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LC-MS-MS analysis of the neuroleptics clozapine, flupentixol, haloperidol, penfluridol, thioridazine, and zuclopenthixol in hair obtained from psychiatric patients.

Hair samples of psychiatric patients were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS) for the neuroleptics clozapine, flupentixol, haloperidol, penfluridol, thioridazine, and zuclopenthixol. In the study, these neuroleptics were administered to the patients regularly for a minimum of six months. Sample preparation was performed by washing, powdering with a ball mill, extraction of drugs from hair by ultrasonication with methanol, cleanup by solid-phase extraction and subsequent LC-MS-MS analysis using multiple reaction monitoring (MRM). Calibration was performed for all drugs in the range of 0.05 to 10 ng/mg using spiked hair powder and doxepin-d3 as internal standard. Twenty to 50 mg of hair powder was used and the detection limits of LC-MS-MS were below 0.05 ng/mg for all drugs tested. Therapeutic dosage, number of subjects, hair color, and detected amounts of drugs were as follows: clozapine (150400 mg/day; n = 3, light brown, medium brown, black; 0.47-0.92 ng/mg), haloperidol (150 mg/3 weeks; n = 1, black/gray; 12.2 ng/mg), penfluridol (20-30 mg/week; n = 2, medium brown, black; 0.08 ng/mg; not detected in one case), thioridazine (100-400 mg/day; n = 4, light brown, medium brown, black; 0.33-9.91 ng/mg, not detected in one case). Besides the active drugs also the desmethyl-metabolites of clozapine and thioridazine were detected by LC-MS-MS. However, flupentixol (5 mg/day; light brown hair) and zuclopenthixol (350 mg/3 weeks; light brown hair) were not detected by these methods in one case each, although the drugs were administered regularly to these patients. The comparison of dosage and hair color in two cases with thioridazine and penfluridol suggests that other interindividual factors may have an influence on drug concentration in hair.

Antipsychotic Agents↗

[The zinc status in a selected Spanish population. A multivariate analysis].

There are no previous studies on the zinc status in the healthy, adult, Spanish population. The objective of this study was to obtain the levels of zinc in the serum and hair of this population to determine the normal nutritional status of zinc, and evaluating the influence of certain factors like age, sex, type of residence, body mass index (BMI) hair color, or recent food intake (zinc and fiber contents of the diet) on this status. Using a simple randomized sampling, 186 blood donors of both sexes with ages comprised between 18 and 65 years, were selected. The results were analyzed using uni- and multi-variate statistical techniques. The average concentration of zinc in serum was 97.22 micrograms/dl (95% CI: 95.1-99.4); the average zinc level in hair was 163.86 micrograms/g (95% CI: 157.8-169.9). The serum zinc was individually associated with the type of residence and the zinc and fiber contents of the diet. The zinc in hair was associated with sex, age, body mass index, and hair color. Using a multivariate analysis, predictive models of multiple regression were obtained for the serum zinc: y = 109.69 - 1.39 (dietary zinc) - 4.63 (sex) - 0.65 (dietary fiber), for the zinc in the serum, and y = 199.34 + 26.62 (sex) - 2.08 (BMI) - 0.47 (age) for the zinc in the hair. The serum concentration decreases as the dietary zinc and fiber decreases and women have lower levels. The zinc in hair is increased in women and is reduced with increasing age and BMI.

Adolescent↗

Recall (report) bias and reliability in the retrospective assessment of melanoma risk.

In a case-control study nested in the Nurses' Health Study cohort, the authors assessed recall bias in the ascertainment of two risk factors for melanoma: hair color and ability to tan. Participants reported on these risk factors in a 1982 questionnaire and in a subsequent case-control questionnaire or telephone interview. The test-retest reliability among controls was high for both questions (Spearman's r = 0.76). Among women diagnosed with melanoma after the first questionnaire and before the second, there was a substantial shift toward reporting a reduced ability to tan when participants were questioned after the diagnosis of melanoma (p = 0.035). No shift was noted for the hair color question (p = 0.8). The authors conclude that recall bias was observed among female nurses with cutaneous melanoma in the assessment of tanning ability, a major risk factor for melanoma.

Adult↗

Assessment of the neurologic effects of dietary deficiencies of phenylalanine and tyrosine in cats.

OBJECTIVE: To determine the neurologic effects of reduced intake of phenylalanine and tyrosine in black-haired cats. ANIMALS: 53 specific pathogen-free black domestic shorthair cats. PROCEDURE: Cats were fed purified diets containing various concentrations of phenylalanine and tyrosine for < or = 9 months. Blood samples were obtained every 2 months for evaluation of serum aromatic amino acid concentrations. Cats were monitored for changes in hair color and neurologic or behavioral abnormalities. Three cats with neurologic deficits underwent clinical and electrophysiologic investigation; muscle and nerve biopsy specimens were also obtained from these cats. RESULTS: After 6 months, neurologic and behavioral abnormalities including vocalization and abnormal posture and gait were observed in cats that had received diets containing < 16 g of total aromatic amino acid/kg of diet. Electrophysiologic data and results of microscopic examination of muscle and nerve biopsy specimens from 3 cats with neurologic signs were consistent with sensory neuropathy with primary axonal degeneration. Changes in hair color were detected in cats from all groups receiving < 16 g of phenylalanine plus tyrosine/kg of diet. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that chronic dietary restriction of phenylalanine and tyrosine in cats may result in a predominantly sensory neuropathy. In cats, the long-term nutritional requirement for phenylalanine and tyrosine appears to be greater for normal neurologic function than that required in short-term growth experiments. Official present-day recommendations for dietary phenylalanine and tyrosine in cats may be insufficient to support normal long-term neurologic function.

Amino Acids, Essential↗

Gluconate zinc in acrodermatitis enteropathica.

Two children with characteristic findings of acrodermatitis enteropathica were found to have low serum zinc levels prior to therapy. Treatment with zinc gluconate in low dosages resulted in an increase in serum zinc levels and clinical improvement. All family members studied had low serum zinc levels. In addition, we noted a change of hair color to red and excessive drooling just prior to exacerbations in these two patients. The hair color returned to normal with remission.

Acrodermatitis↗

[The life of human hair follicle revealed].

The human hair follicle is a unique appendage which results from epithelio-mesenchymal interactions initiated around the 3rd month of development. This appendage has a very complex structure, with a dermal compartment and an epithelial compartment. The dermal compartment comprises the connective tissue sheath and the dermal papilla, both of which are irrigated by microvessels. The epithelial compartment is made of highly replicating matrix cells giving rise to three concentrical domains, namely the outer root sheath, the inner root sheath and the hair shaft. The pigmentation unit, responsible for hair color, is made of fully active melanocytes located on top of the dermal papilla. Altogether a hair follicle contains more than 20 different cell types, engaged in different differentiation pathways and/or interacting with each other. This complex appendage has a unique behavior in mammals since, after a hair production phase, it involutes in place before entering a resting phase after which it renews itself under a cyclical but stochastic way, out of a double reservoir of pluripotent stem cells able to also regenerate epidermis. For yet unknown reasons, this well ordered process can be disturbed, provoking alopecia. The pigmentation unit also renews itself under a cyclical way, out of a melanocyte progenitor reservoir which progressively declines with time, provoking the hair whitening process. Finally, the shape of the hair shaft is programmed from the bulb. What makes this appendage unique and fascinating is its high degree of autonomy, its incredibly complex though stable structure, the number of different cell types interacting under an equilibrated way and its potential of regeneration. It represents a true paradigm of tissue homeostasis, exemplifying in a small living cylinder all the fundamental laws of cell-cell and tissue interactions. This life is revealed in this short synthesis.

Growth Substances↗

A new rabbit species (Sylvilagus, Mammalia: Leporidae) from the lowlands of Venezuela.

A new species of Venezuelan rabbit of the genus Sylvilagus from Fundo Millano (08 degrees 46'N and 69 degrees 56'W) and Chorrosco Bajo (08 degrees 05'N and 69 degrees 18'W), between 190 and 120 masl, state of Barinas, is described based on: 1. Body and skull measurements. 2. Coloration patterns of the pelage. 3. Arrangement and length of the color hair bands of dorsal, lateral, ventral nuchal, and gular patches. Body and cranial measurements, and some color patterns of the new species, Sylvilagus varynaensis, were compared with those of the closest relative groups such as S. brasiliensis (from Venezuela and Brazil), S. b. meridensis from the Venezuelan paramos, and three of the most representative groups of S. floridanus (S. f. continentis, S. f. orinoci, and S. f. valenciae). Most of the values recorded for these parameters were significantly higher for the new species (P < 0.005; Student "t" test). Cluster and principal components analysis of the data recorded for cranial characteristics indicated that S. varynaensis is the largest and darkest of the known Venezuelan rabbits, with a broader elongated skull and a different arrangement of the color hair bands.

Animals↗

The relationship of immediate pigment darkening to minimal erythemal dose, skin type, and eye color.

Immediate pigment darkening (IPD) was recorded in over 1,300 volunteers participating in routine sun protection factor (SPF) testing. Medical history obtained included skin type, hair color, eye color, sunburn sensitivity, tanning ability, and current medications. The presence of IPD and the energy needed to produce it were recorded immediately following exposure to a filtered 2500 W xenon are solar simulator. Minimal erythemal dose (MED) values were recorded 16-24 hours post-exposure. The average MED was lowest for skin type I and highest for skin type IV. The IPD dose was also lowest for skin type I and highest for skin type IV. However, the average IPD dose was greater than the MED for skin type I and lower than the MED for skin type IV. For skin types II and III, the average IPD dose and MED were almost equivalent. For skin type I, 64% required equivalent or greater energy to produce IPD than their MED, and 30% showed no IPD at energy levels sufficient to produce erythema, whereas all skin type IV's had a measurable IPD response. For volunteers of skin type II and III showing no measurable IPD, the predominant eye color was blue or green (74%). Sunscreen usage altered the IPD response for all 4 skin types.

Dose-Response Relationship, Radiation↗

Two approaches for assessing human safety of disperse blue 1.

Disperse Blue 1 is an anthraquinone dye used at low levels in semipermanent hair color formulations. Dietary administration of Disperse Blue 1 in a National Toxicology Program (NTP) carcinogenesis bioassay produced transitional- and squamous-cell tumors, leiomyomas, and leiomyosarcomas of the urinary bladders of male and female F344/N rats. The occurrence of tumors in the urinary bladder of rats was associated with urothelial hyperplasia and the presence of urinary calculi. Despite the occurrence of urinary bladder calculi and other nonneoplastic changes, there was no evidence of urinary bladder carcinogenesis in B6C3F1 mice fed Disperse Blue in the diet for up to 2 years. A study conducted in rats of the same strain by Burnett and Squire confirmed the occurrence of calculi and transitional-cell neoplasms in the rat bladder. However, no mesenchymal-cell tumors were detected at a comparable dietary level. Further, Burnett and Squire found evidence of reversibility of the proliferative changes in the rat urinary bladder following cessation of treatment at 6 months. Disperse Blue 1 has been tested in a variety of in vivo and in vitro genotoxicity assays and was negative in vivo but produced a weak and mixed pattern of genotoxic responses in vitro which may be attributable to a constituent of the commercial preparations. Evaluation of the available data for Disperse Blue 1 and comparison with the responses observed in the urinary bladders of rats administered other rodent bladder carcinogens considered to act through a secondary mechanism indicate that a threshold approach is appropriate for assessing risk. With this approach, an uncertainty factor of 1000 applied to the no-observed-adverse-effect level in the NTP bioassay yielded a safe exposure level of 45-56 micrograms/kg/day. In contrast, with a conventional quantitative risk assessment approach, the exposure level corresponding to an upper limit on lifetime risk of 10(-6) to 10(-5) was 0.39 to 3.9 micrograms/kg/day, respectively. The safe level of Disperse Blue 1 derived using the threshold approach is approximately 20 times greater than the maximum average daily applied dose of 2.7 micrograms/kg/day associated with its use in semipermanent hair color formulations, while the exposure associated with the 10(-5) risk level using the linearized multistage model in the conventional approach was determined to be 1.5 times greater. Because oral absorption is substantially more than dermal absorption, the actual margin of safety is most likely much greater than either of these comparisons suggests.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Human scalp hair as evidence of individual dosage history of haloperidol: a possible linkage of haloperidol excretion into hair with hair pigment.

We report a method for determining haloperidol concentration in human scalp hair and discuss a possible linkage of haloperidol excretion into hair with the hair pigment melanin. First, an animal study was conducted to support the idea that hair contains amounts of haloperidol corresponding to the doses given and pigmented hair contains much more drug than does unpigmented hair. The haloperidol concentration was measured using a radioimmunoassay technique after hairs were dissolved in 2.5 N NaOH solution and the drug extracted. Pigmented and albino rats, whose hair from an area on the back had been removed beforehand by plucking, were administered either 1, 3, or 10 mg of haloperidol (i.p.) per kg body weight every day for 3 weeks. At the end of the administration period hair which had newly grown on the denuded area was plucked and collected. In each of the two groups classified by hair color the drug levels in the hair correlated with the doses given; however, the concentrations in the hair from the albino rats were much lower than those in the hair from the pigmented rats (which was less than 8.5%). Second, black and white hair was collected from each of seven human subjects with grizzled hair, who were receiving or had been administered haloperidol at fixed daily doses for more than 1 month, and the concentration of haloperidol in each type of hair was measured. In the same subject the concentration in the white hair was found to be much lower than that in the black (less than 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Hair follicle pigmentation.

Hair shaft melanin components (eu- or/and pheomelanin) are a long-lived record of precise interactions in the hair follicle pigmentary unit, e.g., between follicular melanocytes, keratinocytes, and dermal papilla fibroblasts. Follicular melanogenesis (FM) involves sequentially the melanogenic activity of follicular melanocytes, the transfer of melanin granules into cortical and medulla keratinocytes, and the formation of pigmented hair shafts. This activity is in turn regulated by an array of enzymes, structural and regulatory proteins, transporters, and receptors and their ligands, acting on the developmental stages, cellular, and hair follicle levels. FM is stringently coupled to the anagen stage of the hair cycle, being switched-off in catagen to remain absent through telogen. At the organ level FM is precisely coupled to the life cycle of melanocytes with changes in their compartmental distribution and accelerated melanoblast/melanocyte differentiation with enhanced secretory activity. The melanocyte compartments in the upper hair follicle also provides a reservoir for the repigmentation of epidermis and, for the cyclic formation of new anagen hair bulbs. Melanin synthesis and pigment transfer to bulb keratinocytes are dependent on the availability of melanin precursors, and regulation by signal transduction pathways intrinsic to skin and hair follicle, which are both receptor dependent and independent, act through auto-, para- or intracrine mechanisms and can be modified by hormonal signals. The important regulators are MC1 receptor its and adrenocorticotropic hormone, melanocyte stimulating hormone, agouti protein ligands (in rodents), c-Kit, and the endothelin receptors with their ligands. Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color.

Animals↗

[The biology of hair follicle].

The human hair follicle is a unique appendage which results from epithelio-mesenchymal interactions initiated around the 3rd month of development. This appendage has a very complex structure, with more than 20 different cell types distributed into 6 main compartments, namely the connective tissue sheath, the dermal papilla, the outer root sheath, the inner root sheath, the shaft and the sebaceous gland. The pigmentation unit, responsible for hair color, is made of fully active melanocytes located on top of the dermal papilla. This complex appendage has a unique behavior in mammals since, after a hair production phase, it involutes in situ before entering a resting phase after which it renews in a cyclical but stochastic fashion, out of a double reservoir of pluripotent stem cells also to able regenerate epidermis. The pigmentation unit also renews in a cyclical fashion, out of a melanocyte progenitor reservoir which progressively declines with time, provoking the hair whitening process. Finally, the shape of the hair shaft is programmed from the bulb. The hair follicle thus behaves as a fully autonomous skin appendage with its own hormonal control, its own autocrine and paracrine network, its own cycle, appearing as an incredibly complex and stable structure which summarizes the main rules of tissue homeostasis.

Aging↗

The association between host susceptibility factors and uveal melanoma: a meta-analysis.

OBJECTIVE: To conduct a meta-analysis, using observational studies, to examine the association between host susceptibility factors and uveal melanoma. METHODS: A review of 132 published reports on risk factors for uveal melanoma revealed 10 case-control studies that provided enough information to calculate odds ratios (ORs) and standard errors for host susceptibility factors. Data from these studies were extracted and categorized. Summary statistics were calculated for all risk factors reported by at least 4 independent studies. RESULTS: Summary statistics using meta-analysis are presented as ORs and their 95% confidence intervals (CIs). Statistically significant risk factors include light eye color (OR, 1.75 [95% CI, 1.31-2.34]), using 10 studies (1732 cases); fair skin color (OR, 1.80 [95% CI, 1.31-2.47]), using 5 studies (586 cases); and ability to tan (OR, 1.64 [95% CI, 1.29-2.09]), using 6 studies (1021 cases). Blond or red hair color, using 7 studies (1012 cases), was not a statistically significant independent risk factor (OR, 1.02 [95% CI, 0.82-1.26]). CONCLUSION: This meta-analysis yielded strong evidence associating the host susceptibility factors of iris color, skin color, and ability to tan with uveal melanoma.

Case-Control Studies↗

Can laboratory findings on eyewitness testimony be generalized to the real world? An archival analysis of the influence of violence, weapon presence, and age on eyewitness accuracy.

The authors conducted 2 studies to assess the effects of levels of violence, the presence of a weapon, and the age of the witness on the accuracy of eyewitness testimony in real-life crime situations. Descriptions of offenders were taken from eyewitnesses' statements obtained by the police and were compared with the actual details of the same offenders obtained on arrest. The results showed that eyewitnesses tended to recall the offenders' hairstyle and hair color most accurately. None of the effects for the level of violence, the presence of a weapon, or age approached statistical significance, with the exception that, in the 1st study, accuracy in describing hair color was better when associated with high levels of violence and in cases of rape. It is argued that caution must be exercised in generalizing from laboratory studies of eyewitness testimony to actual crime situations.

Adult↗

Leukotrichia developed following application of intense pulsed light for hair removal.

BACKGROUND: Lasers and light sources are now used worldwide for permanent or prolonged hair removal. Patients now prefer lasers and light sources for hair removal because of their noninvasiveness and fewer reported side effects. OBJECTIVE: To study and report on leukotrichia that developed following application of intense pulsed light (IPL). METHODS: From February 9, 2001 to February 14, 2002 a total of 821 patients were treated for unwanted hair. The system used was a noncoherent IPL system, with a 650 nm flashlamp filter; the parameters used varied with different Fitzpatrick skin types. The patients were treated monthly, with the rate of hair loss, measured by hair counts, and possible side effects recorded. RESULTS: Twenty-nine of 821 patients treated developed leukotrichia. Thirteen patients had no white or gray hairs before IPL therapy; the remaining 16 patients, who had few white hairs before treatment reported accelerated development of new white hairs starting after the first or second IPL therapy. Restoration of hair color occurred in 9 patients and the remaining 20 patients had no improvement or worsening of the condition within the next 2-6 months. CONCLUSION: Temporary or permanent leukotrichia may develop following IPL and laser hair removal therapy. This finding may be explained by the difference in the thermal relaxation times of melanocytes and germinative cells. The light absorbed and the heat produced by melanin may be sufficient enough to destroy or impair the function of melanocytes but insufficient to damage the hair follicle cells.

Adolescent↗

Syndrome of brittle cornea, blue sclera, and joint hyperextensibility.

In 3 families 4 patients were affected with the syndrome of brittle cornea, blue sclera, and hyperextensible joints (brittle cornea syndrome). From the review of 17 affected patients described previously and our cases, it appears that this rare autosomal recessive syndrome has variable expressivity. Two different groups of patients may be distinguished: one includes 5 families, all of Tunisian Jewish origin. All patients in this group also have red hair. In the second group, 9 families are from various ethnic origins; affected patients in this group have a normal distribution of hair color. A possible explanation for the existence of these 2 different group of patients is that the locus of the gene responsible for the syndrome is closely linked to the locus for a gene responsible for hair color with linkage disequilibrium in Tunisian Jews (Sepharadim).

Corneal Diseases↗

The frequency and distribution of minocycline induced hyperpigmentation in a rheumatoid arthritis population.

OBJECTIVE: Minocycline is particularly useful in patients with rheumatoid arthritis (RA) with previous major sepsis, where anti-tumor necrosis factor is relatively contraindicated. Pigmentation is a documented side effect, but predisposing factors in an RA population have not been established. We investigated minocycline induced pigmentation in a population with RA to determine whether skin type and eye color influence predisposition to this side effect. METHODS: Patients with RA attending a rheumatology unit who had received minocycline were contacted by telephone and some were also interviewed in the clinic. Those receiving therapy for more than 3 months were assessed. Hair color, eye color, tendency to burn in the sun, and dose and duration of therapy were documented. The frequency, type, and distribution of pigmentation were established. RESULTS: Of 37 patients identified, 10 were excluded because the duration of therapy was less than 3 months. Of the remaining 27 patients, 85% were female, with median age 64 years (range 44-88) and median disease duration 23.5 years (range 4-51). Eleven patients (41%) developed pigmentation after a median of 12 months. Four of the 11 stopped their minocycline due to pigmentation. Hair color, eye color, and tendency to burn in the sun did not predict patients who developed pigmentation. CONCLUSION: Pigmentation is a common side effect in patients receiving minocycline therapy for more than 3 months. Most patients do not stop therapy due to pigmentation. Those who stop are more likely to be female, less than 70 years of age, and have facial pigmentation.

Adult↗