Lupus Cerebritis Refractory to Guideline-Directed Therapy: A Case Report.

Systemic lupus erythematosus is an autoimmune disease that affects multiple organs and organ systems, subsequently requiring an elaborate regimen for management. We present the case of a 63-year-old female who developed unrelenting symptoms of drug-induced lupus, which persisted even after the offending agent was withdrawn, unmasking her underlying systemic lupus erythematosus. She continued to develop neuropsychiatric symptoms, including mania and hallucinations, which complicated the management of her disease. After exhausting the bank of anti-inflammatory and immunomodulators recommended by current guidelines, we found that a combination of rituximab infusions with thiothixene, an antipsychotic agent, significantly improved our patient's neuropsychiatric symptoms. Further research should be conducted to determine the efficacy of rituximab in the treatment of resistant lupus cerebritis, and to validate the use of thiothixene in the management of neuropsychiatric symptoms secondary to lupus.

Density functional theory study of structural and electronic properties of trans and cis structures of thiothixene as a nano-drug.

The geometrical structure, electronic and optical properties, electronic absorption spectra, vibrational frequencies, natural charge distribution, MEP analysis and thermodynamic properties of the trans and cis structures of the drug thiothixene were investigated using density functional theory (DFT) and time-dependent DFT (TDDFT) methods with the B3LYP hybrid functional and 6-311 + G(d,p) basis set. The results of the calculations demonstrate that the cis structure of thiothixene has appropriate quantum properties that can act as an active medicine. The relative energies of trans and cis structures of thiothixene shows that the cis structure is more stable than the trans structure, with a small energy difference. TDDFT calculations show that the cis structure of thiothixene has the best absorption properties. The calculated NLO properties show that the NLO properties of the cis structure of thiothixene are higher than the trans structure, and the fact that the chemical hardness of the cis structure is lower than that of the trans structure that indicates that the reactivity and charge transfer of the cis isomer of thiothixene is higher than that of trans thiothixene. The molecular electrostatic potential (MEP) maps of both structures of thiothixene demonstrate that the oxygen atoms of the molecule are appropriate areas for electrophilic reactions. The vibrational frequencies of the two conformations of thiothixene demonstrate that both structures of thiothixene have almost similar modes of vibrations. The calculated thermodynamic parameters show that these quantities increase with enhancing temperature due to the enhancement of molecular vibrational intensities with temperature. Graphical abstract Trans/Cis isomerization of thiothixene drug.

Quantitation of Haloperidol, Fluphenazine, Perphenazine, and Thiothixene in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Haloperidol, fluphenazine, perphenazine, and thiothixene are "typical" antipsychotic drugs that are used in the treatment of schizophrenia and other psychiatric disorders. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with deuterated analog of imipramine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.

Thiothixene in the Management of Delirium: A Case Series.

BACKGROUND: Pharmacologic strategies are often required to help manage agitated patients with delirium. First-and second-generation antipsychotic medications (such as haloperidol, quetiapine, and olanzapine) are commonly used. OBJECTIVE: On the psychiatric consultation service in our hospital, thiothixene has been used based on its favorable potency, sedative, and cost profiles. Little has been written about the utility of this drug for management of delirium. METHODS: We reviewed our experience with thiothixene in this setting using pharmacy records to identify patients who received at least 1 dose between July 2011 and March 2014. We scrutinized the relevant medical records (n = 111) and recorded the following data: age, sex, medical diagnoses, signs and symptoms of delirium, dosing of thiothixene, and response to thiothixene in terms of both apparent benefit as well as side effects. RESULTS: Resolution or improvement was documented in 78% of patients and good tolerability in 82% of patients. CONCLUSIONS: Although further data from a randomized, controlled trial would be ideal, our experience suggests that thiothixene could be a safe and effective pharmacologic treatment for agitation and psychosis due to delirium.

Injectable long-term control-released in situ gels of hydrochloric thiothixene for the treatment of schizophrenia: preparation, in vitro and in vivo evaluation.

Hydrochloric thiothixene (HT) is an antipsychotic drug used in the treatment of various psychoses including schizophrenia, mania, polar disorder, and in behavior disturbances. However, because the psychotics often could not control their behaviors, the independent administration of antipsychotic drug based on medical order was difficult. The omissions of the administration often brought an unsatisfactory therapeutic efficacy. A novel injectable long-term control-released in situ gel of HT for the treatment of schizophrenia was developed based on biodegradable material polylactic acid (PLA). The optimum formulation of the injectable PLA-based HT in situ gel containing 15% (w/w) HT and 45% (w/w) PLA with benzyl benzoate was used as a gelling solvent. The results of the in vitro and in vivo studies showed that this in situ gel had a long-term period of drug release for several weeks and a good histocompatibility without any remarkable inflammatory reactions.

Simultaneous UPLC-MS/MS assay for the detection of the traditional antipsychotics haloperidol, fluphenazine, perphenazine, and thiothixene in serum and plasma.

BACKGROUND: Most antipsychotic drugs that are commonly prescribed in the USA are monitored by liquid and gas chromatographic methods. Method performance has been improved using ultra high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A rapid and simple procedure for monitoring haloperidol, thiothixene, fluphenazine, and perphenazine is described here. METHOD: Antipsychotic drug concentrations in serum and plasma were determined by LCMS/MS (Waters Acquity UPLC TQD). The instrument is operated with an ESI interface, in multiple reaction monitoring (MRM), and positive ion mode. The resolution of both quadrupoles was maintained at unit mass with a peak width at half height of 0.7amu. Data analysis was performed using the Waters Quanlynx software. Serum or plasma samples were thawed at room temperature and a 100µL aliquot was placed in a tube. Then 300µL of precipitating reagent (acetonitrile-methanol [50:50, volume: volume]) containing the internal standard (0.12ng/µL Imipramine-D3) was added to each tube. The samples were vortexed and centrifuged. The supernatant was transferred to an autosampler vial and 8µL was injected into the UPLC-MS/MS. Utilizing a Waters Acquity UPLC HSS T3 1.8µm, 2.1×50mm column at 25ºC, the analytes were separated using a timed, linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into the LC-MS/MS to detect imipramine D3 at transition 284.25>89.10, haloperidol at 376.18>165.06, thiothixene at 444.27>139.24, fluphenazine at 438.27>171.11, and perphenazine at 404.19>143.07. Secondary transitions for each analyte are also monitored for imipramine D3 at 284.25>193.10, haloperidol at 376.18>122.97, thiothixene at 444.27>97.93, fluphenazine at 438.27>143.08, and perphenazine at 404.19>171.11. The run-time is 1.8min per injection with baseline resolved chromatographic separation. RESULTS: The analytical measurement range was 0.2 to 12.0ng/mL for fluphenazine and perphenazine, and was 1 to 60.0ng/mL for haloperidol and thiothixene. Intra-assay and inter-assay imprecisions (CV) were less than 15% at two concentrations for each analyte. CONCLUSIONS: By utilizing a LC-MS/MS method we combined two previously established analytical assays into one, yielding a 75% time-savings on set-up, and a significantly shortened analytical run-time. These changes reduced the turn-around time for analysis and eliminated interference issues resulting in fewer injections and increased column lifetime.

Full circle-old drugs prove more beneficial than newer agents for schizophrenia: a case report.

A 55-year-old female with a diagnosis of schizophrenia currently resides in an assisted living facility in a large metropolitan suburb. For approximately 25 years, the patient was relegated to a life of poor symptom control and social adjustment, largely due to nonadherence, relapse, and rehospitalization. The patient experienced a trial-and-error approach to drug therapy, which resulted in reliance on the older or first generation agents for symptom improvement. This case supports the assertion that the second-generation or atypical antipsychotics used to treat schizophrenia are no better than older drugs in terms of efficacy or tolerability.

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.

Effect of drug type on the degradation rate of PLGA matrices.

We compare the rate of drug release through the degradation of 50:50 polylactic-co-glycolic acid polymer pellets, for six different drugs: Thiothixene, Haloperidol, Hydrochlorothiozide, Corticosterone, Ibuprofen, and Aspirin. Despite using the same polymer matrix and drug loading (20% by weight), we find that the rate of polymer degradation and the drug release profile differ significantly between the drugs. We conclude that the design of biodegradable polymeric drug carriers with high drug loadings must account for the effect of the drug on the polymer degradation and drug release rate.

Submissive behavior in mice as a test for antidepressant drug activity.

Previously, with the administration of antidepressant drugs, it has been demonstrated that the rat model of clinical depression, known as the reduction of submissive behavior model (RSBM), has considerable validity. The present study is an attempt to extend the model to mice. Several antidepressant drugs as well as a number of non-antidepressant agents were administered to mice that had been identified as submissive in a behavioral testing situation. Imipramine, desipramine, amoxapine and fluoxetine, representing three different classes of antidepressant drugs, were each able to increase competitive behavior in submissive mice and to decrease the dominance level between dominant and submissive mice in the behavioral tests. The stimulant amphetamine also reduced submissive behavior while yohimbine (also a stimulant), and the antianxiety agent diazepam had no such effect. The neuroleptic drug thiothixen had antidepressant-like effect on submissive C57BL/6J mice behavior. We conclude that like the rat model of depression from which it was developed, the mouse model responds to various antidepressants as predicted and thus may serve as a potential model of clinical depression.

Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone.

Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.

Flow-injection chemiluminometric determination of some thioxanthene derivatives in pharmaceutical formulations and biological fluids using the [Ru(dipy)3(2+)]-Ce(IV) system.

A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids.

Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension.

OBJECTIVE: The authors sought to replicate and extend previous observations of improvement in some EEG sleep measures during the course of antipsychotic treatment in schizophrenia patients. METHOD: Fourteen medication-free patients with schizophrenia underwent 2 nights of sleep EEG monitoring before and after 3-4 weeks of treatment with clinically determined doses of haloperidol or thiothixene. RESULTS: Measures of sleep continuity improved consistently. REM latency increased, although five of 14 patients continued to exhibit short REM latencies (less than 60 minutes). Stage 3 sleep increased during neuroleptic treatment, while stage 4 sleep did not change. CONCLUSIONS: These data demonstrate partial improvement of some but not all EEG sleep measures in schizophrenic patients through the course of neuroleptic treatment. They suggest that shortened REM latency and disturbed sleep continuity might represent reversible state abnormalities, while reduced slow-wave sleep may represent a more persistent trait abnormality in schizophrenia.

The effect of paroxetine on thiothixene pharmacokinetics.

OBJECTIVE: In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. METHOD: Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 ml blood samples were collected over the next 72 h. RESULTS: None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. DISCUSSION: It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.

The effect of antipsychotic medication on relative cerebral blood perfusion in schizophrenia: assessment with technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography.

Functional neuroimaging studies in schizophrenia have often been confounded by various factors including medication status. To explore the effects of antipsychotic medications on relative regional cerebral perfusion, we scanned a group of 33 persons with schizophrenia twice, while receiving a stable dose of antipsychotic and after being off antipsychotics for 3 weeks, using technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography (Tc-99m HMPAO-SPECT. We found that antipsychotic significantly increased the mean relative cerebral perfusion in the left basal ganglia. Additionally, patients receiving thiothixene (n = 9) had a significantly greater increase in relative cerebral perfusion in the basal ganglia than patients receiving haloperidol (n = 12). These findings indicate that antipsychotics lead to regional increases in cerebral perfusion and that antipsychotic status must be controlled for in functional neuroimaging studies. Functional neuroimaging techniques such as SPECT may be useful in furthering our understanding of the mechanism of antipsychotics.

Phototoxic properties of neuroleptic drugs.

BACKGROUND: Photo-induced eruptions are well-known adverse effects of some neuroleptic drugs, particularly chlorpromazine. OBJECTIVE: By a photohemolysis test we assessed in vitro the phototoxic properties of 12 phenothiazines (chlorpromazine, dixyrazine, fluphenazine, levomepromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, thioridazine, trifluoperazine, triflupromazine) and 5 thioxanthenes (chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol). METHODS: Human erythrocytes from 3 donors were incubated with the compounds and irradiated with light sources rich in UVA or UVB, respectively. Doses were up to 100 J/cm2 UVA or up to 1,600 mJ/cm2 UVB. Photo-induced hemolysis was calculated as percentage of complete hemolysis. RESULTS: Photo-induced hemolysis >10% due to radiation rich in UVA was found with chlorpromazine (maximal median: 98%), dixyrazine (100%), fluphenazine (84%), perazine (100%), perphenazine (100%), promazine (16%), promethazine (25%), prothipendyl (96%), trifluoperazine (100%), triflupromazine (76%), chlorprothixene (100%) and thiothixene (31%). UVB-rich radiation induced hemolysis only with chlorpromazine (73%), dixyrazine (45%) and perazine (60%). CONCLUSION: Most neuroleptics are strongly phototoxic in vitro indicating a potential risk for photo-induced reactions also to occur in patients treated with these drugs.

Tardive tourettism after exposure to neuroleptic therapy.

A case of neuroleptic-induced adult-onset tardive tourettism is presented with video documentation. After prolonged neuroleptic therapy, the patient developed motor and vocal tics at 36 years of age. The tics were identical to those seen in childhood-onset Tourette's syndrome. These cases are rare and have been considered by some to represent tardive akathisia. Previous reports of tourettism after neuroleptic therapy are reviewed.