Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.

BACKGROUND: Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically. AIM: To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH. METHODS: Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters. RESULTS: Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33-3.36), 2.58 (95% CI, 1.68-3.97) and 3.39 (95% CI, 2.19-5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03-14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02-2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment. CONCLUSIONS: Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis.

Treatment options for a patient experiencing pruritic rash associated with transdermal testosterone: a review of the literature.

A 22-year-old man with hypogonadotropic hypogonadism was receiving monthly intramuscular injections of testosterone replacement therapy. The patient refused to self-administer the injections because of discomfort, so the therapy was switched to testosterone patches. He experienced a pruritic, macular, erythematous rash underneath the reservoir area of two different transdermal formulations, which did not improve after pretreatment with topical corticosteroids. Eventually, he tolerated application of a testosterone gel and his serum testosterone levels returned to normal after 1 month of therapy. Commercially available and investigational testosterone products and therapeutic monitoring guidelines for androgen replacement are reviewed.

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis.

STUDY OBJECTIVE: To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis. DESIGN: Open-label, randomized, crossover trial conducted with a phase I-II trial. SETTING: Government research hospital. PATIENTS: Five patients with lupus nephritis. INTERVENTION: Fludarabine 30 mg/m2/day was administered either subcutaneously or as a 0.5-hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m2 on the first day of each cycle. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6-hour intervals for 24 hours. Plasma and urine were analyzed for fluoro-arabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (0.38-0.56) and 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concentration-time curves from 0-24 hours of 4.65 (4.17-4.98) and 4.55 (3.5-4.94) mg x hour/L, respectively. Bioavailability of F-ara-A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing. CONCLUSION: Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration.

Repaglinide-induced factitious hypoglycemia.

We report the first case of repaglinide-induced factitious hypoglycemia in a young male. This case posed a challenging diagnostic dilemma because commercial assays for repaglinide are not available. Furthermore, the patient had a series of positive diagnostic tests such as high proinsulin and localizing intra-arterial calcium stimulation suggestive of insulinoma. This case, again, demonstrates the importance of pure clinical judgment in the face of often-conflicting laboratory data in making a correct diagnosis and the requirement of definitive data for an appropriate therapeutic resolution.

Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders.

OBJECTIVE: To describe a patient with primary hypothyroidism in whom ingestion of levothyroxine with calcium carbonate led to markedly elevated serum thyrotropin concentrations. CASE SUMMARY: A 61-year-old white woman with primary hypothyroidism, systemic lupus erythematosus, celiac disease, and history of Whipple resection for pancreatic cancer was euthyroid with levothyroxine 175-188 micrograms/d. After taking a high dose of calcium carbonate (1250 mg three times daily) with levothyroxine, she developed biochemical evidence of hypothyroidism (thyrotropin up to 41.4 mU/L) while remaining clinically euthyroid. Delaying calcium carbonate administration by four hours returned her serum thyrotropin to a borderline high concentration (5.7 mU/L) within a month. Serum concentrations of unbound and total thyroxine and triiodothyronine tended to decrease, but remained borderline low to normal while the patient concomitantly received levothyroxine and calcium carbonate. DISCUSSION: Concomitant administration of levothyroxine and calcium carbonate often results in levothyroxine malabsorption. While in most patients the clinical consequences of this interaction, even with prolonged exposure, are relatively small, overt hypothyrodism may develop in patients with preexisting malabsorption disorders. However, as the current case illustrates, the clinical manifestations of the initial levothyroxine deficit may not always be apparent and, of all usual laboratory thyroid function tests, only thyrotropin measurement will reliably uncover the exaggerated levothyroxine malabsorption. CONCLUSIONS: Decreased absorption of levothyroxine when given with calcium carbonate may be particularly pronounced in patients with preexisting malabsorption disorders. Once recognized, a change in drug administration schedule usually minimizes or eliminates this interaction.

Use of herbal therapies by adults seen in an ambulatory care research setting: an exploratory survey.

OBJECTIVE: To identify and characterize patterns of use of herbal products among patients participating in selected research clinics. DESIGN: Survey of three National Institutes of Health (NIH) ambulatory care research clinics. SUBJECTS: Convenience sample of 490 adult patients (168 male, 322 female) attending rheumatology, liver, and endocrinology/metabolic research clinics. RESULTS: Of the patients surveyed, 16.7%: (n = 82) reported using herbs. There were no significant sociodemographic differences between herb and nonherb users. Indications for herb use differed among the disease groups; patients in the endocrine and rheumatology clinics were taking herbs predominantly for "energy" or "wellness"; those attending the liver clinic tended to use herbal therapies as treatment for their disease. Mean and median monthly expenditure for herbal products was $30 and $10, respectively. There was a significant positive correlation between number of herbs used and use of other dietary supplements (p < 0.0001). CONCLUSIONS: One in six patients in ambulatory clinical research settings may be taking herbal products in addition to prescribed treatment. This figure is lower than in the general population, possibly because the patients may stop using herbs when participating in a research project. Although empirical evidence on the beneficial or adverse effects of herb therapy alone or in combination with drug therapies is limited, clinical researchers should be aware of the potential for confounding clinical trial results.

Increased levothyroxine requirements presenting as "inappropriate" TSH secretion syndrome in a patient with nephrotic syndrome.

Patients with primary thyroid failure on levothyroxine (LT4) replacement who develop nephrotic syndrome (NS) may rarely present with an increase in LT4 requirements. In this report, we describe a patient with thyroid failure following radioactive iodine ablation for Graves' disease who required an escalation of LT4 doses following the onset of NS. The case presented with disproportionately elevated TSH levels in the presence of normal (or slightly subnormal) thyroid hormone levels, thus, masquerading as a state of "inappropriate" TSH secretion. This pattern of extreme dysregulation in thyroid function indices due to urinary loss of thyroid hormones has not been previously described in NS, and, therefore, extends the spectrum of endocrine manifestations of NS.

Assessing the effects of thyroid suppression on benign solitary thyroid nodules. A model for using quantitative research synthesis.

Systematic review of the available information with a modified, largely quantitative method of research synthesis disclosed that an initial trial of thyroid hormone suppression therapy leads to clinically significant (> or = 50%) reduction of nodule size or arrest of nodule growth in a subset of patients with benign solitary thyroid nodules. In fact, in addition to objective improvements due to decreasing nodule size, L-T4 suppression therapy may benefit patients by reducing perinodular thyroid volume. Consequently, both pressure symptoms and cosmetic complaints may improve (9, 68). Additional studies for the assessment of the risks versus benefits of supraphysiologic doses of L-T4, the optimal level of thyroid suppression and the dose needed to achieve this magnitude of reduction, the optimal length of the initial trial, and the conditions for the continuation of L-T4 thyroid suppression therapy, as well as the identification of markers for patients most likely to respond to this therapy, are warranted. Finally, quantitative assessment of available evidence as described here may be applicable to the review of other controversial issues as well.

A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy.

BACKGROUND: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. PATIENTS AND METHODS: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1-2, 20 mg/m2/day x 2 days, cycles 3-6, 20 mg/m2/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12-48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. RESULTS: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by > or = 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. CONCLUSION: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine.

Levothyroxine replacement therapy in central hypothyroidism: a practice report.

Because of lack of well-documented laboratory criteria, we assessed the usefulness of measuring free thyroxine (FT4) levels for monitoring levothyroxine replacement therapy in patients with central hypothyroidism. This consisted of a retrospective review from 1991-1997 of patient profiles extracted into a Macintosh 4th Dimension data base from the medical information system at a tertiary care biomedical research facility. Information was also retrieved from medical records of 135 ambulatory patients treated by 42 endocrinology practitioners, and 52 ambulatory patients treated by 20 endocrinology practitioners for central and primary hypothyroidism, respectively. Patient profiles were reviewed for most recent thyroid function test results and levothyroxine dosing information. Of 112 (83%) patients with central hypothyroidism who had FT4 levels within the laboratory's reference interval, only 2 had a dosage change. The FT4 concentration was concordant with physician-assessed thyroid status in 65 (82%) of 79 patients (95% CI 72-90, p<0.02) for whom clinical assessment was available in medical records. Thyrotropin, total thyroxine, and triiodothyronine levels were not significantly associated with clinical status (p>0.12) in patients with central hypothyroidism. Despite similar demographic and levothyroxine dosing profiles, patients with central hypothyroidism had significantly lower serum FT4 and thyrotropin concentrations than those with primary hypothyroidism. The appropriateness of levothyroxine replacement therapy in most patients with central hypothyroidism is reflected by a normal FT4 concentration measured with a valid assay. Whether midnormal or upper normal values are necessary for optimal therapy, and whether the therapeutic goal should be different in children than in adults, require prospective studies with independent, objective assessment of thyroid status.

A pilot study: use of fludarabine for refractory dermatomyositis and polymyositis, and examination of endpoint measures.

OBJECTIVE: To study the effects of the adenine analog, fludarabine, on patients with refractory dermatomyositis and polymyositis, and to assess variables used in following myositis patients during medical intervention. METHODS: Patients whose myositis was not controlled by prednisone and at least one other immunosuppressive medication were entered into a pilot study during which they received 6 monthly cycles of intravenous fludarabine. Patients were assessed at baseline, every other month, and at month 7 for primary outcome measures of strength and function. Other measurements including peripheral blood cell subsets, muscle enzymes, and various assessments of disease activity were followed monthly during the fludarabine infusion period and for up to 6 months post therapy. RESULTS: Of 16 patients who entered the study, 4 patients were classified as improved, and 7 patients were classified as unchanged. Five patients who withdrew before month 7 were classified as treatment failures. Fludarabine caused a significant and prolonged lymphopenia without an increase in infectious complications over that seen with other immunosuppressive agents used for myositis. A sudden death of one patient at the end of the study was not thought to be drug related. Variables followed during the study emphasized the distinction between patient functional improvement and disease remission. CONCLUSION: A subset of patients with refractory myositis may benefit from fludarabine therapy and controlled trials are indicated. Refinement and validation of variables useful for following myositis patients await larger studies.

The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis.

STUDY OBJECTIVE: To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA). DESIGN: Open-label, staggered trial conducted in conjunction with a phase I-II clinical trial. SETTING: Government research hospital. PATIENTS: Twenty-six patients with refractory RA. INTERVENTION: Fludarabine 20 or 30 mg/m2/day was administered as a 0.5-hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo). MEASUREMENTS AND MAIN RESULTS: Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two-compartment model. There were no differences in pharmacokinetics between the low- and high-dose groups. The mean+/-SD total clearance, volume of distribution at steady state, and beta-half-life were 13.68+/-5.1 L/hour, 170.08+/-86.5 L, and 10.9+/-3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters. CONCLUSION: Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate-length distribution phase (approximately 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.

The interdisciplinary team's approach to lupus nephritis.

The interdisciplinary team approach in assessment and treatment of patients with chronic disease in general and lupus nephritis in particular provides a global format for identifying the multiple problem areas that retard or prevent optimal patient functioning. These areas include the physical, emotional, economic, psychosocial, and functional. Benefits to the individual patient include a thorough multifaceted assessment by professionals who have the benefit of peer collaboration and validation. This increases the likelihood that the whole patient is considered, not just the problem of nephritis. For example, how does the patient and her or his family cope with the impact of such a disease and how, in turn, do the coping abilities of the patient and family affect the disease. The interdisciplinary team also assesses how the treatment strategies for each problem area influence each other. Finally, the interdisciplinary team serves as a positive role model for effective collaboration among health professionals and for students in their respective disciplines.

Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.

BACKGROUND: Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. METHODS: In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. RESULTS: PAI-1 levels were inversely associated with D-dimer levels at base line (r= -0.540, P=0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (+/-SD) plasma levels of PAI-1 from 32+/-34 ng per milliliter to 14+/-10 ng per milliliter (P<0.001) and from 31+/-29 ng per milliliter to 15+/-11 ng per milliliter (P=0.003), respectively; there was a significant inverse correlation between pretreatment PAI-1 levels and the degree of reduction in these levels during therapy (r= -0.631, P<0.001 for conjugated estrogen; r = -0.507, P=0.004 for combined therapy). The degree of reduction in PAI-1 levels was associated with increases in D-dimer levels both when conjugated estrogen was given alone (r= -0.572, P=0.001) and when combined hormone therapy was given (r= -0.541, P=0.002). Transdermal estradiol caused no significant changes in PAI-1 levels from base-line values. CONCLUSIONS: Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis. These findings may partly explain the protective effect of hormone-replacement therapy with respect to coronary artery disease.

Effects of restricting levothyroxine dosage strength availability.

We conducted a prospective, randomized, controlled trial to assess whether hospital formulary restrictions involving limiting dosage strengths of levothyroxine affect physicians' ability to manage patients effectively and provide pharmacy cost savings in a tertiary care federal government research hospital. Thirty-three endocrinologists were randomly assigned to prescribe levothyroxine from a restrictive (dosage strengths of 25, 50, 100, 125, and 150 micrograms) or a nonrestrictive (dosage strengths of 25, 50, 75, 100, 112, 125, 150, 175, 200, and 300 micrograms) formulary through a central computer system. Their 241 respective outpatients' laboratory results and drug compliance were outcome measures. Achievement of treatment objectives was measured by thyroid function tests (free and total thyroxine, total triiodothyronine, thyrotropin), number of clinic visits, and compliance (survey method). Additional measures were drug distribution patterns, drug costs, and pharmacy inventory costs. Restriction of levothyroxine's dosage strength did not significantly alter therapeutic outcomes. However, the restricted formulary was associated with more complex dosing regimens, and resulted in no significant cost savings. It is not known whether such restriction would adversely affect the care of patients of nonspecialists. Prospective studies are required to verify presumed cost-containment measures before such measures are adopted for widespread application.

Modified oral ondansetron regimen for cyclophosphamide-induced emesis in lupus nephritis.

OBJECTIVE: To evaluate the antiemetic efficacy of a modified regimen of oral ondansetron and dexamethasone in patients with lupus nephritis undergoing treatment with cyclophosphamide whose conventional antiemetic regimen had failed. DESIGN: A before-after prospective observational pilot project. SETTING: A federal research hospital. PATIENTS: Fourteen outpatients with lupus nephritis receiving intravenous cyclophosphamide 0.75-1.0 g/m2 had previously experienced chemotherapy-induced emetic events (vomiting or retching) while receiving a standard combination intravenous antiemetic regimen. The regimen consisted of four doses of thiethylperazine 10 mg and diphenhydramine 25 mg every 6 hours, and two doses of lorazepam 0.5 mg every 6 hours starting at 1 hour prior to cyclophosphamide. A subset of 8 patients previously completed a blinded study in which they received the intravenous formulation of ondansetron (4 doses of 4-16 mg q4h) administered orally beginning 30 minutes prior to the cyclophosphamide infusion. MAIN OUTCOME MEASURES: The number of emetic events and cost of drug administration were assessed for the modified ondansetron intervention and compared with those of the standard antiemetic regimen. The incidence of emetic events and visual analog nausea scores for the subset of eight patients were also evaluated. INTERVENTIONS: To account for the delayed onset of emesis associated with cyclophosphamide, patients received both ondansetron 8 mg orally every 4 hours (3 doses) and dexamethasone 10 mg orally (1 dose) beginning 4 hours after the cyclophosphamide infusion. This is different from the manufacturer's recommended dose schedule, in which ondansetron is administered prior to chemotherapy. RESULTS: No emetic events were observed following the administration of oral ondansetron/dexamethasone. The 95% confidence interval for the true rate of emesis was 0% to 19.3%. There was a significant difference in efficacy between ondansetron/dexamethasone and the triple antiemetic regimen (p < 0.0002). None of the patients experienced adverse effects while receiving the ondansetron/dexamethasone regimen. Cost comparisons (including admixture and nursing administration times) for standard combination therapy and oral ondansetron/dexamethasone were $109.09 and $70.24, respectively. No difference in emetic events or nausea ratings was observed between oral ondansetron/dexamethasone tablets and oral administration of ondansetron using the intravenous formula. CONCLUSIONS: This study suggests that a modified oral ondansetron/dexamethasone regimen is safe and efficacious, and costs less than alternative regimens to prevent cyclophosphamide-induced emesis in patients with lupus nephritis.

Patient-interactive computer system for obtaining medication histories.

A portable, patient-interactive computerized system for obtaining medication histories is described. A comprehensive interview script modeling pharmacist-conducted medication-history interviews was written in lay language. The script contains sections on demographics, current medical conditions, medication regimen, medication compliance, symptoms, allergy history, dietary history, psychosocial history, and occupational and environmental exposure; it also asks the patient to evaluate the system. Some of the information requested is often not obtained by physicians during the history and physical examination. A program that conducts the interview by processing a computerized version of the script was developed with Microsoft QuickBASIC. The program was designed to be run on a personal computer microprocessor so that an interview can be conducted virtually anywhere by using a desktop or laptop computer. Summary reports suitable for inclusion in the medical record are generated after each interview. Patients using the system took an average of 40 minutes to complete an interview. They entered data easily and accurately, and they gave the system a high overall rating. The medication-history interviewing system described produces useful, comprehensive, and consistent reports and requires about the same amount of time to conduct an interview as a human interviewer.

Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients.

Patients receiving exogenous levothyroxine are reported to have higher total and free serum thyroxine levels than euthyroid controls. This may be an artifact of the serum collection time. We explored the effect of collection time on serum levels of thyroid hormones in outpatients receiving levothyroxine for replacement therapy (26 patients) or suppression of thyrotropin (25 patients). Blood samples, obtained during regular clinic visits (random samples) and at more than 22 h from ingestion of levothyroxine (trough samples), were assayed for total and free thyroxine, triiodothyronine, and thyrotropin. Four athyreotic patients on levothyroxine therapy had serial blood sampling over 24 h. Compared to corresponding trough samples, random samples had elevated total thyroxine levels in patients receiving replacement (8.1 +/- 1.2%, mean +/- SE, p = 0.0001) and in patients undergoing suppression (8.8 +/- 1.6%, p = 0.0001). Free thyroxine was increased by 12.7 +/- 2.6% (p = 0.0003) and 14.5 +/- 2.3% (p = 0.0001), respectively, compared with trough samples. Thyrotropin levels were 18.9 +/- 6.8% (p = 0.003) lower in patients receiving replacement and triiodothyronine levels showed small or no changes. Time-course analysis showed that free and total thyroxine levels remained significantly elevated above baseline for 9 and 5 h, respectively, after a levothyroxine dose. In conclusion, there is a transient increase in thyroid hormone levels for 9 h after an oral levothyroxine dose. Accurate assessment of thyroid hormone levels in patients receiving levothyroxine therapy should take this into account. This has greatest significance in selecting minimal levothyroxine dosages for suppression of thyrotropin.

Development of a questionnaire for detecting potential adverse drug reactions.

OBJECTIVE: To develop a comprehensive list of symptoms categorized by body system as part of a questionnaire for detecting potential adverse drug reactions. DATA SOURCES: A preliminary list of symptoms in lay terminology was extracted from the "Side Effects" section of all drug monographs contained in the United States Pharmacopeia Dispensing Information (USP DI) computerized database (Volume II, Advice for the Patient) using natural language processing software. The list was sorted alphabetically and duplicate terms were eliminated. Symptoms were then categorized by body system or anatomic region. A preferred term for each symptom was selected when multiple synonyms and related words were listed. Finally, all of the symptom terms were incorporated into a thesaurus from which the questionnaire was derived. RESULTS: The questionnaire will be used as part of a computer-assisted interview, developed to solicit information from patients regarding their medication regimens and to systematically query them regarding the presence of salient symptoms or complaints. The computer system will eventually interface with the USP DI database to identify drugs from a patient's regimen that may be associated with adverse symptoms. The symptom thesaurus will provide the link to the USP DI database. Preliminary experience with the questionnaire in a limited number of patients has been encouraging. CONCLUSIONS: The questionnaire can assist clinicians in identifying drug-related symptoms including unreported adverse clinical effects of newly marketed or investigational therapeutic agents. When the questionnaire is computerized and linked to a comprehensive database, it can be more widely used to alert healthcare providers of potential adverse drug reactions that may otherwise go undetected.

Automated therapeutic drug monitoring in an ambulatory care endocrine clinic.

OBJECTIVE: To develop and implement an automated therapeutic drug monitoring system for accessing data from endocrine clinic patients who had been prescribed insulin, oral hypoglycemic agents (OHA), or levothyroxine. DATA SOURCES: We designed a computer system to retrieve clinical data from the Medical Information System (MIS), a centralized hospital computer system, and import this information directly into a Macintosh personal computer. Physician entry of prescriptions for insulin, OHA, or levothyroxine into MIS formed the basis for a computer program to retrieve daily diagnostic and prescription information, demographics, and laboratory analyses, including blood glucose and glycosylated hemoglobin for insulin and OHA orders and free and total thyroxine, total triiodothyronine, and thyroid stimulating hormone for levothyroxine orders. The information was imported into a database program (4th Dimension). RESULTS: The system identifies laboratory values outside of predetermined therapeutic ranges, maintains an up-to-date patient profile, and edits and generates reports. Preliminary experience suggests that automation eliminates 75-90 percent of the time required to manually collect the same information, and improves the accuracy, comprehensiveness, and utility of reports. CONCLUSIONS: Automated therapeutic drug monitoring minimizes the time required to collect clinical data, alerts clinicians to potential problems, and provides a means to assess overall therapeutic management. Our methodology can be used to evaluate other medications in a variety of general or specialty clinics.