Human scalp hair as evidence of individual dosage history of haloperidol: longer-term follow-up study

The patients reported in our previous paper were followed further, by analyzing hair samples collected monthly for 4 or 5 months, while growing hair continues to reflect the individual dosage history of haloperidol. In patients in whom the drug had been discontinued, the portion of hair that reflected the change of dose continued to move upward. In hair of patients in whom the dosage was decreased by one-half, the portion of change was also shown to move upward. These results indicate the potential usefulness of hair for assessing the individual past dosage history of haloperidol.     

Human scalp hair as evidence of individual dosage history of haloperidol: method and retrospective study

Hair samples and morning pre-dose plasma were collected from 40 patients who had received fixed daily doses of haloperidol for more than four months and whose compliance was good. After washing, 1 to 2 cm-long portions nearest to the roots of 2 to 3 strands of hair were completely dissolved in 2.5N NaOH. Haloperidol in that sample or alkalinised plasma was extracted and measured by RIA. Haloperidol concentrations in hair correlated well both with the trough concentration in plasma at steady-state (r = 0.772, n = 39) and with the daily dose (r = 0.555, n = 40). Another keratinized tissue, nail, was also collected from 20 of the 40 patients and the haloperidol level was compared with that in hair. The former was only about 4.3% of the latter and was significantly correlated only with the daily dose (r = 0.525, n = 20). Hair from 10 other patients in whom the dosage of haloperidol had been changed within a few months prior to sampling the hair was cut into 0.5 or 1 cm-long portions from the roots and the drug concentration in each portion was measured. If hairs were assumed to grow at 1 cm/month, a history of individual dosage could be deduced in 9 of the 10 patients from the distribution of drug level along the length of the hair. The results suggest that human scalp hair could serve as a useful tool for monitoring individual dosage history over several months, or in demonstrating exposure or non-exposure of a patient to a drug.     

Chlorpromazine in human scalp hair as an index of dosage history: comparison with simultaneously measured haloperidol

Summary The concentration of chlorpromazine (CPZ) in hair was measured to demonstrate its value as an index of individual dosage history and compliance. An animal study using pigmented rats was conducted to confirm the dose-dependent accumulation of CPZ in hair. The concentration of CPZ in hair, newly regrown on a denuded area of the back after the administration of CPZ for 3 weeks, was 4.6, 8.5 and 16.6 ng·mg^–1 hair after daily doses of 1.25, 2.5 and 5 mg·kg^–1·day^–1, respectively, significantly correlated with the daily dose.The concentration of CPZ in black hairs collected from 23 Japanese patients, who had been taking CPZ in fixed daily doses (30–300 mg/day), ranged from 1.6 to 27.5 ng·mg^–1, and was significantly correlated both with the daily dose and with the trough plasma concentration at steady state. Several strands of hair collected from each of 5 patients, whose doses of CPZ had been changed within several months before sampling, were cut into 1-cm pieces successively from the scalp end and the concentration of CPZ in each piece was measured. With the assumption of a hair growth rate of 1 cm per month, the individual history of CPZ doses in all patients could be deduced from the distribution of CPZ along the hair shaft. In 5 patients with grizzled hair the concentration of CPZ in white hairs was much lower (<10%) than in black hairs, suggesting that the strong affinity of CPZ for hair melanin may explain the accumulation of CPZ in black hair.The concentration of co-administered haloperidol (HP) in plasma and hair was also measured in 11 out of 23 patients. The CPZ concentration in hair was much lower than that of HP (about 0.3 to 7.8%), whether the comparison was made on the basis of daily dose or plasma concentration. This finding is discussed in relation to the affinity of the compounds for their melanin and photochemical stability.     

The measurement of haloperidol and reduced haloperidol in hair as an index of dosage history.

1. We report a method for measuring the concentrations of haloperidol (HL) and its major active metabolite, reduced haloperidol (RHL), in human scalp hair. 2. Hair samples were obtained from 59 patients who had been taking HL at fixed daily doses for more than 4 months and whose compliance was good. A morning pre-dose plasma sample was also obtained from 48 of these patients. 3. The concentrations of HL and RHL in hair (ng mg-1 hair) correlated significantly both with the daily dose (micrograms kg-1 body weight) of HL (r = 0.682, P less than 0.001 for HL and r = 0.813, P less than 0.001 for RHL, n = 59) and with the trough concentration (ng ml-1) of the corresponding compound in plasma at steady state (r = 0.558, P less than 0.001 for HL and r = 0.563, P less than 0.001 for RHL, n = 48). The correlation coefficients were slightly higher using the sum of the concentrations of both substances in hair (r = 0.829 for the correlation with daily dose and r = 0.609 for that with trough concentration). 4. Hair from other patients, in whom the dosage of HL had been changed within a few months prior to sampling, was sectioned into 1 cm-long portions successively from the roots and the concentrations of both compounds in each portion were measured. Assuming a growth rate of 1-1.5 cm/month, a history of individual dosage could be deduced in all patients from the distribution of the drug and metabolite along the single hair length.(ABSTRACT TRUNCATED AT 250 WORDS)     

Using ofloxacin as a time marker in hair analysis for monitoring the dosage history of haloperidol

Hair samples were obtained 1–5 months after ingestion of the antimicrobial ofloxacin, which had been given for 1 or 3 days at the commencement of haloperidol administration, or when its dosage was reduced. The axial distribution of ofloxacin, haloperidol and its active metabolite, reduced haloperidol, was analysed in segments from single strands of hair. Ofloxacin was detected where the content of haloperidol and reduced haloperidol along the hair shaft showed a sharp change, corresponding to the change in dose.When we matched the time scale of the dosage history to the growth rate, which was estimated using ofloxacin as the time marker, the distribution of the haloperidol and reduced haloperidol precisely coincided with the rise and fall in the dose of haloperidol.These findings demonstrate that ofloxacin can serve as a time marker when drug distribution along the hair shaft is used to obtain the drug exposure history of an individual.     

Human hair follicles and cultured hair follicle keratinocytes as indicators for individual differences in carcinogen metabolism

Benzo(a)pyrene (BP)-metabolism in freshly isolated human hair follicles, cultured hair follicle keratinocytes and cells cultured from human bronchial epithelium was analysed by high performance liquid chromatography. All three types of tissues resulted in quantitatively comparable amounts of the most important organic solvent-soluble metabolites: 9,10-dihydrodiol-BP, 7,8-dihydrodiol-BP, quinones, and phenols. Besides these metabolites two early eluting compounds were detected: one possibly is BP-3-yl-hydrogen sulfate, the other probably consists of one or more tetrols. Water-soluble metabolites were quantitatively unimportant in both types of cultured cells and appeared to be primarily glucuronide and sulfate conjugates with the monohydroxides and the 7,8-dihydrodiol of BP. This metabolic pattern is compared to that of monocytes and lymphocytes which have been used frequently in population studies and with data from other types of human epithelial cells. It is concluded that human hair follicles and cultured keratinocytes from these organs are useful for detection of individual differences in carcinogen metabolism.     

The measurement of haloperidol and reduced haloperidol in neonatal hair as an index of placental transfer of maternal haloperidol

Hair samples were collected at time of delivery from three neonates and their schizophrenic mothers, who had been taking haloperidol (HP) during the perinatal period to control worsening psychotic symptoms. Maternal hair was cut into 1-cm lengths, and concentrations of HP and its major metabolite, reduced haloperidol (RHP), were measured by high-performance liquid chromatography. Neonatal hair was cut into halves, and the concentrations of HP and RHP in each half were measured. The distribution of both HP and RHP along the maternal hair paralleled the dosage of HP when hair growth was assumed to be 1 cm per month. In the upper half of hair from each of two neonates neither HP nor RHP was detected. Only HP was detected in the lower half from one, and a small peak of HP in the chromatogram was observed in the other, though under the detection limit. In the third neonate both HP and RHP were detected from both halves of hair, but the concentration of HP was larger in the lower half than in the upper. These findings suggest the possibility of monitoring the transfer of maternal HP through placenta by measuring HP and RHP concentrations in neonatal hair.     

A case of chemical scalp burns after hair highlights: experimental evidence of oxidative injuries

Hair highlights are quite common procedures carried out in hair salons by using a mixture of a lightening powder containing persulfates with a suspension containing hydrogen peroxide: a representative case of chemical scalp burns is described as a consequence of this treatment. The aim of the paper is to demonstrate the strict relationship between the scalp damage and the commercial products used in a case of hair highlighting. The results of some chemical analyses have been reported, showing, in particular, that the chemical reactivity of the mixture changes in the time, thus strongly suggesting that the procedure for the application of the mixture is critical for the occurrence of possible accidents. The presence in the powder of chemical compounds bearing aliphatic chains as surfactants explains the appearance of dramatic symptoms after days due to a slow dissolution of the oxidant compounds in the stratum corneum of skin with no effect in reducing injury of palliative treatments. Safety suggestions and recommendations for producers and workers are also included.     

Amoxapine as an antipsychotic: comparative study versus haloperidol

It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics.The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups.The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low.     

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response,side effects,serum haloperidol,and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.     

Mercury concentrations in scalp hair as an environmental contamination index from foods in Korea

Relationships have been established between the mercury (Hg) levels in human scalp hair and environmental or dietary mercury exposures. The average value of total mercury (THg) in scalp hair of male residents in Seoul city was 1.66 +/- 1.10 ppm (+/- SD) and for methylmercury (MeHg) was 1.02 +/- 0.72 ppm (61% of total Hg). For females, THg was 1.06 +/- 0.46 ppm and MeHg was 0.51 +/- 0.27 ppm (48.8% of total Hg). The levels of Hg in scalp hair of male subjects were significantly different according to their occupations and age groups, but in females such variation was not detectable. The Hg levels in fishing village residents were significantly higher than those of Seoul residents. The concentrations of both THg and MeHg of residents in Korean fishing villages were similar to those of residents in fishing villages of other countries. Correlation between THg and MeHg contents in scalp hair was statistically highly significant.     

Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair.

Profiles of the steady-state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4-30 mg/day, three times a day) for greater than 4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high-performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax, respectively) varied widely among patients: 3.0-22.9 and 6.2-32.7 ng/mL for HL and 2.8-21.4 and 5.7-33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration-time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 +/- 0.48, mean +/- standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax, or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.     

Prediction of individual dosage requirements for lignocaine: a validation study for Bayesian forecasting in Japanese patients

The performance of the Bayesian feedback method for predicting lignocaine dosage developed by Vozeh et al. was evaluated in 53 Japanese patients, treated for either suppression or prophylaxis of ventricular arrhythmias, with respect to accuracy, precision, efficiency, and safety. The lignocaine serum concentrations at 12 h (C12) and 24 h (C24) after continuous infusion was started were predicted and compared retrospectively using the early concentration at 2-4 h (C2-4). The mean of the prediction error (PE) and the root mean-squared error (RMSE) were used as a measure of accuracy and precision. The 95% confidence interval of PE for C12 included zero, but those of PE for C24, whether C2-4 was used alone or in combination with C12, were less than zero, meaning that the prediction of C24 was significantly biased. The RMSE for C12 (13.2%) was less than that for C24 (16.2%), but the difference was not statistically significant. The fraction of measurements lying within the statistically approximate 68% prediction interval (+/- 1 SD) was used to evaluate the estimate of the SD of prediction. The fraction of measurements inside the prediction interval was significantly larger than the expected 68% for both C12 and C24 (p less than 0.05), showing that the estimate of the size of the PE is biased on the safer side. The clinical effects of lignocaine were also evaluated from the viewpoints of suppression of number of ventricular premature beats, prevention of more severe grades of arrhythmias, and toxicity. At least the appearance of toxicity, which four patients exhibited, was related to the lignocaine serum concentration (greater than 6 micrograms/ml).     

Rapid prediction of individual dosage requirements for lignocaine

The mean and standard deviation of lignocaine (lidocaine) pharmacokinetic parameters in a patient population were determined on the basis of 327 serum concentration measurements obtained in 42 patients treated for ventricular arrhythmias. The application of a Bayesian forecasting method, which uses the estimates of the population parameters and 1 or 2 serum concentration measurements as feedback information, was tested retrospectively in 17 of the 42 patients (group I, 32 levels), and prospectively in 10 additional patients (group II, 20 levels). With 1 individual feedback concentration, sampled 2 to 4 hours after the start of lignocaine infusion, serum concentrations at 12 and 24 hours could be accurately predicted. The prediction error (measured minus predicted concentration) ranged between -1.2 and +1.6 (mean -0.03) mg/L in group I, and from -0.7 to +1.5 mg/L (mean +0.13) mg/L in group II; the correlation coefficient of measured and predicted levels were 0.92 and 0.86, respectively. In contrast, a prediction of lignocaine concentrations in these patients using only population parameters without feedback was poor: range of the prediction error = -3.1 to +3.0 mg/L (mean = +0.001 mg/L, r = 0.63, groups I and II, n = 52). The results demonstrate that with the Bayesian forecasting technique, accurate assessment of individual dosage requirements can be obtained within a few hours after starting lignocaine therapy.     

Extrapyamidal side-effects with 1-day dosage of haloperidol (author's transl)]

In a double blind study, 30 in-patients (14 females, 16 males, ranging in the age from 18 to 55) suffering from an acute paranoid-hallucinatory syndrome, were treated with haloperidol for 30 days. 13 patients (3-day group) received 3 times a day 3 mg haloperidol (at 8 a.m., 12 a.m,, 5 p.m.) and 17 patients received 9 mg haloperidol only in the evening (9 p.m., 1-day group). Placebo instead of medication was given at the same time to the control group. Every 5 days the following assessments were performed: AMP 3 and 4, Webster and Simpson rating scales, handwriting tests according to Haase and psychometric tests according to Schoppe. In the 1-day dosage group the amount of anticholinergics were significantly reduced (2.4 mg biperiden/day compared to 4.6 mg/day in the 3-day group). The 1 daily application of neuroleptics is useful in treating acute psychosis. This treatment schedule has the advantages of sedation during the night, reduction of side-effects during the day, simpler and cheaper application form and induction of social activity.     

Warfarin dosage following prosthetic valve replacement: effect of smoking history

Warfarin currently is the most widely used agent in the prevention of thrombosis and embolism after prosthetic cardiac valve replacement. Since smoking has been shown to increase the requirement for medications undergoing hepatic metabolism, this study was designed to determine if a correlation exists between smoking history and warfarin daily maintenance dose (DMD) in patients undergoing cardiac valve replacement. Of 200 charts retrospectively reviewed at the New England Medical Center, 174 satisfied the criteria for inclusion in the study (normal hepatic, renal, and hematologic function, and absence of complicating medications). The study population included aortic, mitral, and combined valve replacement. Study groups consisted of 117 nonsmokers (Group A), 23 light smokers (Group B), and 34 heavy smokers (Group C). Thirty-three percent of patients required a low DMD of warfarin (less than or equal to 2.5 mg), 43 percent required a moderate DMD (greater than 2.5-7.5 mg), and 24 percent required a high DMD (greater than 7.5 mg). Each of the subgroups followed a similar pattern. In Group A, there were 31 percent low, 44 percent moderate, and 25 percent high-dose requiring patients. In Group B, there were 48 percent low, 39 percent moderate, and 13 percent high-dose requiring patients and in Group C there were 29.5 percent low, 41 percent moderate, and 29.5 percent high-dose requiring patients. Chi-square analysis did not demonstrate any statistically significant difference between smokers and nonsmokers in regard to daily maintenance warfarin dose (p = 0.5). The study population followed a normal pattern of distribution in regard to warfarin dosage. On the basis of these data we conclude that smoking history does not affect warfarin dose requirement.     

万古霉素个体化用药的方法学评价

万古霉素是目前治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的首选药物，在临床广泛应用，其治疗窗窄，不良反应严重，药动学个体差异大，因此万古霉素的个体化用药非常重要。越来越多的方法被用于万古霉素的个体化用药方案的调整，本文对目前常用的方法进行了总结和评价。