Safety monitoring of treatment in bipolar disorder in a tertiary care setting in Sri Lanka and recommendations for improved monitoring in resource limited settings.

BACKGROUND: Safety monitoring of medicines is essential during therapy for bipolar disorder (BD). We determined the extent of safety monitoring performed according to the International Society for Bipolar Disorders (ISBD) guidelines in patients with BD attending the main tertiary care psychiatry clinics in Sri Lanka to give realistic recommendations for safety monitoring in resource limited settings. METHODS: Patients diagnosed with BD on mood stabilizer medications for more than 1 year were recruited. Data were collected retrospectively from clinic and patient held records and compared with the standards of care recommended by ISBD guidelines for safety monitoring of medicines. RESULTS: Out of 256 patients diagnosed with BD, 164 (64.1%) were on lithium. Only 75 (45.7%) had serum lithium measurements done in the past 6 months and 96 (58.5%) had concentrations recorded at least once in the past year. Blood urea or creatinine was measured in the last 6 months only in 30 (18.3%). Serum electrolytes and thyroid-stimulating hormone (TSH) concentrations were measured in the last year only in 34 (20.7%) and 30 (18.3%) respectively. Calcium concentrations were not recorded in any patient. None of the patients on sodium valproate (n = 119) or carbamazepine (n = 6) had blood levels recorded to establish therapeutic concentrations. Atypical antipsychotics were prescribed for 151 (59%), but only 13 (8.6%) had lipid profiles and only 31 (20.5%) had blood glucose concentration measured annually. Comorbidities experienced by patients influenced monitoring more than the medicines used. Patients with diabetes, hypothyroidism and hypercholesterolemia were more likely to get monitored for fasting blood glucose and (p < 0.001), TSH (p < 0.001) and lipid profiles (p < 0.001). Lithium therapy was associated with TSH monitoring (p < 0.05). Therapy with atypical antipsychotics was not associated with fasting blood glucose or lipid profile monitoring (p > 0.05). A limitation of the study is that although some tests were performed, the results may not have been recorded. CONCLUSIONS: Safety monitoring in BD was suboptimal compared to the ISBD guidelines. ISBD standards are difficult to achieve in resource limited settings due to a multitude of reasons. Realistic monitoring benchmarks and recommendations are proposed for methods to improve monitoring in resource limited settings based on our experience.

Assessment of Concentrations of Four Phenothiazine Antipsychotics in Serum and Whole Blood Using Different Diatomaceous Earth-based Solid-phase Columns: A Comparative Analysis.

This study attempted to determine the phenothiazine antipsychotics concentration in serum and whole blood samples using various diatomaceous earth-based solid-phase columns and elution solvents and subsequently evaluate their efficiency. Phenothiazine antipsychotics concentrations of 5 - 2000 ng/mL were extracted from serum and whole blood using each column. All compounds were analyzed using liquid chromatography-tandem mass spectrometry. Phenothiazine antipsychotics extraction in serum and whole blood using diatomaceous earth-based solid-phase columns seemed to have an affinity with the elution solvent.

Potential Benefits to Patients and Payers From Increased Measurement of Antipsychotic Plasma Levels in the Management of Schizophrenia.

Approximately 40% of patients with schizophrenia either do not respond to the prescribed antipsychotic drug or cannot tolerate it because of side effects, resulting in poor disease control and negative health and economic outcomes. Identifying the root cause of such complicated courses of treatment is a critical step in the treatment of these patients. Although measurement of antipsychotic plasma levels can be used to discern potential root causes, this tool is not routinely used in the United States. The authors of this column discuss the potential effects on patient outcomes and on the value of care from greater use of this diagnostic tool, especially under emerging payment models and delivery system reform efforts.

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia.

OBJECTIVE: Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non-adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment-resistant by their treating clinician. METHOD: Between January 2012 and April 2017, antipsychotic plasma levels were measured in 99 individuals provisionally diagnosed with treatment-resistant schizophrenia by their treating clinicians, but not prescribed clozapine. Patients were followed up to determine whether they were subsequently admitted to hospital. RESULTS: Thirty-five per cent of plasma levels were subtherapeutic, and of these, 34% were undetectable. Black ethnicity (P = 0.006) and lower dose (P < 0.001) were significantly associated with subtherapeutic/undetectable plasma levels. Individuals with subtherapeutic/undetectable levels were significantly more likely to be admitted to hospital (P = 0.02). CONCLUSION: A significant proportion of patients considered treatment-resistant have subtherapeutic antipsychotic plasma levels, and this is associated with subsequent admission. The presence of subtherapeutic plasma levels may suggest a need to address adherence or pharmacokinetic factors as opposed to commencing clozapine treatment. While antipsychotic levels are not recommended for the routine adjustment of dosing, they may assist with the assessment of potential treatment resistance in schizophrenia.

Accuracy of Clinician Assessments of Medication Status in the Emergency Setting: A Comparison of Clinician Assessment of Antipsychotic Usage and Plasma Level Determination.

PURPOSE: The present study aimed to assess the level of agreement between clinicians' routine assessments of medication status and plasma levels of commonly prescribed antipsychotic medications in patients presenting to an emergency room with an exacerbation of psychosis. METHODS: We studied 105 patients presenting to an emergency room and admitted to an inpatient psychiatric unit with a diagnosis of schizophrenia, schizoaffective disorder, bipolar I disorder, or psychotic disorder not otherwise specified and a prior outpatient medication regimen including risperidone, olanzapine, quetiapine, aripiprazole, or paliperidone. Plasma levels of antipsychotics were drawn and sent to a specialty laboratory for testing. FINDINGS: Of the 97 patients with usable samples, 33 (34%) were found to have therapeutic antipsychotic levels. Of these, 22 were judged by emergency room staff to be taking their medications at the appropriately prescribed doses, whereas 11 were judged not to be taking medication at all. Sixty-four patients were found to have subtherapeutic antipsychotic levels, 31 of whom had been assessed to be taking medication as prescribed. Emergency assessment of medication status predicted therapeutic and nontherapeutic antipsychotic levels at rates of 41.5% and 75%, respectively. Emergency staff assessment was statistically independent from the likelihood of having a therapeutic antipsychotic level. IMPLICATIONS: In patients presenting to emergency rooms with exacerbations of psychosis who are subsequently admitted to an inpatient facility, common assessments of medication status are frequently misleading. Readily available methods for rapidly measuring antipsychotic plasma levels in clinical settings are needed for clinicians to make reliable assessments.

Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats.

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

Worldwide Differences in Regulations of Clozapine Use.

Clozapine remains the drug of choice for treatment-resistant schizophrenia. As a consequence of its long history and complex pharmacology, we suspected wide variation in the regulations of clozapine use across different countries. The summaries of product characteristics (SPCs) from clozapine manufacturers, as well as local and national guidelines in the following selected countries, were reviewed: China, Denmark, Ireland, Japan, The Netherlands, New Zealand, Romania, the UK and the US. Clozapine is available as tablets in all countries, as an oral suspension in all included countries, with the exception of Japan and Romania, as orally disintegrating tablets in the US and China, and as an injectable in The Netherlands. General practitioner prescribing is only available in The Netherlands, New Zealand, the UK and the US, although with some restrictions in some of the countries. In Ireland and China, clozapine is only dispensed through hospital pharmacies. Hematological monitoring is mandatory in all countries but varies substantially in frequency, e.g. in Denmark hematologic monitoring is mandatory weekly for 18 weeks, followed by monthly monitoring, compared with Japan where blood work is required weekly for 26 weeks, followed by biweekly hematologic monitoring thereafter. In most included countries, with the exception of Denmark, Romania and The Netherlands, the manufacturer provides a mandatory hematological monitoring database, and dispensing of clozapine is not permissible without acceptable white blood count and absolute neutrophil count results. Local guidelines in New Zealand recommend echocardiography and routine troponin during the initial phases of treatment with clozapine. Regulations of clozapine vary widely with regard to rules of prescribing and monitoring. A worldwide update and harmonization of these regulations is recommended.

How appropriate is therapeutic drug monitoring for lithium? Data from the Belgian external quality assessment scheme.

BACKGROUND: Lithium remains a mainstay in the management of mood disorders. As with many psychotropic drugs, lithium treatment requires continuous observation for adverse effects and strict monitoring of serum concentrations. The present study aimed to assess the appropriateness of lithium assays used by Belgian laboratories, and to evaluate acceptability of their clinical interpretations. METHODS: Nine in-house serum samples spiked with predetermined concentrations of lithium were distributed to 114 participants in the Belgian external quality assessment scheme. Laboratories were requested to report the assay technique, lithium measurements and interpretations with regard to measured concentrations. Inter/intramethod imprecision and bias were reported and acceptability of clinical interpretations was assessed. The intramethod variability was evaluated by selecting methods used by 6 laboratories or more. Flame photometry (IL 943) was considered as the reference method. RESULTS: Laboratories returned assay results using colorimetry (69.3%), ion selective electrode (15.8%), flame photometry (8.8%), atomic absorption spectroscopy (5.2%) or mass spectrometry (0.9%). Lithium concentrations were systematically higher when measured with the Vitros assay (median bias: 4.0%), and were associated with consecutive biased interpretations. In contrast, the Thermo Scientific Infinity assay showed a significant negative bias (median bias: 9.4%). 36.0% of laboratories reported numerical values below their manufacturer cut-off for the blank sample; 16.6% of these laboratories detected residual lithium concentrations. CONCLUSIONS: The present study revealed assay-related differences in lithium measurements and their interpretations. Overall, there appeared to be a need to continue EQA of therapeutic drug monitoring for lithium in Belgium.

Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment.

The aim of this study was to evaluate whether genetic polymorphisms in CYP3A5 and ABCB1 are responsible for the interindividual variability observed in quetiapine pharmacokinetics. Pharmacokinetic data from a randomized crossover study evaluating 2 quetiapine 25 mg immediate-release tablets after single oral dose were used to develop a population pharmacokinetic model. The single nucleotide polymorphisms (SNPs) evaluated for the genotype effects of quetiapine pharmacokinetics were CYP3A5 A6986G and ABCB1 C3435T, along with other demographic variables and formulations. A one-compartment distribution model with linear elimination plus four transit compartments for the delayed absorption adequately described quetiapine disposition. CYP3A5 *1/*1 individuals (n = 3) had 29% increased clearance compared to *1/*3 and *3/*3 individuals. The impact of an increased clearance was evaluated by simulations. By computing the probability of target attainment (PTA) of steady-state therapeutic goal at 1-hour and 12-hour time points after 50-400 mg twice-daily regimens, the results indicated that CYP3A5 genotype has minimal impact on the PTA of the 1-hour concentrations but a significant impact on the 12-hour concentrations. The interpretation based on the simulations does not call for a genotype-based dosing scheme and is consistent with consensus guidelines for quetiapine that therapeutic drug monitoring is considered useful. Clinical Pharmacology in Drug Development.

Determination of mesoridazine by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in rats.

The object of the present study was to develop and validate an assay method of mesoridazine in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma samples from rats were prepared by simple protein precipitation and injected onto the LC-MS/MS system for quantification. Mesoridazine and chlorpromazine as an internal standard (IS) were separated by a reversed phase C18 column. A mobile phase was composed of 10mM ammonium formate in water and acetonitrile (ACN) (v/v) by a linear gradient system, increasing the percentage of ACN from 2% at 0.4min to 98% at 2.5min with 4min total run time. The ion transitions monitored in positive-ion mode [M+H](+) of multiple-reaction monitoring (MRM) were m/z 387>126 for mesoridazine and m/z 319>86 for IS. The detector response was specific and linear for mesoridazine at concentrations within the range 0.001-4µg/ml and the correlation coefficient (R(2)) was greater than 0.999 and the signal-to-noise ratios for the samples were ≥10. The intra- and inter-day precision and accuracy of the method were determined to be within the acceptance criteria for assay validation guidelines. The matrix effects were approximately 101 and 99.5% from rat plasma for mesoridazine and chlorpromazine, respectively. Mesoridazine was stable under various processing and/or handling conditions. Mesoridazine concentrations were readily measured in rat plasma samples after intravenous and oral administration. This assay method can be practically useful to the pharmacokinetic and/or toxicokinetic studies of mesoridazine.

Study on psychoeducation enhancing results of adherence in patients with schizophrenia (SPERA-S): study protocol for a randomized controlled trial.

BACKGROUND: Poor adherence to pharmacotherapy negatively affects the course and the outcome of schizophreniaspectrum psychoses, enhancing the risk of relapse. Falloon and coworkers developed a Psychoeducation Program aimed at improving communication and problem-solving abilities in patients and their families. This study set out to evaluate changes in adherence to pharmacotherapy in patients diagnosed with schizophrenia-spectrum psychoses, by comparing one group exposed to the Falloon Psychoeducation Program (FPP) with another group exposed to family supportive therapy with generic information on the disorders. METHODS: 340 patients diagnosed with schizophrenia and related disorders according to standardized criteria from 10 participating units distributed throughout the Italian National Health System (NHS), will be enrolled with 1:1 allocation by the method of blocks of randomized permutations. Patients will be reassessed at 6, 12 and 18 months after start of treatment (duration: 6 months).The primary objective is to evaluate changes in adherence to pharmacotherapy after psychoeducation. Adherence will be assessed at three-month intervals by measuring blood levels of the primary prescribed drug using high pressure liquid chromatography, and via the Medication Adherence Questionnaire and a modified version of the Adherence Interview. Secondary objectives are changes in the frequency of relapse and readmission, as the main indicator of the course of the disorder.Enrolled patients will be allocated to the FPP (yes/no) randomly, 1:1, in a procedure controlled by the coordinating unit; codes will be masked until the conclusion of the protocol (or the occurrence of a severe negative event). The raters will be blind to treatment allocation and will be tested for blinding after treatment completion. Intention-to-treat will be applied in considering the primary and secondary outcomes. Multiple imputations will be applied to integrate the missing data. The study started recruitment in February 2013; the total duration of the study is 27 months. DISCUSSION: If the psychoeducation program proves effective in improving adherence to pharmacotherapy and in reducing relapse and readmissions, its application could be proposed as a standard adjunctive psychosocial treatment within the Italian NHS. TRIAL REGISTRATION: Protocol Registration System of ClinicalTrials.gov NCT01433094; registered on 20 August 2011; first patient was randomized on 12 February 2013.

Assessment of the stability of 30 antipsychotic drugs in stored blood specimens.

The stability of 30 common antipsychotics (APs) in spiked whole blood was investigated over ten weeks in a preliminary experiment (designated "P experiment"). Pools of blank blood spiked with drugs at two different therapeutic levels were stored at four different temperatures: 20 °C, 4 °C, -20 °C, and -60 °C and extracted once weekly in duplicate, using a previously published method. A loss of >15% of the initial drug concentration was considered to indicate possible instability and the respective drugs were selected for further investigation in a final experiment (designated "F experiment"). Eight APs (chlorpromazine, chlorprothixene, fluspirilene, droperidol, olanzapine, thioridazine, triflupromazine, and ziprasidone) were incorporated into the F experiment. The same conditions were used in both experiments, however only a high therapeutic drug concentration was chosen for the F experiment and the storage time was extended to 20 weeks. All drugs of interest in the F experiment showed significant losses after 20 weeks of storage under at least one storage condition. The most notable results involved olanzapine, where losses of almost 100% in all storage temperatures were observed. Drug degradation in fluspirilene samples was significant after 20 weeks under all storage conditions. Overall, extensive degradation was seen with approximately 80% drug loss when stored at 20 °C and 4 °C with samples also seriously affected by degradation of up to 50% when stored at -20 °C and -60 °C, respectively. Ziprasidone remained stable when stored at 4 °C, -20 °C, and -60 °C over 9 weeks, however significant degradation was observed when stored at 20 °C, with a loss of almost 100% after 20 weeks of storage. The time period and temperature of storage of biological samples can have a significant influence on the stability of several APs. It is therefore important to be aware of potential changes in drug concentrations during storage when interpreting analytical results.

Sensitive quantification of clozapine and its main metabolites norclozapine and clozapine-N-oxide in serum and urine using LC-MS/MS after simple liquid-liquid extraction work-up.

An LC-MS/MS method for the determination of the atypic neuroleptic clozapine and its two main metabolites norclozapine and clozapine-N-oxide has been developed and validated for serum and urine. After addition of d4-clozapine as deuterated internal standard a fast single-step liquid-liquid extraction under alkaline conditions and with ethyl acetate as organic solvent followed. The analytes were chromatographically separated on a Synergi Polar RP column using gradient elution with 1 mM ammonium formate and methanol. Data acquisition was performed on a QTrap 2000 tandem mass spectrometer in multiple reaction monitoring mode with positive electrospray ionization. Two transitions were monitored for each analyte in order to fulfill the established identification criteria. The validation included the determination of the limits of quantification (1.0 ng/mL for all analytes in serum and 2.0 ng/mL for all analytes in urine), assessment of matrix effects (77% to 92% in serum, 21 to 78% in urine) and the determination of extraction efficiencies (52% to 85% for serum, 59% to 88% for urine) and accuracy data. Imprecision was <10%, only the quantification of norclozapine in urine yielded higher relative standard deviations (11.2% and 15.7%). Bias values were below ±10%. Dilution of samples had no impact on the correctness for clozapine and norclozapine in both matrices and for clozapine-N-oxide in serum. For quantification of clozapine-N-oxide in urine a calibration with diluted calibrators has to be used. Calibration curves were measured from the LOQ up to 2,000 ng/mL and proved to be linear over the whole range with regression coefficients higher than 0.98. The method was finally applied to several clinical serum and urine samples and a cerebro-spinal fluid sample of an intoxicated 13-month-old girl.

Assessment of monitoring for glucose and lipid dysregulation in adult Medi-Cal patients newly started on antipsychotics.

BACKGROUND: Because patients receiving antipsychotics are at increased risk for coronary heart disease, standards of care for such patients now include periodic glucose and lipid testing. The objective of this study was to examine rates of glucose and lipid monitoring among adult Medicaid patients initiated on antipsychotic therapy. METHODS: California Medicaid (Medi-Cal) claims of 6601 patients identified as "new" antipsychotic users between July 1, 2004 and June 30, 2005 were analyzed. Rates of glucose and lipid testing were compared for 6 months prior to and post-initiation of antipsychotic therapy. Odds ratios (ORs) for testing associated with first-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) use were determined while controlling for patient level factors. RESULTS: In a multivariate analysis, SGA patients were more likely than FGA patients to undergo glucose testing (OR, 1.38; 95% confidence interval [CI], 1.13 to 1.70; P < .01) and lipid testing (OR, 1.43; 95% CI, 1.14 to 1.81; P < .01), respectively. SGA patients were also more likely than FGA patients to receive both glucose and lipid testing in the 6 months following initiation of antipsychotic treatment (OR, 1.40; 95% CI, 1.11 to 1.79, P < .01). CONCLUSION: Although increases in glucose and lipid testing rates were observed among Medi-Cal patients after initiation of antipsychotic therapy, recommended monitoring does not appear to occur universally in this population. Interventions to increase monitoring of these patients are warranted.

Relative bioavailability and pharmacokinetic comparison of two 2-mg risperidone tablet formulations: A single dose, randomized-sequence, double-blind, 2-way crossover study in healthy male volunteers in Thailand.

BACKGROUND: Data regarding the pharmacokinetic properties of risperidone in the Thai population are limited. A new generic tablet formulation was recently developed, but bioequivalence research is necessary to obtain marketing authorization for it in Thailand. OBJECTIVE: The aim of this study was to evaluate and compare the pharmacokinetic properties of risperidone and its active metabolite, 9-hydroxyrisperidone (which reportedly contributes to the drug's pharmacodynamic effects), in a newly developed generic tablet formulation (test) and a branded formulation (reference) in healthy, fasting, male Thai volunteers. METHODS: A single-dose, randomized-sequence, double-blind, 2-way crossover design was used in this study. The study took place from October 21 through November 28, 2007. After a ≥10-hour overnight fast, volunteers were orally administered one 2-mg risperidone tablet, either the test formulation (Condrug International Company, Ltd.) or the reference formulation-according to the randomization schedule-followed by a 14-day washout period and administration of the alternate formulation. Blood samples were collected over a period of 96 hours. Risperidone and 9-hydroxyrisperidone plasma concentrations were simultaneously determined using a validated HPLC/ion trap mass spectrometry method. The plasma concentration-time curves of the active moiety, risperidone, and 9-hydroxyrisperidone were generated for each volunteer, from which the C(max), T(max), AUC0₋(last), AUC0₋(∞), and t(½) were determined using noncompartmental analysis. The effects of formulation, period, sequence, and subject (within sequence) on pharmacokinetic parameters were analyzed using ANOVA. According to regulatory requirements set forth by Thailand, the Association of Southeast Asian Nations, and the US Food and Drug Administration, products meet the criteria for bioequivalence if the 90% CIs of the treatment ratios for C(max) and AUC are within the range of 0.80 to 1.25. Tolerability was assessed by patient interview, monitoring vital signs (ie, resting blood pressure, heart rate, body temperature), physical examination, and laboratory tests (ie, urinalysis, hematology, blood chemistry) before and after the study. RESULTS: A total of 22 Thai male volunteers (mean [SD] age, 28.18 [8.27] years [range, 20.62-44.19 years]; weight, 62.43 [4.76] kg [range, 55.03-76.02 kg]; and body mass index, 21.76 [2.07] kg/m² [range, 18.9924.91 kg/m²]) completed the study. The mean (SD) relative bioavailabilities of test to reference formulations determined from AUC of the active moiety, risperidone, and 9-hydroxyrisperidone were 1.06 (0.18), 1.07 (0.29), and 1.04 (0.17), respectively. The ANOVA suggested no statistically significant effect of formulation, period, or sequence on the studied pharmacokinetic parameters of the active moiety, risperidone, or 9-hydroxyrisperidone. The 90% CIs for the natural logarithm-transformed ratios of C(max), AUC0₋(last), and AUC0₋(∞) were as follows: for active moiety, 0.94 to 1.03, 0.98 to 1.11, and 0.98 to 1.10, respectively; for risperidone, 0.90 to 1.10, 0.96 to 1.13, and 0.96 to 1.14, respectively; and for 9-hydroxyrisperidone, 0.91 to 1.03, 0.97 to 1.10, and 0.96 to 1.09, respectively. All met the criteria for bioequivalence. The most commonly reported adverse events (AEs) were somnolence (100.0%), orthostatic hypotension (13.6%), headache (4.5%), and syncope (2.3%). AEs were mild and disappeared within 1 day. No volunteers withdrew from the study because of AEs. CONCLUSIONS: The single-dose pharmacokinetic data in this small, all-male, selected sample of fasting, healthy volunteers met Thailand's regulatory criteria for assuming bioequivalence of the tested generic and reference 2-mg risperidone tablets. Both formulations were well tolerated.

A liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitation of aripiprazole in human plasma.

A rugged liquid chromatographic-electrospray ionization-tandem mass spectrometric (LC-ESI-MS-MS) method was developed and validated for accurate monitoring of steady-state plasma aripiprazole. Haloperidol-d(4) was chosen as the internal standard. ESI of aripiprazole and haloperidol-d(4) yielded abundant MH(+) ions, m/z 448 and 379, respectively. These ions were collision-dissociated to respective product ions of m/z 285 and 168. Ion-suppression experiments with blank plasma extracts showed substantial depressions of the product ions at retention times between 0.5 to 2 min, prohibiting development of a high-throughput LC-MS-MS method. A steep-gradient elution LC permitted a robust LC-ESI-MS-MS method with a 12-min analysis time. Aripiprazole was quantified from 0.2-mL aliquots of human plasma with acceptable precision and accuracy down to a lower limit of quantitation of 2 ng/mL. Aripiprazole was stable in plasma samples stored at room temperature for 24 h or exposed to three freeze-thaw cycles and in processed extracts stored at -20 degrees C for six days or on the autosampler at 10 degrees C for four days. The method has been successfully used for determinations of steady-state concentrations of aripiprazole in human subjects given daily oral doses of 15 mg. All measured concentrations were well within the quantitative range of 2 to 400 ng/mL.

[Endogenous intoxication parameters in the assessment of a risk for pneumonias in acute azaleptin intoxications].

In cases of acute azaleptin poisoning (AAP), the parameters of endogenous intoxication (EI) were studied in patients both with complicated pneumonias and without them. The integral EI index endogenous intoxication coefficient (Cei) was developed, which simultaneously reflects the coupling capacity of albumin of hydrophilic toxins and lipid peroxidation products: Cei (MMWP x MDA/EAC) x 1000, where MMWP is medium molecular-weight peptides; MDA is malonic dialdehyde; EAC is the effective albumin concentration. The use of Cei significantly enhances the efficiency of diagnosis of early-stage EI and provides a more objective assessment of therapy in AAP patients. EI is more severe when poisoning is concurrent with complicated pneumonias. Cei is of informative value in the assessment of a risk for pneumonias in AAP, which may be used in various emergencies accompanied by EI.

Determination of perospirone by liquid chromatography/electrospray mass spectrometry: application to a pharmacokinetic study in healthy Chinese volunteers.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT(1A) receptor agonism as well as 5-HT(2A) and D(2) receptor antagonism. A simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of perospirone hydrochloride in human plasma. N-hexane was used to extract perospirone hydrochloride and amlodipine benzenesulfonate (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a XTerra MS C(18) column (100mmx2.1mm, i.d. 3.5microm) using methanol -10mM ammonium acetate (84:16, v/v) as a mobile phase. The quantification of target compounds was obtained by using a selected ion monitoring (SIM) at m/z 427.5 [M+H](+) for perospirone hydrochloride, and at m/z 431.4 [M+Na](+) for IS (amlodipine benzenesulfonate). Perospirone and IS eluted as sharp, symmetrical peaks with retention times of 3.11+/-0.01min and 4.15+/-0.2min, respectively. Calibration curves of perospirone hydrochloride in human plasma at concentrations ranging from 0.10 to 21.1ng/mL exhibited excellent linearity (r(2)=0.9997). The mean absolute recovery of the drug from plasma was more than 85%. Intra- and inter-day relative standard deviations were less than 6.43% and 11.9% for perospirone hydrochloride at the range from 0.32 to 10.6ng/mL. Stability characteristics of the drug-containing plasma were thoroughly evaluated to establish appropriate conditions to process, store and prepare for chromatographic analysis without inducing significant chemical degradation. The following pharmacokinetic parameters were elucidated after administering a single dose of 8mg perospirone hydrochloride. The area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) was 15.48+/-4.23microg/Lh; peak plasma concentration (C(max)) was 2.79+/-0.78microg/L; time to C(max) (T(max)) was 1.79+/-0.45h; and elimination half-life (t(1/2)) 6.78+/-1.38h. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity and can be used for pharmacokinetic studies, therapeutic drug monitoring, and drug abuse screening.

Development and validation of a sensitive liquid chromatography/electrospray tandem mass spectrometry assay for the quantification of olanzapine in human plasma.

A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the quantification of olanzapine, atypical antipsychotic drug, in human plasma using loratadine as internal standard (IS). Following liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a reverse phase C18 column and analyzed by MS in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 313/256 for olanzapine and m/z 383/337 for the IS. The assay exhibited a linear dynamic range of 0.1-30 ng/mL for olanzapine in human plasma. The lower limit of quantification was 100 pg/mL with a relative standard deviation of less than 10%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The average absolute recovery of olanzapine from spiked plasma samples was 85.5+/-1.9%. A run time of 2.0 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability or bioequivalence studies.