Onychomadesis following childhood hand-foot-mouth disease in two pairs of siblings- a familial predisposition?

Onychomadesis is presented in four patients as a result of hand-foot-mouth disease.

Dermatology referrals in an East Asian tertiary hospital: a need for inpatient medical dermatology.

BACKGROUND: Within hospitals, there is a need for dermatological expertise, as hospitalized patients have a wider spectrum of severe and serious dermatological conditions, associated with significant morbidity. AIM: To characterize the patient profile and referral pattern of inpatient dermatology consultations, and to evaluate the diagnostic accuracy of non-dermatologists. METHODS: This was a retrospective study reviewing all inpatient referrals for dermatology consultations during a 1-year period from July 2005 to June 2006 (inclusive), at the largest multi-disciplinary tertiary hospital in Singapore. RESULTS: Of the 731 referrals made for dermatology consultations, 26.9% of patients had ≥ 3 important underlying comorbidities. Eczema/dermatitis (33.1%; n = 242) and cutaneous infections (23.4%; n = 171) accounted for over half of the dermatological consultations, followed by cutaneous adverse drug reactions (12.3%; n = 90). The provisional diagnoses of the referring doctors agreed with the final diagnoses confirmed by dermatologists in only 30.2% of all referrals; incorrect diagnoses were made in 35.2% of cases, and no provisional diagnoses were made in the remaining 34.6% of cases. Most misdiagnosed skin diseases were in fact common dermatoses (such as eczemas, cutaneous infections, drug rash) that required only standard treatment. CONCLUSION: Our study reiterates the importance of inpatient medical dermatology in terms of both service and education. There should be continual efforts to ensure that dermatologists have the highest level of training and experience in medical dermatology, to provide collaborative optimum care for hospitalized patients with dermatological diseases.

Cutaneous adverse drug reactions in hospitalised patients.

INTRODUCTION: Serious adverse drug reactions are common in hospitalised patients. There have been few studies examining the clinical presentation, implicated drugs and outcomes in Singapore. METHODS: The clinical and laboratory data of all inpatient dermatology consultations with a diagnosis of cutaneous adverse drug reaction were retrospectively analysed over a one-year period. RESULTS: A total of 97 patients were diagnosed with cutaneous adverse drug reactions. Eight different clinical reaction patterns were noted, namely drug exanthems (46.4 percent), drug rash with eosinophilia and systemic symptoms (18.6 percent), Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum (14.4 percent), urticaria/angioedema (11.3 percent), acute generalised exanthematous pustulosis (3.1 percent), fixed drug eruptions (3.1 percent), generalised exfoliative dermatitis (2.1 percent) and drug-induced vasculitis (1.0 percent). The putative medications included antibiotics (50.5 percent), anticonvulsants (11.3 percent), allopurinol (8.2 percent), chemotherapeutic agents (7.2 percent), nonsteroidal anti-inflammatory agents (7.2 percent), intravenous contrasts (3.2 percent), complementary medications (2.1 percent) and various other medications (10.3 percent). 30 patients were admitted primarily for their adverse drug reaction, with an average length of hospital stay of nine days, while the remaining 67 patients developed these reactions as a complication of their inpatient stay. A total of five deaths were recorded. CONCLUSION: The presentation of cutaneous adverse drug reactions in hospitalised patients is diverse, ranging from self-limiting and benign reaction patterns to those that are life-threatening. Early recognition, accurate diagnosis, withdrawal of putative medications and specific treatments when indicated may improve outcome.

Demographical profile and clinical features of patients with bipolar disorder in an outpatient setting in Singapore.

INTRODUCTION: Bipolar disorder, or manic depressive psychosis, is a psychiatric disorder characterised by extreme changes in mood, thinking, energy and behaviour. Western studies on this condition show a delay in diagnosis and treatment. The aim of this study is to examine the demographical profile and clinical features of this group of patients in Singapore to see if there is a similar delay. METHODS: Data of patients diagnosed with this condition and treated in two separate outpatient practices in the private sector from January 1999 to October 2003 were retrieved from case files and analysed. RESULTS: Of the 121 patients with bipolar disorder treated, there were 45 percent male and 55 percent female patients, and most of them were in the 20-39 year age group. Chinese formed the largest ethnic group while Malays were underrepresented. 58 percent were employed, and 48 percent were married. While the age of onset of illness ranged mainly from age 10 to 29 years, the age when they first sought treatment was from 20 to 39 years. A duration of illness of more than two years was found in 79 percent of these patients. In terms of diagnostic categories, 17 percent were bipolar I, 76 percent were bipolar II and 7 percent of the bipolar disorders, not otherwise specified. The first episode presented was depression in 75 percent and bipolar disorder was the initial diagnosis in only 34 percent of the cases. A delay in the correct diagnosis for more than two years accounted for 34 percent of the cases. Only 17 percent had a family history of bipolar disorder. 28 percent had a history of antidepressant-induced manic episodes and 17 percent had a previous episode of mixed state. Psychotic symptoms were absent in 75 percent, and 65 percent had never been hospitalised for their condition. Nine percent had made a past suicide attempt and 39 percent had a comorbid diagnosis. 46 percent were treated with a combination of mood stabilizers, neuroleptics and antidepressants and 16 percent had electroconvulsive therapy. Only 34 percent were in full remission of their illness. CONCLUSION: There was a preponderance towards the younger age groups for the age of onset, and the type of first episode was typically depression. There was a significant delay in diagnosis and treatment of patients with bipolar disorder. These features were strikingly similar to Western studies. Bipolar II was the diagnostic category seen more than bipolar I in the outpatient setting. Polypharmacy was the norm and a large group of patients did not achieve full remission.

Simulation of the impact of atropisomer interconversion on plasma exposure of atropisomers of an endothelin receptor antagonist.

BMS-207940, a potent endothelin receptor antagonist, exists as rapidly interconverting atropisomers. The plasma interconversion t(1/2) is approximately 2.5 hours at 400 microg/mL under room temperature and decreases to < 0.1 hours at 20 microg/mL, making it extremely difficult to conduct pharmacokinetic studies of individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940 in humans were reasonably described by a one-compartmental model with an apparent terminal elimination t(1/2) of 15 hours. Given the above rates, simulations were conducted based on a one-compartmental model to explore the possible range of individual rates of atropisomer elimination and potential difference in plasma exposure to the two atropisomers. Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and between 0.046 and 0.092 h(-1), respectively. The estimation of the upper bounds for atropisomer elimination rate constants is robust and relatively insensitive to the rate of atropisomer interconversion compared to the rate of racemate elimination. Simulations of the administration of a single atropisomer or the 50/50 racemate, based on all the possible scenarios of individual atropisomer elimination, showed little difference in plasma exposure to the two atropisomers. Potential differences in plasma exposure to the two atropisomers depend, to a larger extent, on the ratio of the rate of atropisomer interconversion versus racemate elimination and, to a lesser extent, on the conformation of atropisomers administered. When atropisomer interconversion is 10-fold or more rapid than racemate elimination, the largest possible difference in plasma exposure between the two atropisomers is below 20%, regardless of the route and conformation of the atropisomer(s) administered.

Psychiatric illness, personality traits and the irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome is a common functional gastrointestinal disorder. Although its aetiology is still unknown, visceral hypersensitivity, disorders of motility and psychosocial factors have been proposed as possible factors that affect the "gut-brain" function. The objective of this study was to determine if psychiatric disorders exist in patients with irritable bowel syndrome. PATIENTS AND METHODS: During a 10-month period, 43 outpatients, after exclusion of organic bowel pathology and meeting Manning's criteria for the diagnosis of irritable bowel syndrome, were assessed using the Eysenck Personality Questionnaire. In addition, a psychiatric interview was conducted by two psychiatrists. Twenty patients with organic bowel disorders, who were age matched, were selected as patient control. RESULTS: Psychiatric diagnoses (62.5%) were present in significantly more female patients with irritable bowel syndrome than female patients with organic bowel disorders (16.7%, P < 0.05). On Eysenck Personality testing, female patients with irritable bowel syndrome scored significantly higher on neuroticism (15.25 versus 8.58) and lower on need for social desirability (14.04 versus 17.0) than the organic disease group. Male patients with irritable bowel syndrome were comparable with male patients with organic bowel disorders in terms of presence of minor psychiatric morbidity, psychiatric diagnoses and Eysenck Personality scores. CONCLUSION: There is a difference between male and female patients with irritable bowel syndrome in terms of psychopathology.

Assessment of dose proportionality, absolute bioavailability, and immunogenicity response of CTLA4Ig (BMS-188667), a novel immunosuppressive agent, following subcutaneous and intravenous administration to rats.

PURPOSE: The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. METHODS: A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. RESULTS: After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1-4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. CONCLUSIONS: The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.

A sensitive enzyme immunoassay for the quantitation of human CTLA4Ig fusion protein in mouse serum: pharmacokinetic application to optimizing cell line selection.

A sensitive, accurate, and precise enzyme immunoassay (EIA) for the quantitation of human CTLA4Ig in mouse serum was validated. The EIA method employed a technique in which a monoclonal anti-CTLA4 antibody was adsorbed onto 96-well polystyrene microtiter plates and used to capture the CTLA4Ig in mouse serum samples. The captured CTLA4Ig was then detected using a goat anti-human IgGFc antiserum conjugated to the enzyme horseradish peroxidase. The validation included assessments of method accuracy and precision, range of reliable response, lower limit of quantitation (LLQ), inter-analyst robustness, storage stability in mouse serum and assay specificity. The results indicate that this validated assay is precise, accurate, and reproducible. This EIA has a range of reliable response in 10% mouse serum of 0.14-4.58 ng ml-1 resulting in a 100% serum equivalent curve of 1.4-45.8 ng ml-1. Assessment of individual standard curve variations indicated a reproducible response with R2 values of > or = 0.995. The LLQ was established at 1.4 ng ml-1. The accuracy and precision estimates, based on the quality control values, were within 3.8% and 5.2% respectively, for CTLA4Ig. Stability of CTLA4Ig was established in mouse serum for 5 days at both 4 degrees C and room temperature, for 2 months at -70 degrees C and through five freeze-thaw cycles. This validated assay was successfully employed in the assessment of pharmacokinetic characteristics of CTLA4Ig in mice and to aid in the selection of an optimal CTLA4Ig-producing cell line.

Quantitative determination of butorphanol and its metabolites in human plasma by gas chromatography-electron capture negative-ion chemical ionization mass spectrometry.

Two separate analytical methods have been developed for the determination of butorphanol and its metabolites in human plasma. One method is specific for butorphanol (I) while the other determines the metabolites, hydroxybutorphanol (II) and norbutorphanol (III). Both procedures incorporate solid-phase extraction, chemical derivatization and separation, and detection using gas chromatography-electron-capture negative-ion chemical ionization mass spectrometry (GC-ECNCI-MS). Both methods use the cyclopropyl analog of I (BC-2605, IV) as the internal standard and the procedures for extraction of the analytes from plasma are identical. However, following extraction, either the pentafluorobenzoyl ester of I or the tris and bis-trifluoroacetyl esters of II and III, respectively, were prepared. The derivatives were analyzed by GC-ECNCI-MS with selected-ion monitoring of the molecular ions. The standard curves were linear over the concentration ranges of 20-2000, 20-1000 and 50-1000 pg/ml for I, II and III, respectively. All standard curves from the assay validation had r2 values of > or = 0.994, 0.991 and 0.985 for I, II and III, respectively. For all three compounds, the intra- and inter-assay precisions (C.V.) and inter-assay accuracy (deviation from nominal) were within 12% for plasma quality control samples. All derivatives were stable in the reconstitution solvent for at least 24 h. The assays are being used for the determination of plasma concentrations of I, II and III in humans following repeated administration of nasal spray.

A pharmacokinetic study of intravenous CTLA4Ig, a novel immunosuppressive agent, in mice.

Three skin-intact mice in each group received a single 0.07-, 0.29-, or 0.57-mg dose of CTLA4Ig intravenously (i.v.). Three skin-grafted mice received a single 0.29-mg dose i.v. and another three skin-grafted mice received a 0.29-mg dose once daily for 7 days (the dose was administered via the tail vein). Serial blood samples (0.15 mL) were obtained by retro-orbital bleeds up to 240 h after all single doses and up to 360 h after the last multiple dose. Serum samples were analyzed for CTLA4Ig by a validated enzyme immunoassay method. The concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUCinf values increased in a dose-proportional manner in skin-intact mice. The CLT values were dose independent. The MRT, t1/2, and Vdss values at the 0.07-mg dose level were significantly lower than those obtained for both the 0.29- and 0.57-mg dose levels; however, the respective values between the 0.29- and 0.57-mg dose levels were not significantly different. No significant differences were found in the pharmacokinetic parameters between the skin-intact and skin-grafted mice.

Pharmacokinetics and pharmacodynamics of CTLA4lg (BMS-188667), a novel immunosuppressive agent, in monkeys following multiple doses.

The dose proportionality and multiple dose pharmacokinetics of CTLA4Ig, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4Ig in suppressing the immunoresponses to sheep red blood cell (SRBC) was also assessed. Two monkeys per gender were randomly assigned to one of the three dose levels, 1.0, 2.9, and 8.7 mg/kg of CTLA4Ig. The monkeys in each dose level received the assigned intravenous dose of CTLA4Ig by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4Ig on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4Ig on day 18 (last dose). In addition, predose blood samples were obtained on days 1, 4, 8, 11, 15, and 18. Serum samples were analyzed for the concentrations of CTLA4Ig using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4Ig attained steady state by day 11 regardless of the dose levels. The mean AUC0-720 values of CTLA4Ig increased in a dose proportional manner. The mean values of Cmax increased in a ratio of 1:3:3:8:5 while the dose administered increased in a ratio of 1:3:9. Predose serum concentrations (Cmin) of CTLA4Ig increased in a dose proportional manner. The mean T1/2 values were not significantly different among the dose groups, suggesting that the elimination characteristics of CTLA4Ig were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4Ig (78-98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4Ig exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0-8.7 mg/kg in monkeys.

Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV.

OBJECTIVE: The validity of rapid cycling as a distinct course modifier for bipolar disorder was assessed by comparing patients with and without a history of rapid cycling (4 or more affective episodes in 12 months) on demographic, clinical, family history, and outcome variables. These data were also used to formulate operational criteria for the modifier. METHOD: Data on subjects with rapid-cycling (N = 120) and nonrapid-cycling (N = 119) bipolar disorder from four sites were pooled and analyzed by using case-control and historical cohort methods. RESULTS: The rapid-cycling group contained more women and more subjects from higher social classes than the nonrapid-cycling group. Family history did not differ between the groups. The diagnosis had predictive validity in that the rapid-cycling patients had more episodes than the nonrapid-cycling patients during prospective follow-up. The relationship between gender and episode frequency supported the validity of the cutoff point of 4-8 episodes per year. The data regarding whether patients with rapid cycling based on truncated episodes more closely resembled rapid-cycling or nonrapid-cycling patients were equivocal. Patients whose only rapid cycling was associated with antidepressants resembled spontaneously rapid-cycling patients, while the majority of spontaneously rapid-cycling patients also had periods of antidepressant-associated rapid cycling. CONCLUSIONS: The validity of rapid cycling as a distinct course modifier for bipolar disorder is supported by differences in gender, prospectively assessed outcome, and perhaps social class between rapid-cycling and nonrapid-cycling patients. The relationship of gender to episode frequency supports the cutoff of 4 or more episodes per year.

High-performance liquid chromatographic method for the quantitative determination of butorphanol, hydroxybutorphanol, and norbutorphanol in human urine using fluorescence detection.

A sensitive, quantitative reversed-phase high-performance liquid chromatographic method has been established for the simultaneous determination of butorphanol, a synthetic opioid, and its metabolites, hydroxybutorphanol and norbutorphanol, in human urine samples. The method involved extraction of butorphanol, hydroxybutorphanol, and norbutorphanol from urine (1.0 ml), buffered with 0.1 ml of 1.0 M ammonium acetate (pH 6.0), onto 1-ml Cyano Bond Elut columns. The eluent was evaporated under nitrogen and low heat, and reconstituted with the HPLC mobile phase, acetonitrile-methanol-water (20:10:70, v/v/v), containing 10 mM ammonium acetate and 10 mM TMAH (pH 5.0). The samples were chromatographed on a reversed-phase octyl 5-microns column. The analysis was accomplished by detection of the fluorescence of the three analytes, at excitation and emission wavelengths of 200 nm and 325 nm, respectively. The retention times for hydroxybutorphanol, norbutorphanol, the internal standard, and butorphanol were 5.5, 9.0, 13.0, and 23.4 min respectively. The validated quantitation range of the method was 1-100 ng/ml for butorphanol and hydroxybutorphanol, and 2-200 ng/ml for norbutorphanol in urine. The observed recoveries for butorphanol, hydroxybutorphanol, and norbutorphanol were 93%, 72%, and 50%, respectively. Standard curve correlation coefficients of 0.995 or greater were obtained during validation experiments and analysis of study samples. The method was applied on study samples from a clinical study of butorphanol, providing a pharmacokinetic profiling of butorphanol.

High-performance liquid chromatographic procedure for the quantitative determination of paclitaxel (Taxol) in human plasma.

An isocratic high-performance liquid chromatographic method has been developed and validated for the quantitative determination of paclitaxel (Taxol), a novel antimitotic, anticancer agent, in human plasma. The analysis required 0.5 ml of plasma, and was accomplished by detection of the UV absorbance of paclitaxel at 227 nm following extraction and concentration. The method involved extraction of paclitaxel from plasma, buffered with 0.5 ml of 0.2 M ammonium acetate (pH 5.0), onto 1-ml cyano Bond Elut columns. The eluent was evaporated under nitrogen and low heat, and reconstituted with the mobile phase, acetonitrile-methanol-water (4:1:5, v/v/v) containing 0.01 M ammonium acetate (pH 5.0). The samples were chromatographed on a reversed-phase octyl 5 microns column. The retention time of paclitaxel was 10 min. The validated quantitation range of the method was 10-1000 ng/ml (0.012-1.17 microM) of paclitaxel in plasma. Standard curve correlation coefficients of 0.995 or greater were obtained during validation experiments and analysis of clinical study samples. The observed recovery for paclitaxel was 83%. Epitaxol, a biologically active stereoisomer, and baccatin III, a degradation product, were also chromatographically separated from taxol by this assay. The method was applied to samples from a clinical study of paclitaxel in cancer patients, providing a pharmacokinetic profiling of paclitaxel.

Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression.

Records of patients who had been systematically evaluated at the Center for Anxiety and Depression were reviewed. Included in this report are records of patients who had a diagnosis of bipolar II or unipolar affective disorder as determined by one of the authors and who also underwent a Structured Clinical Interview for DSM-III (SCID). A second study was undertaken with L.K.T. observing the clinical interview of D.L.D. and both clinicians making a diagnosis for the patient. There was reasonable diagnostic agreement between D.L.D. and the SCID for diagnosis of bipolar II disorder. Twelve of 34 patients clinically diagnosed as bipolar II were diagnosed by the SCID as unipolar. These 12 patients failed to demonstrate clinical factors, which could help explain the diagnostic difference between SCID and the clinical diagnosis. There was excellent agreement on 34 patients as to the presence or absence of hypomania, comparing two clinicians. The SCID interview underestimates the diagnosis of hypomania, a condition that can be diagnosed reliably by clinicians trained to make this diagnosis. This finding has some implications for DSM-IV, where there is a proposal for inclusion of bipolar II disorder as a parallel entity with bipolar disorder.

Effect of food on the bioavailability of gepirone in humans.

A randomized two-period crossover study was conducted in 20 healthy male volunteers to assess the effect of food on the pharmacokinetics of gepirone (BMY-13805) and its metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) after a single 20-mg dose of gepirone either after fasting or after consumption of a standard high-fat breakfast. There was a 1-week washout period between treatments. Plasma samples were obtained predose and at specified time points after dosing and analyzed for gepirone and 1-PP content by a specific gas chromatographic-mass spectrometric method. Food did not significantly affect gepirone maximum peak plasma concentration (Cmax) and half-life (t1/2). The mean gepirone Cmax was 16.98 +/- 8.12 ng/mL (fed) and 18.73 +/- 10.30 ng/mL (fasted), with mean t1/2 of 3.32 +/- 1.84 hours (fed) and 2.94 +/- 0.90 hours (fasted). Food significantly increased the mean area under the curveinf (AUCinf) from 55.26 +/- 35.74 ng.hour/mL (fasted) to 75.69 +/- 42.79 ng.hour/mL (fed), and the mean residence timeinf (MRTinf) from 4.31 +/- 0.78 hours (fasted) to 5.37 +/- 1.21 hours (fed). The median time to maximum plasma concentration (tmax) for gepirone was also significantly increased in the presence of food, 2.0 hours, versus 0.75 hours in the absence of food. For 1-PP, food had no affect on Cmax, t1/2, or AUCinf. Mean t1/2 for 1-PP in the presence and absence of food was 6.06 +/- 1.75 and 5.76 +/- 1.75 hours, respectively. MRTinf, however, was increased significantly from 9.32 +/- 2.68 hours (fasted) to 10.53 +/- 2.89 hours (fed).(ABSTRACT TRUNCATED AT 250 WORDS)

The site of gastrointestinal absorption of gepirone in humans.

This study was conducted in seven healthy male subjects and was performed over four sessions with a 1-week washout between sessions. It was designed to compare the bioavailability of an oral 20-mg gepirone dose (treatment 1) with that obtained after application of the same dose by gastric intubation to the distal (treatment 2) and proximal (treatment 3) regions of the small intestine, and after 4 consecutive 5-mg gepirone doses given orally at hourly intervals (treatment 4). Serial blood samples were taken over 24 hours after dose after each treatment. Plasma concentrations of gepirone and 1-(2-pyrimidinyl)-piperazine (1-PP), a metabolite of gepirone, were quantitated by gas chromatography-mass spectrometry. Mean gepirone time to reach peak concentration (tmax) after treatments 1, 2, and 3 ranged between 0.57 and 1.07 hours. There were no significant differences between sites and treatments for gepirone t1/2, which ranged between 2.8 and 3.3 hours. The mean gepirone maximum peak plasma concentration (Cmax) was significantly higher (P less than .05) after treatment 2 (12.92 +/- 7.24 ng/mL) compared with treatment 1 (6.79 +/- 3.54 ng/mL) or treatment 3 (6.33 +/- 2.26 ng/mL). Gepirone area under the curve (AUCinf) was also significantly higher (P less than .05) after treatment 2 (29.83 +/- 17.42 ng.h/mL) compared with treatment 1 (18.07 +/- 6.10 ng.h/mL) or treatment 3 (17.74 +/- 7.69 ng.h/mL). There were no significant differences in gepirone AUCinf between treatments 1 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

A report on three patients with "rapid cycling" unipolar depression.

We report three cases of unipolar depression who meet criteria for "rapid cycling" by having four or more major depressive episodes within a 1-year period. This report describes the clinical characteristics of the three patients and discusses the concept of false unipolar depression, and compares these patients with the "pseudounipolar" group described by Akiskal et al. Our findings support the clinical notion that rapid cycling in unipolar depression is a rarity.

Metabolism of 14C-2',3'-dideoxyinosine by the in situ perfused rat liver preparation.

The metabolism and biliary excretion of 14C-dideoxyinosine (14C-ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2 h of perfusion through the liver, approximately 70-75 per cent of the total 14C-radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15-18 per cent was retained in the liver. Hepatic clearance of ddI was 1.5 +/- 0.1 ml min-1 and half-life for the elimination of ddI from the medium was 22.9 +/- 2.0 min (n = 3). Hepatic extraction was estimated to be 7.5 per cent. HPLC analysis of the effluent perfusate indicated that ddI was metabolized to hypoxanthine, xanthine, uric acid, and to a polar metabolite which was tentatively identified as allantoin. Approximately 60-65 per cent of the ddI dose was converted to allantoin after 2 h of perfusion. Of the other three metabolites, uric acid levels increased to 20-30 per cent of the dose after 45 min and declined to about 5 per cent of the dose by the end of the perfusion period. Levels of hypoxanthine and xanthine were low and both compounds were not detected in the perfusate after 45 min post-infusion. In bile, the major peak, which accounted for about 50 per cent of the 14C-radiolabel co-eluted with the putative metabolite, allantoin (0.4 per cent of the dose). Uric acid (0.06 per cent of the dose) was the only other metabolite detected in bile. These results suggest that biliary excretion is a minor pathway for the elimination of ddI. Furthermore, ddI is rapidly cleared and metabolized by the liver to hypoxanthine, xanthine, uric acid, and to allantoin.