol decanoate, but not for fluphenazine decanoate.
Adult↗
A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy.
BACKGROUND: Haloperidol decanoate is a long-acting depot antipsychotic agent used for the treatment of schizophrenic patients. The decanoate formulation was developed to treat schizophrenics who have a history of noncompliance with oral medication. Studies of techniques to convert from oral to depot therapy have not utilized the pharmacokinetics of the decanoate formulation. This study is a prospective evaluation for converting patients from oral to depot treatment. METHOD: Twenty-one patients meeting DSM-III-R criteria for schizophrenia participated in the study. Patients were treated with oral haloperidol for 6 weeks and then were switched to decanoate. Haloperidol decanoate 100 mg was administered on a weekly basis for the first 4 weeks. Afterward, injection intervals were increased to every 2 weeks and then to every 4 weeks. Plasma haloperidol concentrations were obtained prior to the next injection and assayed by HPLC with electrochemical detection. Patients were monitored by the psychiatrists and nursing staff for symptoms of clinical deterioration. RESULTS: All patients completed the conversion trial during the first 4 weeks without any problems or adverse side effects. By the third week, mean plasma haloperidol concentrations from the decanoate injections were comparable with those of the 10-mg oral haloperidol treatment (7.95 +/- 4.94 ng/mL vs. 7.79 +/- 4.79 ng/mL). Steady-state conditions for the decanoate therapy were achieved by the fourth week. CONCLUSION: These findings suggest that schizophrenic patients can be easily converted from oral to depot therapy without problems. Further studies with haloperidol decanoate and its conversion from oral treatment utilizing plasma concentrations are needed.
Administration, Oral↗
Microscopic analysis of ester hydrolysis reaction catalyzed by Candida rugosa lipase.
The relationship between the kinetics of the lipase-catalyzed oil hydrolysis and the surface area distribution of oil droplets was investigated using ethyl decanoate and gum Arabic (GA) as a model oil and an emulsifier, respectively. Along an ethyl decanoate concentration gradient between 2 and 8 mM, the initial hydrolysis rate increased at 0.25% (w/v) GA but did not change at 1.0% (w/v) GA. At 0.25% GA, the surface area of droplets was narrowly distributed regardless of the ethyl decanoate concentration. However, at 1.0% GA and with ethyl decanoate concentrations higher than 2 mM, the fraction of relatively large droplets with a surface area larger than approximately 200 microm2, suddenly increased. The microscopy of ethyl decanoate emulsion during the hydrolysis reaction indicates that the large oil droplets were not hydrolyzed. At 20 mM ethyl decanoate where the hydrolysis rate remained the same between 0.25% and 1.0% GA, the surface area of droplets was narrowly distributed at 0.25% and 1.0% GA. Therefore, the constant hydrolysis rate observed in the emulsion of ethyl decanoate between 2 and 8 mM containing GA at 1.0%, is believed to be caused by the relatively large oil droplets with the interface quality differing from that of the small oil droplets.
Candida↗
Nature, type of linkage, and absolute configuration of (hydroxy) fatty acids in lipopolysaccharides from Xanthomonas sinensis and related strains.
The fatty acids present in lipopolysaccharides from Xanthomonas sinensis were identified as decanoic, 9-methyl-decanoic, 2-hydroxy-9-methyl-decanoic, 2-hydroxy-9-methyl-decanoic, D-3-hydroxy-decanoic, D-3-hydroxy-9-methyl-decanoic, D-3-hydroxy-dodecanoic, and D-3-hydroxy-11-methyl-dodecanoic acid. These fatty acids occur in the lipid A component where they are bound through ester and amide linkages to glucosamine residues. All types of fatty acids are ester bound; however, part of D-3-hydroxy-dodecanoic and D-3-hydroxy-11-methyl-dodecanoic acid is also involved in amide linkage. The hydroxyl groups of ester-linked 3-hydroxy fatty acids are not substituted. Similar fatty acid patterns were obtained from lipopolysaccharides of nine other Xanthomonas species.
Chemical Phenomena↗
On the biologic origin of C6-C10-dicarboxylic and C6-C10-omega-1-hydroxy monocarboxylic acids in human and rat with acyl-CoA dehydrogenation deficiencies: in vitro studies on the omega- and omega-1-oxidation of medium-chain (C6-C12) fatty acids in human and rat liver.
C6-C10-dicarboxylic acid C6-C10-omega-1-hydroxy monocarboxylic acids were measured in postmitochondrial (10,000 g) fractions of rat liver after incubation with hexanoic, octanoic, and decanoic acids. In livers both from fed and starved rats, the proportion of decanoic acid converted to sebacic acid was high (approximately 25%) with only minor accumulation of the intermediate 10-hydroxy decanoic acid (1-2%). The conversion of octanoic and hexanoic acids to suberic and adipic acids, respectively, was low (less than 1%). The intermediate 8-hydroxy octanoic and 6-hydroxy hexanoic acids were also accumulated in very small amounts (less than 1%). It was concluded that cytochrome-P-450-mediated omega-hydroxylation was of decisive importance for the production rate of the dicarboxylic acids. Analysis of kinetic parameters of human and rat liver microsomal omega- and omega-1-hydroxylation of hexanoic, octanoic, decanoic, and dodecanoic acids gave the following results: in rats, the apparent Km values for the omega-hydroxylation for dodecanoic and decanoic acids are low, ie., 171 and 3.1 mumole/liter, respectively, whereas they are high for octanoic and hexanoic acids (8211 and 8822 mumole/liter, respectively). In two different humans, the corresponding Km values for dodecanoic, decanoic, octanoic, and hexanoic acids are 3.6-186, 522-247, 4861-3892, and 6825-10400 mumole/liter, respectively. Based on these results, it is argued that adipic and suberic acids found in urine from rats and humans with acyl-CoA dehydrogenation deficiencies are not biosynthesized by direct omega-oxidation of hexanoic and octanoic acids, but most probably by means of beta-oxidation of sebacic and dodecanedioic acids, produced by direct omega-oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipates↗
Accumulation of 3-hydroxy-fatty acids in the culture medium of long-chain L-3-hydroxyacyl CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein-deficient skin fibroblasts: implications for medium chain triglyceride dietary treatment of LCHAD deficiency.
Dietary management of long-chain l-3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency involves a regimen that contains adequate carbohydrate, protein, and essential lipids, and supplementation with medium-chain fatty acids in the form of medium-chain triglycerides, providing energy from fats that bypasses the long-chain metabolic block. This study analyzes the effects of dietary treatment of LCHAD deficiency in an in vitro model. Cultured skin fibroblasts from LCHAD-deficient and normal individuals were grown in media supplemented with physiologic combinations of medium-chain fatty acids octanoate and decanoate, and the long-chain palmitate. Medium was removed from the cells after various incubation times, and assayed for 3-hydroxy-intermediates of fatty acid oxidation. The 3-hydroxy-fatty acids were measured by stable-isotope dilution gas chromatography/mass spectrometry. We found that the addition of medium-chain fatty acids caused a decrease in the accumulation of long-chain fatty acid oxidation intermediates in LCHAD-deficient cells when the cells were incubated in untreated medium, and also when they were incubated in this medium with palmitate added. Medium with decanoate alone was better at achieving this effect than medium with only octanoate added. A 1:3 ratio of octanoate to decanoate worked best over an extended time period in LCHAD-deficient cells in untreated medium, whereas a 1:1 ratio of octanoate to decanoate worked best in the same cells incubated in medium containing palmitate. In all dietary medium-chain triglyceride preparations, the ratio of octanoate was greater than that of decanoate. Our results suggest that a medium-chain triglyceride preparation that is higher in decanoate may be more effective in reducing the accumulation of potentially toxic long-chain 3-hydroxy-fatty acids in LCHAD deficiency.
3-Hydroxyacyl CoA Dehydrogenases↗
Hair analysis and detectability of single dose administration of androgenic steroid esters.
Detection of anabolic steroids in hair samples has been possible only in fatal cases or in cases of high-continuous dosages. In order to verify the possibility of detecting an acute administration, a sensitive and specific assay has been developed for the simultaneous determination of testosterone, nandrolone and some of their esters in hair. The analytes were extracted from finely cut hair with methanol-trifluoroacetic acid overnight. After the incubation, the mixture was evaporated to dryness, redissolved and extracted with hexane. The dried organic layer was silanised and analysed by GC-MS and GC-MS-MS. A sensitivity of at least 20 pg injected was obtained for all the analytes. In guinea pigs treated with a single intramuscular dose of 10 mg/kg nandrolone decanoate, neither nandrolone decanoate nor nandrolone were found in hair collected after 13 days, while both compounds were clearly detectable after four repeated doses (each dose every 3-4 days) of 20 mg/kg nandrolone decanoate. Neither nandrolone decanoate nor nandrolone could be detected in hair from a male healthy volunteer 1 month after treatment with 50 mg nandrolone decanoate, while his urine still tested highly positive for the main nandrolone metabolite (> 100 ng/ml). Testosterone esters could not be detected in hair of healthy subjects collected respectively 3, 2 and 1 month after a single intramuscular administration of 250 mg testosterone enanthate (five subjects), a single intramuscular coadministration of 25 mg testosterone propionate plus 110 mg testosterone enanthate (one subject), or a single oral administration of 120 mg testosterone undecanoate (three subjects). Otherwise, hair analysis revealed an increase of testosterone concentration corresponding to the period of treatment. Analysis of blood and urine samples confirmed the absorption of those compounds. At the sensitivity achieved by the present method, no detection of nandrolone, nandrolone decanoate nor testosteron esters in hair seems to be obvious after a single dose administration.
Adult↗
Rehospitalization risk with second-generation and depot antipsychotics.
Decreasing hospital admissions is important for improving outcomes for people with schizophrenia. Second-generation antipsychotics (SGAs) are better tolerated for long-term therapy than traditional medications and may contribute to a lower rehospitalization risk, but have not been compared to depot forms with regard to long-term outcomes. This study evaluates the risk of readmission in patients discharged from six State of Maryland inpatient mental health facilities between Jan. 1, 1997 and Dec. 31, 1997 on clozapine (N = 41), risperidone (N = 149), and olanzapine (N = 103). These patients were compared with those discharged from the two largest state facilities during the same time period on fluphenazine decanoate (N = 59) or haloperidol decanoate (N = 59). One-year readmission risk (measured by Kaplan-Meier survival analysis with Holm's adjustment for multiple comparison on Log Rank tests) were 10% for clozapine, 12% for risperidone, and 13% for olanzapine. These risks were not significantly lower than the readmission risk for fluphenazine decanoate (21%) but were significantly lower than haloperidol decanoate (35%) for all three SGAs. Demographic and clinical variables did not predict readmission for any of the medications. In patients with similar demographic and clinical characteristics, 1-year risk of readmission for patients treated with SGAs were at least comparable to the 1-year risk for patients receiving fluphenazine decanoate and lower than the risk for patients treated with haloperidol decanoate. SGAs may provide better long-term prognoses and outcomes for patients with schizophrenia.
Adult↗
Impairment of VLDL secretion by medium-chain fatty acids in chicken primary hepatocytes is affected by the chain length.
To determine the effect of the chain length of medium-chain fatty acids (MCFAs) on VLDL secretion, the media of chicken hepatocyte cultures were supplemented with hexanoate (6:0), octanoate (8:0), decanoate (10:0), or dodecanoate (12:0). The supplementation of palmitate (16:0) or bovine serum albumin (BSA) alone in media was used as the positive control or the control, respectively. Palmitate significantly increased intracellular triacylglycerol (TG) accumulation and VLDL-TG, -cholesterol, and -apolipoprotein (apo)B secretion. On the other hand, the addition of hexanoate did not affect these variables relative to control cultures supplemented with BSA alone, whereas octanoate, decanoate, and dodecanoate decreased apoB secretion from the chicken hepatocytes. ApoB secretion from hepatocytes cultured with 1.0 mmol/L MCFA, in particular decanoate and dodecanoate, in the presence of 0.2 mmol/L palmitate was significantly lower than that obtained with 0.2 mmol/L palmitate alone. Decanoate at 0.25-1.0 mmol/L dose dependently reduced apoB mRNA expression compared with the control (BSA alone). The levels of 3-hydroxy-3-metylglutaryl-CoA reductase and apoA-I mRNA were significantly lower in cultures supplemented with hexanoate, octanoate, and decanoate than in cultures with dodecanoate and palmitate. These changes did not correspond to the reduction in VLDL-apoB secretion. We suggest that MCFAs with different chain lengths differentially affect apoB secretion and mRNA expression, with decanoate being the most effective at decreasing VLDL-apoB secretion by regulating apoB mRNA expression at the transcriptional level.
Animals↗
Movement disorders in patients treated with long-acting injectable antipsychotic drugs.
The frequencies of antipsychotic drug-induced movement disorders documented by physicians and identified by researchers using standardized clinical rating scales were compared, as were the frequencies associated with use of fluphenazine decanoate and haloperidol decanoate. All outpatients at a Veterans Affairs medical center who were being maintained with intramuscular injections of fluphenazine decanoate or haloperidol decanoate and were in otherwise good health were studied. The patients were assessed by a pharmacist using the Abnormal Involuntary Movement Scale to evaluate the presence and severity of tardive dyskinesia (TD) and the Simpson-Angus EPS Rating Scale to evaluate the presence and severity of extrapyramidal symptoms (EPS). The patients' medical records for the previous two years were reviewed to determine whether a movement disorder had been documented, whether the patient's informed consent for antipsychotic drug use had been obtained, and to collect other data about the patient and his or her drug therapy. A total of 50 patients were evaluated. A neurologic examination by a physician had been documented in the chart within six months before clinical testing for 36 patients; abnormal movements had been found in 8 patients. Twenty-one subjects met the study criteria for probable TD or EPS or both. Of these patients, only six had been identified within the previous six months as having a movement disorder. Two patients with medical-record documentation of a movement disorder were not so identified by their test scores. Informed consent had been obtained from only 10 patients. Patients receiving haloperidol decanoate had a higher frequency of EPS but were also receiving higher drug dosages than patients given fluphenazine decanoate.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The effects of medium chain fatty acids and fluoride on fissure caries in Wistar rats.
This work was to compare the degree of caries protection provided by fatty acids with chain lengths of 9-12 carbons and to assess the anti-caries potential of a fluoride-fatty acid mixture. Male Wistar rats were weaned at 21 days, maintained on a standard laboratory diet for 7 days and then provided with a cariogenic, 45% sucrose diet for 34 days. This regimen produced a very reproducible degree of fissure caries and the inclusion of 1% powdered potassium nonanoate or decanoate in the diet gave large and significant reductions in total and advanced lesions. Decanoate was significantly more inhibitory towards advanced lesions than was nonanoate. In contrast, 1% potassium laurate was considerably less effective under these conditions. Caries protection with a mixture of 0.25% decanoate and 76 parts/10(6) fluoride was found to be cumulative rather than synergistic. It is suggested that the optimal effect obtained with decanoate was due to a favourable combination of the surfactant and wetting properties of this molecule at the low pH values found in fissure dental plaque. It is also suggested that fluoride and decanoate acted in an independent manner to enhance remineralization of early lesions and to inhibit the acidogenic flora, respectively.
Animals↗