Kinetics of chloral hydrate and its metabolites in male human volunteers.

Chloral hydrate (CH) is a short-lived intermediate in the metabolism of trichloroethylene (TRI). TRI, CH, and two common metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA) have been shown to be hepatocarcinogenic in mice. To better understand the pharmacokinetics of these metabolites of TRI in humans, eight male volunteers, aged 24-39, were administered single doses of 500 or 1,500 mg or a series of three doses of 500 mg given at 48 h intervals, in three separate experiments. Blood and urine were collected over a 7-day period and CH, DCA, TCA, free trichloroethanol (f-TCE), and total trichloroethanol (T-TCE=trichloroethanol and trichloroethanol-glucuronide [TCE-G]) were measured. DCA was detected in blood and urine only in trace quantities (<2 microM). TCA, on the other hand, had the highest plasma concentration and the largest AUC of any metabolite. The TCA elimination curve displayed an unusual concentration-time profile that contained three distinct compartments within the 7-day follow-up period. Previous work in rats has shown that the complex elimination curve for TCA results largely from the enterohepatic circulation of TCE-G and its subsequent conversion to TCA. As a result TCA had a very long residence time and this, in turn, led to a substantial enhancement of peak concentrations following the third dose in the multiple dose experiment. Approximately 59% of the AUC of plasma TCA following CH administration is produced via the enterohepatic circulation of TCE-G. The AUC for f-TCE was found to be positively correlated with serum bilirubin concentrations. This effect was greatest in one subject that was found to have serum bilirubin concentrations at the upper limit of the normal range in all three experiments. The AUC of f-TCE in the plasma of this individual was consistently about twice that of the other seven subjects. The kinetics of the other metabolites of CH was not significantly modified in this individual. These data indicate that individuals with a more impaired capacity for glucuronidation may be very sensitive to the central nervous system depressant effects of high doses of CH, which are commonly attributed to plasma levels of f-TCE.

The effects of soy milk and isoflavone supplements on cognitive performance in healthy, postmenopausal women.

RATIONALE: The decline in estrogen concentrations in women after menopause can contribute to health related changes including impairments in cognition, especially memory. Because of the health concerns related to hormone replacement therapy (HRT), alternative approaches to treat menopausal symptoms, such as nutritional supplements and/or diet containing isoflavones, are of interest. OBJECTIVES: This study investigated whether soy isoflavones (soy milk and supplement) could improve cognitive functioning in healthy, postmenopausal women. PARTICIPANTS, INTERVENTION AND DESIGN: A total of 79 postmenopausal women, 48-65 years of age, completed a double-blind, placebo-controlled trial in which they were randomly assigned to one of three experimental groups: cow's milk and a placebo supplement (control); soy milk and placebo supplement (soy milk, 72 mg isoflavones/day); or cow's milk and isoflavone supplement (isoflavone supplement, 70 mg isoflavones/day). MEASUREMENTS: Cognitive functioning was assessed using various cognitive tasks before the intervention (baseline) and after the intervention (test). RESULTS: In contrast to predictions, soy isoflavones did not improve selective attention (Stroop task), visual long-term memory (pattern recognition), short-term visuospatial memory (Benton Visual Retention Test), or visuo-spatial working memory (color match task). Also, the soy milk group showed a decline in verbal working memory (Digit Ordering Task) compared to the soy supplement and control groups. CONCLUSION: Soy isoflavones consumed as a food or supplement over a 16-week period did not improve or appreciably affect cognitive functioning in healthy, postmenopausal women.

The need for an iterative process for assessing economic outcomes associated with SSRIs.

Pharmacotherapeutic advances in the treatment of depression have included the development of the selective serotonin reuptake inhibitors (SSRIs), thereby providing alternatives to tricyclic antidepressants. Concurrent with these events have been significant structural (e.g. pharmaceutical formularies) and regulatory (e.g. required pharmacoeconomic evaluations) changes in the delivery, financing, and oversight of healthcare programmes throughout the world. International cost-containment initiatives are increasingly mandating a demonstration of value for money, defined in terms of a measurable health and/or financial outcome, and, in the case of medicines, attributable to a given expenditure, for a given pharmacotherapeutic option. We examine the inherent strengths and weaknesses of 5 study designs used to discern and contrast financial outcomes stemming from the use of antidepressant pharmacotherapy for the treatment of depressive illness [randomised controlled trials (RCTs); meta-analyses; decision-analytical models (DAMs); retrospective database investigations; randomised naturalistic inquiry]. We argue that the economic appraisal of pharmacotherapy requires an iterative process extending from the developmental (RCTs; meta-analyses; DAMs) through to the postmarketing phase (database reviews; naturalistic inquiry), thereby resulting in a portfolio of evidence as to the safety, efficacy and effectiveness of a given pharmacotherapeutic category (e.g. SSRIs) and/or a specific medication. Database reviews, while nonrandomised, and prospective naturalistic inquiry afford greater insight into the patterns of use and financial merits of prescribing specific pharmacotherapeutic options for the treatment of depression within the context of clinical practice as compared with RCTs, meta-analyses and DAMs. The portfolio of evidence to date indicates that the first-line use of SSRIs in the treatment of depression is clinically warranted, and represents value for money.

Trends in the rate of depressive illness and use of antidepressant pharmacotherapy by ethnicity/race: an assessment of office-based visits in the United States, 1992-1997.

OBJECTIVE: This study was undertaken to determine ethnicity/race-specific (white, black, and Hispanic) population-adjusted rates of US office-based physician visits in which a diagnosis of a depressive disorder was recorded or in which a diagnosis of a depressive disorder was recorded and antidepressant pharmacotherapy was prescribed. METHODS: Data from the National Ambulatory Medical Care Survey for 1992 through 1997 were partitioned into three 2-year periods: 1992-1993, 1994-1995, and 1996-1997. For each 2-year period, data from office-based physician visits for patients aged 20 to 79 years were extracted to assess, by ethnicity/race, (1) the number of visits in which a diagnosis of a depressive illness was recorded (International Classification of Diseases, Ninth Revision, Clinical Modification codes 296.2-296.36, 300.4, or 311) and (2) the number of visits in which a diagnosis of a depressive illness was recorded and antidepressant pharmacotherapy was prescribed. We calculated ethnicity/race-specific rates (per 100 US population aged 20 to 79 years) of office-based visits in which a diagnosis of a depressive disorder was recorded and in which a diagnosis of a depressive disorder was recorded and antidepressant pharmacotherapy was prescribed. The specialty of the reporting physician and the proportion of patients receiving a selective serotonin reuptake inhibitor (SSRI) were also discerned. RESULTS: From 1992-1993 to 1996-1997, the rate of office-based visits (per 100 US population aged 20 to 79 years) in which a diagnosis of a depressive disorder was recorded increased 3.7% for whites (from 10.9 to 11.3; P = 0.001), 31.0% for blacks (from 4.2 to 5.5; P = 0.001), and 72.9% for Hispanics (from 4.8 to 8.3; P = 0.001). The rate of office-based visits in which a diagnosis of a depressive disorder was recorded and antidepressant pharmacotherapy was prescribed increased 18.5% for whites (from 6.5 to 7.7 per 100; P = 0.001), 38.5% for blacks (from 2.6 to 3.6 per 100; P = 0.001). and 106.7% for Hispanics (from 3.0 to 6.2 per 100; P = 0.001). Between 1992-1993 and 1996-1997, use of an SSRI increased among whites and blacks (from 50.0% to 65.8% and from 40.5% to 58.2%, respectively), but declined among Hispanics (from 51.4% to 48.6%; all comparisons P = 0.001). CONCLUSION: By 1996-1997, the population-adjusted rates for Hispanics were within a quartile of those observed for whites, whereas the rates for blacks remained at less than half those observed in whites. The observed divergence in population-adjusted rates by ethnicity/race may reflect the nature of the patient-physician relationship, sensitivity and specificity of diagnostic techniques and instruments, and the wider social context in which an office-based visit occurs, including access to and type of health insurance and coverage for mental health services.

Economic appraisal of citalopram in the management of single-episode depression.

A retrospective intent-to-treat analysis (N = 1,339) was conducted to discern the natural course of antidepressant use and direct health service expenditures for the treatment of single-episode depression (DSM-IV code 296.20) among patients initiating antidepressant pharmacotherapy with either a tricyclic antidepressant (TCA) (amitriptyline, N = 237) or a selective serotonin reuptake inhibitor (SSRI) (citalopram, N = 71; fluoxetine, N = 411; paroxetine, N = 334; or sertraline, N = 286). Data were derived from the computer archive of a network-model health maintenance organization for the period of January 1, 1996, through April 30, 1999. Comparisons at the end of the 6-month post-period (180 days) were undertaken between cohorts initiating antidepressant pharmacotherapy with citalopram and each SSRI or TCA. Consistent with the intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate models were adjusted for patient's age, gender, number of concomitant disease state processes, use of health services in the 6-month time frame (180 days) before initiating antidepressant pharmacotherapy, specialty of physician recording a diagnosis of single-episode depression, and the presence or absence of a previous diagnosis of single-episode depression and receipt of antidepressant pharmacotherapy. Patients initiating antidepressant pharmacotherapy with citalopram were far more likely to (1) have been diagnosed by a psychiatrist (37%; p < or = 0.05); (2) continue with the original pharmacotherapeutic option (79%) compared with patients originally prescribed amitriptyline (51%; chi2 = 17.29, df = 1, p < or = 0.05) or sertraline (65%; chi2 = 36.91, df = 1, p < or = 0.05); no significant difference was found compared with patients initiating antidepressant pharmacotherapy with paroxetine (72%; p = not significant [NS]) or fluoxetine (83%; p = NS); (3) obtain 90 days or more of antidepressant pharmacotherapy (86%) compared with those prescribed amitriptyline (69%; chi2 = 8.09, df = 1, p < or = 0.05); no significant difference was found compared with sertraline (77%), paroxetine (81%), or fluoxetine (84%); and (4) obtain 6 months (180 days) of antidepressant pharmacotherapy (68%) compared with those prescribed amitriptyline (39%; chi2 = 18.26, df = 1, p < or = 0.05) or sertraline (51%; chi2 = 6.02, df = 1, p < or = 0.05); no significant difference was found compared with paroxetine (56%) or fluoxetine (59%). Receipt of amitriptyline or sertraline as initial medication was associated with a per capita increase (p < or = 0.05) in health service utilization (17% and 9%, respectively) relative to citalopram. No significant difference (p > 0.05) in health service utilization was discerned between citalopram and either fluoxetine or paroxetine. Multivariate models adjusted for nonrandom assignment to the initial pharmacotherapeutic option confirmed these findings. Further research over a longer time course is warranted.

Ethnicity and the prescribing of antidepressant pharmacotherapy: 1992-1995.

Little is known about the prescribing pattern for antidepressant pharmacotherapy by ethnicity. The present study was designed to determine the rates of office-based visits documenting the utilization of antidepressant pharmacotherapy, a diagnosis of a depressive disorder, or both, among whites, blacks, and Hispanics age 20-79 years. Data from the National Ambulatory Medical Care Survey for 1992-93 and 1994-95 were utilized for this analysis. Comparing these time periods, we observed several trends: (1) The annualized mean rate per 100 US population of office-based visits documenting the use of antidepressant pharmacotherapy for any reason increased from 13.4 to 15.9 among whites (p < or = 0.0001) and from 6.5 to 7.7 among blacks (p < or = 0.0001), but remained unchanged at 7.3 for Hispanics (p > 0.05). (2) Documentation of a diagnosis of a depressive disorder increased for whites (10.9 to 12.0; p < or = 0.0001), for blacks (4.2 to 5.6; p < or = 0.0001), and for Hispanics (4.8 to 5.6; p < or = 0.0001). (3) The recording of a diagnosis of a depressive disorder in concert with the initial prescription or continuation of antidepressant pharmacotherapy also increased for whites (6.5 to 7.7; p < or = 0.0001), for blacks (2.6 to 3.4; p < or = 0.0001), and for Hispanics (3.0 to 3.2; p < or = 0.0001). We conclude that the rate of office-based visits documenting the utilization of antidepressant pharmacotherapy, a diagnosis of a depressive disorder, or both, was comparable among blacks and Hispanics by 1994-95, but was less than half the rate for whites in either time period examined. Further prospective research is required to discern the reasons for observed differences by ethnicity.

National trends in the prevalence of attention-deficit/hyperactivity disorder and the prescribing of methylphenidate among school-age children: 1990-1995.

It has been reported that during the past decade the prevalence of attention-deficit/hyperactivity disorder (ADHD) (ICD-9-CM code 314.00 or 314.01) and its pharmacologic treatment have increased dramatically in the United States. Herein, a single national data source is used to discern trends in the prevalence of U.S. office-based visits resulting in a diagnosis of ADHD, and trends in the prescribing of stimulant pharmacotherapy (including methylphenidate) for its treatment. Data from the National Ambulatory Medical Care Survey (NAMCS) for the years 1990 through 1995, for children aged 5 through 18 years, were utilized for this analysis. Results indicate that the number of office-based visits documenting a diagnosis of ADHD increased from 947,208 in 1990, to 2,357,833 in 1995. Between 1990 and 1995, the number of visits by girls diagnosed with ADHD rose 3.9-fold (p < 0.05), and the mean patient age increased by more than 1 year, from 9.7 in 1990, to 10.8 in 1995 (p < 0.05). The percentage of office-based visits resulting in a diagnosis of ADHD increased from 1.1% of all visits in this age group in 1990, to 2.8% by 1995. We discerned a 2.3-fold increase (p < 0.05) in the population-adjusted rate of office-based visits documenting a diagnosis of ADHD; a 2.9-fold increase (p < 0.05) in the population-adjusted rate of ADHD patients prescribed stimulant pharmacotherapy; and a 2.6-fold increase (p < 0.05) in the population-adjusted rate of ADHD patients prescribed methylphenidate.

Economic appraisal of antidepressant pharmacotherapy: critical review of the literature and future directions.

In the United States, an estimated $44 billion is expended annually for the treatment, morbidity, and mortality associated with depression. Domestic and international cost-containment initiatives are mandating a demonstration of value for money defined in terms of a measurable health and/or financial outcome, and, in the case of medicines, attributable to a given expenditure for a given pharmacotherapeutic option. Recent pharmacotherapeutic advances in the treatment of depression have included the development of selective serotonin reuptake inhibitors (SSRIs), thereby providing an alternative to tricyclic antidepressants (TCAs). Herein, we review the pharmacoeconomic literature relative to antidepressant pharmacotherapy and identify issues for future inquiry.

Comparison of the effects of iodine and iodide on thyroid function in humans.

Concerns have been raised over the use of iodine for disinfecting drinking water on extended space flights. Most fears revolve around effects of iodide on thyroid function. iodine (I2) is the form used in drinking-water disinfection. Risk assessments have treated the various forms of iodine as if they were toxicologically equivalent. Recent experiments conducted in rats found that administration of iodine as I- (iodide) versus I2 had opposite effects on plasma thyroid hormone levels. I2-treated animals displayed elevated thyroxine (T4) and thyroxine/triiodothyronine (T/T3) ratios, whereas those treated with I- displayed no change or reduced plasma concentrations of T4 at concentrations in drinking water of 30 or 100 mg/L. The study herein was designed to assess whether similar effects would be seen in humans as were observed in rats. A 14-d repeated-dose study utilizing total doses of iodine in the two forms at either 0.3 or 1 mg/kg body weight was conducted with 33 male volunteers. Thyroid hormones evaluated included T4, T3, and thyroid-stimulating hormone (TSH). TSH was significantly increased by the high dose of both I2 and I-, as compared to the control. Decreases in T4 were observed with dose schedules with I- and I2, but none were statistically significant compared to each other, or compared to the control. This human experiment failed to confirm the differential effect of I2 on maintenance of serum T4 concentrations relative to the effect of I- that was observed in prior experiments in rats. However, based on the elevations in TSH, there should be some concern over the potential impacts of chronic consumption of iodine in drinking water.

Economic outcomes with antidepressant pharmacotherapy: a retrospective intent-to-treat analysis.

Herein we describe a retrospective intent-to-treat evaluation designed to compare the natural course of antidepressant utilization and direct health service expenditures for the treatment of a single episode of major depression among patients enrolled in a multistate network-model health maintenance organization and initially prescribed either a tricyclic antidepressant (amitriptyline or nortriptyline) or the serotonin selective reuptake inhibitor (SSRI) fluoxetine. Patient-level paid-claims data for the period July 1, 1988, through December 31, 1991, were abstracted. During the above time frame, fluoxetine was the only SSRI available in the United States. Patients prescribed amitriptyline were more than three times as likely to require a change in antidepressant pharmacotherapy (OR = 3.27, 95% CI = 2.31 to 5.49), while patients prescribed nortriptyline were nearly four times more likely to change medication (OR = 3.82, 95% CI = 2.74 to 6.83) relative to patients initially prescribed fluoxetine. Consistent with our intent-to-treat design, all accrued health service expenditures were assigned to the pharmacotherapeutic option initially prescribed. Multivariate analyses revealed that initiation of antidepressant pharmacotherapy with amitriptyline resulted in a 25.7% increase in per capita depression-related health service expenditures per year, while initiation of antidepressant pharmacotherapy with nortriptyline resulted in a 28.1% increase in per capita depression-related health service expenditures per year relative to patients initially prescribed fluoxetine. A financial break-even point was achieved at the conclusion of Month 5, at which time all three intent-to-treat cohorts had comparable health service expenditures in total. From a financial perspective, results stemming from this inquiry suggest that the initiation of antidepressant pharmacotherapy with an SSRI is warranted.

Antidepressant prescribing patterns: a comparison of blacks and whites in a medicaid population.

OBJECTIVE: This paper reports results stemming from a retrospective inquiry designed to determine the prescribing pattern of tricyclic antidepressants (TCAs) relative to selective serotonin reuptake inhibitors (SSRIs), and the subsequent effect on regimen adherence among African American (Black) and White beneficiaries enrolled in the state of South Carolina Medicaid programme. PATIENTS AND METHODS: Adjudicated patient-level paid-claims data for the time-frame 1 January 1990 to 31 December 1994 were abstracted resulting in a statewide cohort of 8596 ambulatory beneficiaries, 18 to 64 years of age, without receipt of antidepressant pharmacotherapy in the 1-year time-frame prior to initiating a regimen of either a TCA or SSRI, and remaining Medicaid-eligible for 1 year thereafter. RESULTS: Black race [odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.43 to 1.70], age 40 to 64 years (OR = 1.15, 95% CI = 1.06 to 1.26), and male gender (OR = 1.27, 95% CI = 1.14 to 1.41) were significant predictors of initiating antidepressant pharmacotherapy with a TCA. Relative to Whites, Blacks were found to be less likely to have obtained at least a 3-month (>/=90 days) supply of a TCA (22.1 vs 31.7%) or an SSRI (30.7 vs 36.1%), or to have obtained a 6-month (>/=180 days) supply of a TCA (6.4 vs 10.9%) or an SSRI (8.1 vs 13.2%). CONCLUSION: Further prospective research is required to discern the reasons for observed differences in prescribing and adherence patterns for antidepressant pharmacotherapy by age, gender and race, and to foster the development of educational programming designed to ensure clinically rational and equitable access to pharmacotherapeutic innovation.

What factors influence the prescribing of antidepressant pharmacotherapy? An assessment of national office-based encounters.

OBJECTIVE: This study was designed to identify: 1) predictors of antidepressant pharmacotherapy among patients diagnosed with depression; and 2) predictors of prescription for either a selective-serotonin reuptake inhibitor (SSRI), or a serotonin-norepinephrine reuptake inhibitor (SNRI). METHOD: Data from the 1995 National Ambulatory Medical Care Survey (NAMCS) were used to discern the number of office-based encounters documenting a diagnosis of depression (ICD-9-CM codes 296.2-296.36; 300.4; or 311) among patients eighteen years of age or older. Logistic regression-derived odds ratios (OR) and 95 percent confidence intervals (CI) were used to elucidate factors predictive of receipt of antidepressant pharmacotherapy, and, more specifically, factors predictive of receipt of an SSRI or an SNRI. Model variables included age (18-49 years as compared to > or = 50 years); race (white as compared to nonwhite, inclusive of Hispanics); gender; self-report of depression as a reason for the office-based encounter; and payer type (private insurance program as compared to public). RESULTS: Among the estimated 18,046,293 office-based visits resulting in a diagnosis of depression, 56.2 percent of patients self-reported depression as a reason for the office-based encounter; 67.5 percent were prescribed or continued a regimen of antidepressant pharmacotherapy; and 48.3 percent were prescribed an SSRI or an SNRI. Factors predictive of receipt of antidepressant pharmacotherapy included age less than fifty years (OR = 1.30, CI = 1.01-1.67); female gender (OR = 1.45, CI = 1.13-1.85); and self-report of depression as a reason for the office-based encounter (OR = 1.98, CI = 1.57-2.51). Factors predictive of receipt of an SSRI or an SNRI included age less than fifty years (OR = 1.31, CI = 1.03-1.65); female gender (OR = 1.55, CI = 1.23-1.95); and self-report of depression as a reason for the office-based encounter (OR = 1.56, CI = 1.25-1.95). In addition, having private insurance increased the likelihood of having been prescribed an SSRI or SNRI by 46 percent (OR = 1.46, CI = 1.13-1.89). CONCLUSIONS: Among patients with a diagnosis of depression, the pattern of prescribing antidepressant pharmacotherapy is influenced by a patient's age, gender, self-report of depression, and type of insurance coverage. Further research is required to discern the reasons for these observed effects and to advance clinically rational and equitable access to pharmacotherapeutic innovation.

Cancer-screening determinants among Hispanic women using migrant health clinics.

This study was designed to identify determinants of breast and cervical cancer screening among rural, low-income Hispanic women using migrant health clinics in eastern Washington state. Five hundred and twelve foreign-born Hispanic women were interviewed. Odds ratios and 95 percent confidence intervals generated via logistic regression analysis were used to discern the influence of independent factors on use or nonuse of Papanicolaou (Pap) smear, breast self-examination (BSE), and mammography. Being married, having a higher income, more years of education, and longer U.S. residency predicted receipt of Pap smear. Women who performed BSE had higher incomes and were more likely to have been taught how to perform the procedure. Low concern for direct expenditure and increasing years of U.S. residency predicted receipt of mammogram. On the basis of these findings, implications for developing cancer-screening interventions using inreach and outreach strategies to target this high-risk subgroup are discussed.

Metered-dose inhaler technique and quality of life with airways disease: assessing the value of the Vitalograph in educational intervention.

The efficacy of delivering medicines by metered-dose inhaler (MDI) is well established, and the patient's technique with MDIs is related directly to achieving the desired clinical outcome. The present study was designed to assess and improve MDI technique by using a Vitalograph Aerosol Inhalation Monitor (VAIM) in an airways disease education programme. Baseline measurements were made immediately prior to educational intervention incorporating feedback from a VAIM unit. At 6 weeks' follow-up, MDI technique was found to have regressed to the sub-optimal measures recorded at baseline prior to educational intervention. However, patients reported a significant improvement in physical function between baseline and follow-up as measured by the Rand 36-Item Health Survey (SF-36), Version 1.0. The results reinforce the need for a longitudinal educational programme for patients prescribed medications delivered by MDI. The VAIM unit provided health educators and patients with both a visual and a quantitative assessment of patients' MDI technique, and was thus of positive value as part of the intervention process.