Ocular penetration and pharmacokinetics of topical fluconazole.

The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC). Peak corneal levels occurred essentially immediately at 5 min in the corneas [debrided, 8.2 +/- 1.2 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)] and at 15 min after application in the aqueous [debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min. A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.

Gender differences in beliefs of why women live longer than men.

Research supports an interaction of biological and sociocultural factors to account for why women live longer than men. This study investigated whether men and women of college age have similar attributions for this difference in longevity. Responses to an open-ended questionnaire by 507 college aged students confirmed a significant gender difference in attribution of life expectancy. Young men attributed such differences to greater physical labor of men and the less stressful life of women. Young women, in contrast, thought women took better care of their health.

The role of stereotactic biopsy in assessment of nonpalpable breast lesions.

BACKGROUND: When mammography identifies a lesion suspicious for cancer, stereotactic needle core biopsy (SCNB) and needle localization (NL) surgical biopsy are options for obtaining tissue. This study compared the results of these two biopsy methods in evaluating nonpalpable radiologically suspicious breast lesions. METHODS: Records of 292 women who underwent SCNB or surgical biopsy at two institutions were reviewed over 28 months. The women were separated into two groups, under 50 years of age and 50 years of age and older. RESULTS: A total of 70 women over the age of 50 had stereotactic biopsy. One hundred and three had NL biopsies. The rate of positivity was 37% and 33% for stereotactic and NL biopsy respectively (P = 0.693). A total of 44 women under the age of 50 had stereotactic biopsy. Seventy had NL biopsies. The rate of positivity was 7% and 21%, respectively, for stereotactic and NL (P = 0.082). NL surgical biopsy costs on average $2354.00. SCNB averages $949 including follow-up mammogram. CONCLUSION: SCNB is a cost-effective, accurate method of breast biopsy. This report retrospectively compares SCNB with surgical open biopsy aided by NL. The cost savings occurred primarily in surgeon's fees and anesthesia fees. We found no statistical difference in < 50- or > 50-year-old patients in the frequency of the diagnosis of breast cancer when comparing the two types of biopsies.

Determination of SCH 39304 by megabore capillary gas-liquid chromatography.

A gas-liquid chromatographic procedure for determination of SCH 39304 at low nanogram concentrations in serum, cerebrospinal fluid, and urine is presented. The methodology combines a high selectivity and sensitivity nitrogen-specific detector, a gas chromatograph equipped with a capillary "megabore" column, and an internal standard that is very similar in chemical structure to the drug being assayed. This method is suitable for both pharmacokinetic studies as well as for monitoring drug levels in patients receiving SCH 39304 for antifungal treatment.

Simultaneous chronic lymphocytic leukemia and chronic myelogenous leukemia. Evidence of a separate stem cell origin.

The authors studied a patient with the simultaneous occurrence of chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). The coexistence of these two hematologic malignancies leads to questions about their cell of origin. Through analysis of this patient's DNA, the authors studied the derivation of the two malignancies. They separated the blood into a myeloid-rich fraction and a fraction containing the malignant lymphocytes. JH and bcr probes were used to study these loci in the myeloid and lymphoid fractions and in unfractionated white blood cells. The authors found that the unfractionated leukocytes contained the bcr and JH rearrangements. Conversely, the lymphoid fraction contained only the JH rearrangement, and the myeloid fraction contained only the bcr rearrangement, suggesting that these malignancies arose from separate stem cells. This is the first reported patient with simultaneously occurring CML and CLL definitively shown to arise from distinct progenitors, and this report raises questions about the origin of these two cell lines.

Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing.

The pharmacokinetics of SCH-39304, an investigational, orally active, broad-spectrum antifungal agent, were evaluated in 17 adult, human immunodeficiency virus-positive males. Patients were studied on days 1 and 16 and were divided into the following three treatment groups: (i) patients with culture-proven oropharyngeal candidiasis who were not receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 6); (ii) patients with culture-proven oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 5); and (iii) patients with or without oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 200 mg of SCH-39304 daily (n = 6). All patients received a single daily dose of the study medication for 16 days. Plasma samples for SCH-39304 concentration measurement were collected for 6 h following the initial dose and for 504 h following the day 16 dose. Urine was collected for 24 h following SCH-39304 administration on days 1 and 16. All samples were assayed for SCH-39304 by gas chromatography. Wide intersubject variations in SCH-39304 plasma concentration-versus-time profiles were observed on each study day. Absorption appeared to be slow, with mean day 1 peak plasma SCH-39304 concentrations of 1.2 micrograms/ml at 2.1 h (50 mg) and 3.9 micrograms/ml at 4.0 h (200 mg) after drug administration. Mean peak plasma SCH-39304 concentrations on day 16 were 7.6 micrograms/ml at 4.3 h (50 mg) and 17.2 micrograms/ml at 3.2 h (200 mg) after drug administration. Mean elimination half-lives on day 16 for the 50- and 200-mg daily dosages were 100 and 89 h, respectively. SCH-39304 was cleared primarily unchanged in the urine. Mean areas under the plasma concentration-versus-time curve (from 0 to 24 h) on day 16 reflect a lower than expected increase with the 200-mg/day regimen (314.5 microgram.h/ml) compared with that for the 50-mg/day regimen (139.9 microgram.h/ml), suggesting the potential for reduced bioavailability at higher dosages. No significant effect of concurrent zidovudine therapy on the kinetics of SCH-39304 was observed.

Assay of fluconazole by high-performance liquid chromatography with a mixed-phase column.

A mixed-phase liquid chromatographic column was used to assay fluconazole in plasma, serum, and cerebrospinal fluid. The assay was linear from 0.2 to 20 micrograms/ml, with an average coefficient of variation of less than 5%. The partitioning of the drug between serum and cerebrospinal fluid was determined for 34 patients. The method was demonstrated to be suitable for both pharmacokinetic studies and monitoring of patients receiving treatment with this antifungal agent.

Effect of high-flux hemodialysis on quality of life and neuropsychological function in chronic hemodialysis patients.

The objective was to evaluate the effect of high-flux hemodialysis on quality of life, intra- and interdialytic symptoms and neuropsychological function. The study was double-blind single cross-over with random allocation to order of treatment. The patients were stable adult hospital hemodialysis patients. Both the conventional and high-flux membranes were cellulose acetate, the dialysate was bicarbonate, and dialysate sodium was held constant. The high-flux membrane had an ultrafiltration rate of 15 ml/h/mm Hg transmembrane pressure, a B12 clearance of 88 ml/min and a beta 2-microglobulin clearance of 11.4 ml/min. The values of the conventional membrane were 3.5-5.0, 34-45 and negligible. Each treatment period was 4 months. Twenty-two patients completed both phases of the cross-over. The KT/V value was higher during high-flux than conventional treatment; 1.42 versus 1.27(p < 0.05). There were no differences between high-flux and conventional treatment with respect to quality of life. Symptoms during dialysis were less severe during high-flux than conventional treatment for 12/14 items. Only 3 items reached statistical significance (0.05 > p > 0.01) and none were clinically significant. Symptoms between dialyses were less severe during high-flux than conventional treatment for 18/20 items. No single item had a statistically significant improvement but 3 had clinically important improvement. Among the 23 neuropsychological variables, none demonstrated statistically significant changes.

Induction of type I diabetes by Kilham's rat virus in diabetes-resistant BB/Wor rats.

Type I diabetes mellitus is an autoimmune disease resulting from the interaction of genetic and environmental factors. A virus that was identified serologically as Kilham's rat virus (KRV) was isolated from a spontaneously diabetic rat and reproducibly induced diabetes in naive diabetes-resistant (DR) BB/Wor rats. Viral antigen was not identified in pancreatic islet cells, and beta cell cytolysis was not observed until after the appearance of lymphocytic insulitis. KRV did not induce diabetes in major histocompatibility complex-concordant and discordant non-BB rats and did not accelerate diabetes in diabetes-prone BB/Wor rats unless the rats had been reconstituted with DR spleen cells. This model of diabetes may provide insight regarding the interaction of viruses and autoimmune disease [corrected]

A comparison of evaluative indices of quality of life and cognitive function in hemodialysis patients.

In the setting of end-stage renal disease, the reproducibility and responsiveness of three health-related quality-of-life instruments were evaluated. The Time Trade Off instrument (TTO) is a generic instrument used to evaluate the utility of a health state. The Hemodialysis Quality-of-Life questionnaire (HQL) is a disease-specific instrument. A series of function-specific tests evaluated neurocognitive function. The TTO and HQL instruments are patient centric in that patient values define the health status while the neurocognitive function tests reflect the values of healthcare professionals. Forty-seven chronic hemodialysis patients participated. Those with adequate dialysis, defined as a Kt/V (a measure of small solute removal during hemodialysis) above 1.0 were maintained at the level for two administrations of the three instruments separated by six to eight weeks. The test-retest intraclass correlation coefficient exceeded 0.90 for all five domains of the HQL questionnaire and exceeded 0.70 for nine neurocognitive function tests. Patients with inadequate dialysis (Kt/V less than 0.8) had Kt/V increased to above 1.0. The TTO was not responsive. For the HQL questionnaire, an item was considered responsive if a 1-point improvement, on a 7-point Likert type scale, occurred significantly more often among those with an improvement in hemodialysis treatment compared to those without improvement. Only one item had such a change and therefore the HQL cannot be considered responsive.(ABSTRACT TRUNCATED AT 250 WORDS)

Accuracy of common drug screen tests.

Forty consecutive urine specimens, obtained from patients seen in the emergency center, positive for either cocaine and/or marijuana, were analyzed using five methods of analysis. A new latex agglutination inhibition assay, Abuscreen OnTrak, (Roche Diagnostic Systems, Nutley, NJ), was compared with four other drug abuse assays: mass spectrometry, (Hewlett-Packard Co, Richardson, TX); an automated homogeneous enzyme immunoassay technique, ETS System, (Syva Co, Palo Alto, CA); a manual enzyme multiplied immunoassay technique; EMIT-st, (Syva); and a fluorescence polarization immunoassay, TDx, (Abbott Laboratories, Chicago, IL). For statistical purposes, mass spectrometry was the reference point for the presence or absence of a specific substance. All instrument sensitivities, with the exception of mass spectrometry, were set with the same "cut off" point of 100 micrograms/L for marijuana and 300 micrograms/L for cocaine and its metabolites. Efficiency in the detection of cocaine and its metabolites was 95% by all methods. Efficiency for the detection of marijuana and its metabolites ranged from 70% (Roche's OnTrak) to 90% (Syva's ETS). Simple to use, assays of minimal cost are presently available for rapid, accurate drug of abuse screening.

Penetration of SCH-39304, a new antifungal triazole, into cerebrospinal fluid of primates.

We characterized the cerebrospinal fluid (CSF) penetration and pharmacokinetics of SCH-39304 in adult rhesus monkeys receiving a single oral dose of SCH-39304 (2.0 mg/kg of body weight). The mean CSF-to-plasma area under the curve ratio was 0.63 (+/- 0.18, standard error of the mean); maximum concentrations were 1.34 micrograms/ml (+/- 0.18) in CSF and 1.96 micrograms/ml (+/- 0.43) in plasma. The mean plasma half-life was 45.7 h (+/- 11), and mean CSF half-life was 38.7 h (+/- 3.5). The mean levels of SCH-39304 at 24 h were 1.48 micrograms/ml (+/- 0.3) in plasma and 0.96 microgram/ml (+/- 0.12) in CSF. We conclude that SCH-39304 effectively penetrates into CSF and achieves concentrations considered active against many opportunistic yeasts and that these concentrations are sustained in CSF for greater than or equal to 24 h.

Assay of free and total tocainide by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection.

A rapid high performance liquid chromatographic (HPLC) method for the determination of tocainide, using N-(2,6-dimethylphenyl)-2-amino-butanimide as an internal standard, was developed. A methylene chloride extraction involving salting out at pH 9.0 was employed. An 85:15 mixture of 0.025M monobasic potassium phosphate at pH 3.0 and acetonitrile was used as the mobile phase. The separation and quantitative analysis of tocainide was performed on a mixed phase column with a 1.0-mL/min flow rate and detection at 210 nm. Separation of tocainide from some of its metabolites required the use of heptane sulfonic acid as an ion-pairing reagent. For the free-drug assay, the specimen was centrifuged through an Amicon Centrifree filter before being processed.

Assay of fluconazole by megabore capillary gas-liquid chromatography with nitrogen-selective detection.

A megabore column gas-liquid chromatographic method which uses nitrogen-phosphorus detection was developed for the analysis of fluconazole in plasma, serum, cerebrospinal fluid, or urine. The assay was linear from 0.2 to 200 micrograms/ml and had an average coefficient of variation of 7%. The suitability of the assay for pharmacokinetic studies was demonstrated.

Determination of codeine and morphine in human plasma by high performance liquid chromatography with serial electrochemical detection.

A method is described for the determination of codeine and its metabolite, morphine, at low nanogram concentrations in plasma. Analysis is accomplished by high-performance liquid chromatography utilizing a cyanopropyl normal bonded phase (NBP) column in reversed-phase mode and two electrochemical detectors in series configuration. Two internal standards are utilized, ethyl morphine for codeine and nalorphine for morphine. Codeine and morphine concentration data are presented for several patients receiving codeine-containing medications. The lower limit of detectability was 2.00 +/- 0.39 ng per mL for codeine and 1.20 +/- 0.83 ng per mL for morphine. The patient sample mean within-run coefficients of variation for codeine and morphine (at 10 ng per mL) were less than 10 percent, n = 30. The between-run coefficient of variation for codeine was also less than 10 percent (over a range of two to 190 ng per mL, n = 61), and was approximately 15 percent for morphine (over a range of two to 40 ng per mL, n = 31).

Can psychological assessment address borderline phenomena?

Literature about psychological test findings in borderline disorders reflects changes in the meaning of the term and can be confusing when viewed from today's prespective. Most descriptions have referred to a concept of borderline schizophrenia. This paper reviews psychological assessment of borderline patients by means of the Rorschach, by using WAIS/Rorschach patterns, and, post-DSM-III, by using the MMPI. It focuses on the Rorschach's sensitivity to several dimensions relevant to borderline pathology. The concept that borderline disorders can include mild forms of affective and schizophrenic illness was examined by applying a Rorschach content scoring system to a borderline sample. The findings demonstrate Rorschach ability to identify borderline subtypes and offer independent validation of affective and schizotypal subtypes in the borderline realm.

Enkephalinase inhibition: regulation of ethanol intake in genetically predisposed mice.

This is the first report of alteration in alcohol intake in mice with a genetic predisposition to alcohol preference and known to have innate brain enkephalin deficiencies. We have been able to significantly attenuate both volitional and forced ethanol intake respectively by acute and chronic treatment with hydrocinnamic acid and D-phenylalanine, known carboxypeptidase (enkephalinase) inhibitors. Since these agents, through their enkephalinase inhibitory activity, raise brain enkephalin levels, we propose that excessive alcohol intake can be regulated by alteration of endogenous brain opioid peptides.

Bioequivalence and pharmacokinetic profile of promethazine hydrochloride suppositories in humans.

A bioequivalence study of promethazine hydrochloride (10-[2-(dimethylamino)propyl]-phenothiazine monohydrochloride) was conducted in 20 male human subjects with the purpose of comparing, under blind condition, the human serum levels of promethazine in three different formulations. The formulations tested were a 50-mg promethazine hydrochloride polyethylene glycol suppository, a 50-mg promethazine hydrochloride cocoa butter-white wax suppository, and a 50-mg oral dose of promethazine hydrochloride syrup. Each subject received single doses of each of the three formulations on each of three different days on a crossover basis. From the measured serum levels, estimates of the bioavailability parameters (area under the serum concentration versus time curve, time-to-peak serum concentration, and peak serum concentration) were obtained by least-squares digital computer fitting. Also, a one-compartment pharmacokinetic open model with two consecutive first-order input steps is proposed. Statistical analysis of the results was performed by using a linear multiple regression approach for the analysis of variance. No significant differences between the syrup and the polyethylene glycol suppositories were obtained (p greater than 0.05) for the above three bioavailability parameters. However, the polyethylene glycol suppositories provided statistically higher peak serum concentration, shorter time-to-peak serum concentration, and larger area under the serum concentration versus time curve than the cocoa butter-white wax suppositories.

Regional brain [Met]-enkephalin in alcohol-preferring and non-alcohol-preferring inbred strains of mice.

Scrutiny of the data from these studies reveals that the C58/J alcohol-preferring mice have significantly lower baseline methionine-enkephalin levels in both the corpus striatum and hypothalamus compared to C3H/CHRGL/2 non-alcohol-preferring mice. In other brain regions in these two strains, specifically, pituitary, amygdala, midbrain, and hippocampus, analysis of methionine-enkephalin levels did not show any significant differences. This suggests that the hypothalamus may indeed be a specific locus involved in the regulation of alcohol intake, via the molecular interaction between neuroamines, opioid peptides, as they are influenced by genetics and environment.