Interest of Single Hair Analysis to Document Drug Exposure: Literature Review and a Case Report Involving Zuclopenthixol.

The analysis of hair to detect drugs and drugs of abuse is performed in various contexts, including child protection cases, abstinence control programs, and workplace drug testing. This alternative matrix offers several advantages, such as a large detection window (months) and non-invasive collection. Segmental analysis of multiple hair strands for drugs and metabolites has been widely reported in the literature over the past three decades, whereas a review of the literature showed that there are only 26 articles that report the analysis of a single hair. They focus on two approaches: mass spectrometry imaging techniques, which improve the resolution of dating an intoxication or conventional methods, such as gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (LC-MS/MS). Improved sensitivity of LC-MS/MS techniques allows the evaluation of drug content in segments of a single hair. However, the units used to express the results vary, and depend on the authors. Following a review of the literature, we present a case that illustrates drug analyses both in a strand of hair and a single hair. In this case of exposure of a child to zuclopenthixol (ZPT), the analysis of ZPT in a single segmented hair by LC-MS/MS strengthened the presumption of a single administration.

Frontal D2/3 Receptor Availability in Schizophrenia Patients Before and After Their First Antipsychotic Treatment: Relation to Cognitive Functions and Psychopathology.

BACKGROUND: We have previously reported associations between frontal D2/3 receptor binding potential positive symptoms and cognitive deficits in antipsychotic-naïve schizophrenia patients. Here, we examined the effect of dopamine D2/3 receptor blockade on cognition. Additionally, we explored the relation between frontal D2/3 receptor availability and treatment effect on positive symptoms. METHODS: Twenty-five antipsychotic-naïve first-episode schizophrenia patients were examined with the Positive and Negative Syndrome Scale, tested with the cognitive test battery Cambridge Neuropsychological Test Automated Battery, scanned with single-photon emission computerized tomography using the dopamine D2/3 receptor ligand [(123)I]epidepride, and scanned with MRI. After 3 months of treatment with either risperidone (n=13) or zuclopenthixol (n=9), 22 patients were reexamined. RESULTS: Blockade of extrastriatal dopamine D2/3 receptors was correlated with decreased attentional focus (r = -0.615, P=.003) and planning time (r = -0.436, P=.048). Moreover, baseline frontal dopamine D2/3 binding potential and positive symptom reduction correlated positively (D2/3 receptor binding potential left frontal cortex rho = 0.56, P=.003; D2/3 receptor binding potential right frontal cortex rho = 0.48, P=.016). CONCLUSIONS: Our data support the hypothesis of a negative influence of D2/3 receptor blockade on specific cognitive functions in schizophrenia. This is highly clinically relevant given the well-established association between severity of cognitive disturbances and a poor functional outcome in schizophrenia. Additionally, the findings support associations between frontal D2/3 receptor binding potential at baseline and the effect of antipsychotic treatment on positive symptoms.

Network-assisted investigation of antipsychotic drugs and their targets.

Antipsychotic drugs are tranquilizing psychiatric medications primarily used in the treatment of schizophrenia and similar severe mental disorders. So far, most of these drugs have been discovered without knowing much on the molecular mechanisms of their actions. The available large amount of pharmacogenetics, pharmacometabolomics, and pharmacoproteomics data for many drugs makes it possible to systematically explore the molecular mechanisms underlying drug actions. In this study, we applied a unique network-based approach to investigate antipsychotic drugs and their targets. We first retrieved 43 antipsychotic drugs, 42 unique target genes, and 46 adverse drug interactions from the DrugBank database and then generated a drug-gene network and a drug-drug interaction network. Through drug-gene network analysis, we found that seven atypical antipsychotic drugs tended to form two clusters that could be defined by drugs with different target receptor profiles. In the drug-drug interaction network, we found that three drugs (zuclopenthixol, ziprasidone, and thiothixene) tended to have more adverse drug interactions than others, while clozapine had fewer adverse drug interactions. This investigation indicated that these antipsychotics might have different molecular mechanisms underlying the drug actions. This pilot network-assisted investigation of antipsychotics demonstrates that network-based analysis is useful for uncovering the molecular actions of antipsychotics.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

OBJECTIVE: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. METHOD: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. RESULTS: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. CONCLUSION: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Fluctuation of serum zuclopenthixol concentrations in patients treated with zuclopenthixol decanoate in viscoleo.

Zuclopenthixol serum concentrations were measured in 58 psychiatric patients referred for routine therapeutic drug monitoring (TDM). Patients were treated for prolonged time with zuclopenthixol decanoate in viscoleo in doses of 50-500 mg, administered intramuscularly at 14-day intervals. The serum concentration was determined at days 7 (C7) and 14 (C14) following injection. The mean ratio C7/C14 was 2.0 and was independent of the dosage given. In 14 patients, additional blood samples were drawn at day 3 (C3) following injection. The mean ratio C3/C14 of this group was 3.2. An almost log-linear decline of the serum concentration from day 3 to 14 appeared, which corresponds to an apparent half-life of zuclopenthixol in this dosage form of 7.4 days. The marked fluctuations of serum concentrations of zuclopenthixol from peak to trough levels in patients given fortnightly injections of the depot preparation indicate that shorter intervals between injections should be considered in many cases in order to diminish side effects.

[Clinical pharmacokinetics of haloperidol decanoate. Comparison with other prolonged-action neuroleptics]. / Pharmacocinétique clinique du décanoate d'halopéridol. Comparison avec celles des autres neuroleptiques d'action prolongée.

Precise pharmacokinetic data of long-acting neuroleptics: apparent half life (T 1/2), time of peak plasma concentration (Tmax), bioavailability, has been a major contribution to determine optimal dosage of the drug. If the aim of the depot neuroleptic is to obtain a stable plasma concentration of the neuroleptic after I.M. injection of the ester form equivalent to that following oral administration, it is logical to obtain the same pharmacological effect; this is true for haloperidol decanoate. Mean value of T 1/2 of clopenthixol decanoate and haloperidol decanoate are 19 and 21 days, respectively, they thereby justify monthly administration. Flupenthixol decanoate and fluphenazine enanthate should be injected with dosing intervals of 3 and 1 weeks, respectively in respect with their half-lives: 17 and 4 days. Fluphenazine decanoate have a half-life of 14 days, however, the longer time the treatment, the longer the apparent half-life, suggesting to reduce the dose or to enlarge the dosing interval. Optimal dose has been determined from the bioavailability of the oral formulation and the interval between two injections, it averages 15, 20 times the oral daily dose for haloperidol decanoate. A lower conversion factor is frequently used (0.5 to 5 times) for other depot-neuroleptics such as pipotiazine palmitate, fluphenazine enanthate or decanoate; these low factors are not entirely explainable by the low bioavailability of the oral forms and produces more lower plasma concentration than after oral administration.

Characteristics of D-1 dopamine receptors labelled by [3H]fluphenazine in homogenates of rat neostriatum.

The properties of the site labelled by [3H]fluphenazine in membranes prepared from the rat neostriatum were examined using radioligand binding methodology. Binding of [3H]fluphenazine was rapid, saturable and of high affinity (K4 = 0.4 nM). Drug displacement experiments demonstrated that the site labelled by [3H]fluphenazine possessed pharmacological characteristics consistent with those of a D-1 dopamine receptor.

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)

[A new injectable delayed-action neuroleptic with sedative and antipsychotic action: cis-(Z)-clopenthixol decanoate. Clinical trials]. / Un nouveau neuroleptique retard injectable à action sédative et anti-psychotique: le décanoate de cis (Z) clopenthixol. Essais cliniques.

70 psychiatric patients were treated with a depot preparation of cis (Z) clopenthixol decanoate, a new sedative and anti-psychotic neuroleptic. The mean dosage interval was two weeks, an amount of drug from 50 to 1000 mg for each I.M. injection. Significant improvements were obtained on thinking disturbance, hostile-suspiciousness and anxious-depression symptoms groups. Thus, paranoid schizophrenia seems the best indication of cis (Z) clopenthixol decanoate. Side effects (parkinsonism, weight increase) were of low intensity, and no depression was observed. This new long-acting depot neuroleptic may be used not only in hospitalized chronic schizophrenic patients, but also in outpatients as maintenance treatment: excellent results were obtained in such patients with a very low (less than 200 mg) fortnightly dosage. Advantages and indications of cis (Z) clopenthixol decanoate are discussed.

Serum concentrations of the isomers of clopenthixol and a metabolite in patients given cis(Z)-clopenthixol decanoate in viscoleo.

Cis(Z)-clopenthixol decanoate in Viscoleo (Sordinol Depot, Cisordinol Depot, Clopixol Inj.) was given intramuscularly to nine schizophrenic patients with dosage intervals of 1 or 2 weeks. Serum concentrations of the two geometric isomers of clopenthixol and its N-dealkyl metabolite were recorded in two successive dosage intervals. Significant correlations were found for dose vs area under the serum concentration curve and vs serum concentrations measured on individual days. The last mentioned concentrations are good measures of the area under the serum concentration curve, which expresses the drug load of the patient. The serum concentration curves in two successive dosage intervals were very similar. Maximum serum concentration was seen 5-7 days after injection and the mean maximum/minimum fluctuation was 1.6 with the 2-week dosage interval. The finding of very low amounts of the trans(E)-isomers of clopenthixol and the N-dealkyl-metabolite shows that isomerization of the cis(Z)-compounds into the corresponding trans(E)-isomers does not take place within the organism.

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.

A specific method for assay of drug levels in serum of patients treated with clopenthixol decanoate injections.

A fluorimetric method is presented for the simultaneous and specific assay in serum of clopenthixol decanoate, clopenthixol and a clopenthixol metabolite, deprived of the ethanol group in the side chain. The separation is achieved by extractions and thin layer chromatography and fluorescence brought about by treatment with sulphuric acid. The limit of detection in 3 ml serum samples is about 2 ng/ml for clopenthixol and mtabolite, and somewhat higher for the ester. In addition serum data are presented for patients treated with intramuscular injections of 100-600 mg clopenthixol decanoate in Viscoleo every second week. Relatively stable (mean max./min. ratio about 2; maximum after 3-7 days) clopenthixol levels were recorded through-out the dosage interval. Somewhat lower metabolite levels were found. There was no evidence for the presence of clopenthixol decanoate.

Pharmacokinetic studies on clopenthixol decanoate; a comparison with clopenthixol in dogs and rats.

The release from the depot, hydrolysis and distribution in the organsim as well as the metabolism and elimination of intramuscularly injected clopenthixol decanoate in Viscoleo have been studied in dogs and rats with radioactive as well as non-labelled drug after single as well as repeated administration. The studies clearly demonstrate the depot effect of clopenthixol decanoate given intramuscularly in oil compared to orally administered clopenthixol. The amounts of drug remaining at the site of injection in dogs suggest monoexponential release of drug from the depot and a half-life of 4-5 days. Rapid hydrolysis to clopenthixol in the organism was indicated by in vitro experiments and in vivo findings. Clopenthixol was found to be the main compound in the organism after single as well as repeated doses. The clopenthixol formed by hydrolysis appeared to be metabolized in the same way as clopenthixol given orally i.e. by dealkylation of the side chain and by S-oxide and N-oxide formation. The elimination pattern with predominant fecal excretion also appeared to be the same after clopenthixol and its esterified derivative apart from the reflection in the latter case of the slow release from depot. A rapid exchange in the organism between tritium from the drugs and hydrogen from the body water was demonstrated. This has to be considered in studies with tritium labelled drugs, where estimation of total radioactivity gives the sum of tritium in drug, metabolites and water.