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PubMed2005

Intestinal perforation in very low birth weight infants: growth and neurodevelopment at 1 year of age.

OBJECTIVE: To compare growth and neurodevelopment in surviving very low birth weight (VLBW) infants with an intestinal perforation (IP) caused by necrotizing enterocolitis (NEC) versus spontaneous intestinal perforation (SIP). STUDY DESIGN: Retrospective, observational cohort study. Infants born between January 1996 and December 1999 with birth weight <1500 g and a diagnosis of intestinal perforation were identified and data extracted from NICU, surgical and hospital databases. RESULTS: IP was identified in 62 of 1357 VLBW infants (5%); 39 infants (63%) had surgical NEC and 23 (37%) had SIP. Among survivors, 21/28 with surgical NEC (75%) and 13/18 with SIP (72%) returned for follow-up. At 1-year adjusted age, there were no differences in growth parameters but the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) were lower in survivors with NEC versus SIP (mean difference in MDI=15; 95% confidence limits=3, 28; p=0.02; mean difference in PDI=14; 95% confidence limits=0.4, 28; p=0.04). CONCLUSIONS: Intestinal perforation caused by NEC, as compared to SIP, is associated with worse neurodevelopmental outcome at 1 year.

Child Development↗
PubMed1999

Level of amputation following failed arterial reconstruction compared to primary amputation--a meta-analysis.

OBJECTIVES: To determine if the level of amputation after failed vascular reconstruction was comparable to the level of amputation after primary amputation. DESIGN AND METHODS: Medline literature search (1975-1996), meta-analysis. RESULTS: The odds ratio of transtibial to transfemoral (TT/TF) amputations was 927/657 = 1.41 (95% confidence limits: 1.278-1.561) in postrevascularisation amputation (PRVA) and 1590/1162 = 1.37 (95% confidence limits: 1.269-1.477) in primary amputation (PA) (p = 0.65). The pooled data show that the number of conversions from transtibial (TT) to transfemoral (TF) amputations due to amputation stump complications were 85/369 (23%) in PRVA against 93/752 (12.4%) in PA (p < 0.01). CONCLUSIONS: We could not detect any difference in TT/TF ratio between PRVA and PA. However, the risk of conversion i.e. reamputation to a higher level is higher after PRVA compared to PA. The chance of having a successful transtibial amputation is approximately 58% for postrevascularisation amputation as well as for primary amputations. An aggressive approach towards vascular reconstruction seems justified.

Amputation, Surgical↗
PubMed1988

A clinical trial of nonoxynol-9 for preventing gonococcal and chlamydial infections.

A randomized, double-blind, placebo-controlled trial was conducted to evaluate the spermicidal agent nonoxynol-9 as prophylaxis for cervical infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Eight hundred eighteen women were recruited from a sexually transmitted disease clinic. Only subjects who were using reliable birth control methods (oral contraceptives, intrauterine device, or sterilization) were eligible. Subjects were randomly assigned to use either a commercially available spermicidal agent containing nonoxynol-9 or a placebo preparation. Subjects were followed up for six months; specimens were collected monthly for culture of the two pathogens. Women assigned to the nonoxynol-9 group were less likely to become infected with N. gonorrhoeae (relative rate, 0.75; 90% confidence limits, 0.58 and 0.96) and C. trachomatis (relative rate, 0.79; 90% confidence limits, 0.64 and 0.97). Among women who used their assigned gel for the majority of coital episodes, a stronger protective effect was observed.

Adult↗
PubMed1989

Evaluation of a blood gas and chemistry monitor for use during surgery.

An observational study was performed to evaluate a new blood gas and chemistry monitor (GEM-6 Diamond Sensor Systems, Ann Arbor, Michigan) in nine patients during cardiac surgery. Paired blood samples were analyzed by the instrument under test and by standard clinical laboratory instruments. The differences between the measurements of the new and the standard instruments are summarized as follows (mean +/- standard deviation, units of measure, number of samples): pH (-0.039 +/- 0.02, 154); PCO2 (2.63 +/- 1.8 mmHg, 154); venous PO2 (-2.0 +/- 3.0 mmHg, 72), hematocrit (4.7 +/- 2.7%, 98), potassium (0.18 +/- 0.13 mmol, 100), and ionized calcium (0.195 +/- 0.11 mmol, 100). Because the differences in arterial PO2 measurements were markedly heteroscedastic, a logarithmic transformation was employed, which upon retransformation gave the test instrument's 95% confidence limits as within 5.1% below to 46% above the nominal value on 82 samples. However, on the 14 samples having nominal values below 165 mmHg (the upper limit of the calibrated range of the GEM-6) the 95% confidence limits were from 5.4% below to 23.6% above the nominal reading. No failures of the test instrument occurred during the evaluation, and quality control standards run before, midway through, and again after sampling from each patient all gave readings within the manufacturer's tolerance. For all variables except hematocrit and ionized calcium, this instrument matches the values from the laboratory well enough over the clinically important range to supplant it for intraoperative monitoring purposes.

Acid-Base Equilibrium↗
PubMed1993

Dietary vitamin C and serum lipids in black and white girls.

We examined the cross-sectional relation of dietary vitamin C intake to serum lipids in 1,825 preadolescent black and white girls. Dietary vitamin C intake exclusive of supplement use, determined by 3-day diet record, appeared unrelated to total serum cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels. Because other investigators have demonstrated an inverse association between vitamin C and total serum cholesterol in individuals with elevated total serum cholesterol levels, we analyzed the subgroup of 285 girls (142 blacks and 143 whites) with total serum cholesterol levels > or = 200 mg per dl. Multivariate analyses of this subgroup, which adjusted for saturated fat, polyunsaturated fat, monounsaturated fat, cholesterol, fiber, and energy intake and for body mass index, demonstrated negative association between vitamin C intake and total serum cholesterol. In girls with total serum cholesterol levels > or = 200 mg per dl, each 100 mg per day increase in dietary vitamin C intake (ranges 13-373 and 14-242 mg per day for blacks and whites, respectively) was associated with a total serum cholesterol decrease of 4 mg per dl (95% confidence limits = -10.34, 2.77) in blacks and 13 mg per dl (95% confidence limits = -22.99, -2.68) in whites. If the observed association is causal and generalizable, our results suggest that increased vitamin C intake could play an important role in the cholesterol homeostasis of females with elevated total cholesterol levels.

Ascorbic Acid↗
PubMed1997

Social support, stress, and blood pressure in black adults.

Psychosocial factors arising from socioeconomic disadvantage and discrimination may contribute to the excess risk of elevated blood pressure in African-Americans. The purpose of this study was to assess the association of social support and stress with blood pressure in a community-based sample of 25-to 50-year-old black adults in Pitt County, NC. A stratified random sample of dwellings was selected in 1988, and 1,784 black adults (80% of those eligible) were interviewed. Analyses were sex specific and adjusted for age, obesity, and waist/hip ratio. In separate analyses of emotional support, instrumental support, and stress with blood pressure, all associations were in the predicted direction (inverse for support, direct for stress) but were stronger for systolic than for diastolic blood pressure. Differences in systolic blood pressure associated with low support or high stress ranged from 5.2 to 3.6 mmHg in women and 3.5 to 2.5 mmHg in men. In simultaneous regression analyses of support and stress, each of the separate effects was reduced for women, but a sizable aggregate effect of low support and high stress remained [+7.2 mmHg (95% confidence limits = +1.3, +13.1) for systolic blood pressure and +4.0 mmHg (95% confidence limits = +0.1, +7.9) for diastolic blood pressure.

Adult↗
PubMed2004

Scandinavian Total Ankle Replacement (STAR).

Fifty-eight patients with either rheumatoid arthritis or osteoarthritis were treated with meniscal-bearing ankle prostheses. The concept was to mobilize, align, and stabilize the ankle before resurfacing it. Cement was used for prostheses fixation in 33 patients (1986-1989) and 25 patients had fixation without cement (1990-1995). All patients in one prospective series were followed up yearly with radiographs and with a clinical scoring system giving a maximum of 100 points. This allowed for a patient-controlled prospective study. No patients were lost to followup. The only detectable difference in the treatment was the fixation mode. For the purpose of comparing patients with cemented and uncemented prostheses, the patients who had surgery between 1986 and 1989 were not followed up after 1997, and patients who had surgery between 1990 and 1995 were not followed up after 2002. The mean followup was 9.4 years. Failure was defined as prosthesis revision or change to arthrodesis for any reason. In the cemented group, nine of 33 patients had revision surgery or fusion. In the uncemented group, one of 25 patients had revision surgery. Survivorship analysis for 12 years based on life tables showed a 70% survival rate (confidence limit, 60.3-78.5) for the cemented group and 95.4% survival rate (confidence limit, 91.0-99.9) for the uncemented group. The average clinical scores at the latest followup were 74.2 +/- 19.3 for the cemented group and 91.9 +/- 7.4 points for the uncemented group. Therefore, unconstrained meniscal-bearing ankle prostheses should be uncemented.

Adult↗
PubMed1993

A comparison between estimates of GFR using [99mTc]DTPA clearance and the approximation of Cockcroft and Gault.

BACKGROUND: The formula of Cockcroft and Gault, relating age, weight, sex and plasma creatinine is widely used to estimate glomerular function. Its ability to predict [99mTc]DTPA clearance, an accepted measure of GFR, is therefore of interest. AIM: To test prospectively the reliability of the formula in predicting the [99mTc]DTPA clearance in subjects with normal and sub-normal renal function. METHODS: The 24 hour creatinine clearance (Ccr), the derived clearance using the formula (Cder), and the [99mTc]TPA clearance have been compared in 47 male and 47 female subjects, aged between 15 and 71 years. Obese and non-obese subjects (males > 90 kg, females > 80 kg body weight) were considered separately. RESULTS: Across the range of [99mTc]DTPA clearance studied (14 to 125 mL/minute), in non-obese subjects, both Ccr and Cder were correlated similarly with [99mTc]DTPA clearance in males and females. In obese subjects as a group, Cder was also closely correlated with [99mTc]DTPA clearance but the scatter of data was wider. Among non-obese subjects, correlations were high between either Ccr or Cder and [99mTc]DTPA clearance values < 101 mL/minute but were not significant at [99mTc]DTPA clearance values > 100 mL/minute. For [99mTc]DTPA clearance values between 14 and 100 mL/minute, Cder was a more direct and more precise predictor of [99mTc]DTPA clearance [DTPA clearance = 1.01 (Cder) + 2.34, with 95% confidence limits of +/- 18 mL/minute] than of Ccr [Ccr = 1.34(CderC)-10.86, confidence limits +/- 28 mL/minute]. CONCLUSION: For very mild through to moderate renal failure, the formula of Cockcroft and Gault can evidently be used as a reasonable estimate of GFR.

Adolescent↗
PubMed1992

Impact of enalapril therapy on in vitro coronary artery responsiveness in pacing-induced heart failure.

In vitro coronary artery responsiveness to angiotensin I, angiotensin II, noradrenaline, phenylephrine, BHT 920, and potassium chloride together with functional relaxation to acetylcholine was investigated in dogs with pacing-induced heart failure treated with enalapril (oral administration of 10 mg.day-1) for a mean duration of 26 days. Although maximal responses generated to both angiotensin I and angiotensin II were unaltered in the enalapril-treated group, angiotensin II became more potent following enalapril treatment: the EC50 for angiotensin II following placebo treatment was 2.4 (0.6-5.8; 95% confidence limits) nM and following enalapril treatment was 0.03 (0.007-0.1; 95% confidence limits) nM. In addition to the above changes, coronary artery rings from dogs treated with enalapril developed significantly less tension to noradrenaline, phenylephrine, and BHT 920. In contrast, responses to potassium chloride were unaltered following enalapril treatment. However, the relaxation to acetylcholine was enhanced from 38.9 +/- 3.0 to 50.4 +/- 3.5% (placebo versus enalapril, p < 0.05). These findings indicate that enalapril may possess alpha-blocking properties and enhance the relaxation response to acetylcholine through an endothelial-dependent mechanism in addition to inhibiting converting enzyme.

Acetylcholine↗
PubMed1985

Effect of cigarette smoking on the pulmonary function of children and adolescents.

The effect of personal cigarette smoking on the growth of lung function in children and adolescents has been assessed in a longitudinal study of a group of 669 subjects 5 to 19 yr of age at initial examination. Subjects were seen annually and assessed with standard questionnaires and measurements of forced expiratory volume in one second (FEV1) and forced expiratory flow during the middle half of the forced vital capacity (FEF25-75). Multiple regression analysis revealed that after correction for previous FEV1 or FEF25-75, age, sex, height, change in height, interactions of age and change in height, and sex and height, and mother's smoking, the personal smoking by the children led to a significant decrease in the rate of growth of FEV1 (p less than 0.001) and FEF25-75 (p = 0.033). On the basis of this analysis, it is estimated that, on average, children who begin to smoke at 15 yr of age and continue to smoke would achieve only 92% (95% confidence limit, 87 to 96%) of their expected FEV1 and 90% (95% confidence limit, 81 to 99%), of their expected FEF25-75 at 20 yr of age. These data suggest that relatively small amounts of cigarette use (median total consumption of 7,300 cigarettes in this study) by adolescents can lead to significant effects on the growth of lung function.

Adolescent↗
PubMed1983

Distribution and metabolism of L- and D-triiodothyronine (T3) in the rat: preferential accumulation of L-T3 by hepatic and cardiac nuclei as a probable explanation of the differential biological potency of T3 enantiomers.

Previous studies have reported markedly lower biological potency of D-T3 than would be predicted from its relative affinity for the specific nuclear L-T3 receptor as measured in vitro. Studies were undertaken to define the basis of this discrepancy. In vitro studies of the relative binding affinities of [125I]L-T3 and [125I]D-T3 using either whole nuclei or partially purified solubilized receptor confirmed several previous reports which had indicated only small relative differences. The mean L/D binding ratio of all in vitro studies was 1.43. In contrast, we determined from measurement of final alpha-glycerophosphate dehydrogenase activity that the potency ratio (L/D) after seven daily injections of graded doses of L- and D-T3 was 6.7 for liver, with 95% confidence limits of 4.1 to 10.8, and 15.9 for heart, with 95% confidence limits of 5.1 to 50.2. Difference in biological potency could not be attributed to differences in the metabolism of L- and D-T3. Thus, tracer [125I]L- and [125I]D-T3 studies showed that the mean residence time, t, of L-T3 was not different from that of D-T3 [10.6 +/- (SE) 3.1 h vs. 11.4 +/- 3.8 h]. The MCR for L-T3 was 19.1 +/- 4.4 ml/h . 100 g BW and for D-T3, 26.1 +/- 5.6 ml/h . 100 g BW. The volume of distribution of L-T3 (181 ml/100 g BW) was 68% that of D-T3 (263 ml/100 g BW), in part owing to the 27% greater plasma binding (bp) of L-T3. Moreover, the calculated free hormone clearance (MCR X bp) of D-T3 was only 8% greater than for L-T3. Throughout the 24 h after injection of the [125I]L- or D-T3, concentrations of the D-enantiomer in liver were almost twice those of [125I]L-T3, whereas in heart [125I]D-T3 concentrations were half or less those of [125I]L-T3. Nevertheless, in both liver and heart, the integrated nuclear occupancy of L-T3 was 5 to 6 times that of D-T3, approaching the ratio in biological potency observed in the tissues. Thus, selective nuclear binding of L-T3 vs. D-T3 in vivo appears to be a major determinant in the relative biological effects of these enantiomers.

Animals↗
PubMedDate not supplied

A comparison of urine sample to urethral swab for detection of Chlamydia trachomatis in asymptomatic young men using two enzyme immunoassays.

First catch early morning urine samples were compared to urethral swabs for detection of Chlamydia trachomatis in 405 male military conscripts, using 2 enzyme immunoassays, Syva Microtrak EIA (SME) and ABBOTT Chlamydiazyme (AC). The prevalence rate of C. trachomatis was 7.9% (95% confidence limits 5.5%-11.0%), and the asymptomatic carrier rate was 7.8% (95% confidence limits 5.2%-11.2%). Only 5 of 32 conscripts with positive test results for C. trachomatis complained of urethritis symptoms, and of 13 conscripts with symptoms, only 5 had positive test results for C. trachomatis. The sensitivity of SME in detecting C. trachomatis was 82.1% for both urine samples and urethral swabs. Assayed with AC, the sensitivity was 62.1% for urine samples and 41.4% for urethral swabs (P greater than 0.05). With urine as specimen type, the sensitivity of SME was 82.8% and the sensitivity of AC was 62.1% (P greater than 0.05). With urethral swab as specimen type, the sensitivity of SME was 92.3% and the sensitivity of AC was 46.1% (P less than 0.01). In all assays, the specificity was at least 98.0%. First catch early morning urine seems to be a valid specimen type for the detection of C. trachomatis in young men in comparison to ordinary urethral swab specimens. It is a noninvasive method and suitable for screening of asymptomatic young men.

Adult↗
PubMedDate not supplied

Planned sequence of gemcitabine followed by vinorelbine in the treatment of elderly patients with advanced non-small cell lung cancer.

BACKGROUND: The rationale for planned sequential chemotherapy is based on the principle that sequential administration of non-cross-resistant cytotoxic agents has the advantage of eliminating additive toxicity and permitting the delivery of full doses of each drug. At present, there is a lack of data on the results of planned sequential single agent administration in elderly patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to explore the possibility of increasing the time-to-progression (TTP) by a 1.5 factor in comparison with the historical results of monochemotherapy with a first-line planned sequential administration of gemcitabine (GEM) and vinorelbine (VNR). PATIENTS AND METHODS: GEM 1000 mg/m2 was administered intravenously (i.v.) for 30 min on days 1, 8 and 15 and recycled on day 28 for a total of 3 cycles. Independently of response, VNR was administered i.v. as a bolus at a dose of 25 mg/m2 on days 1, 8 and 15 of a 28-day cycle. VNR treatment was continued until disease progression or intolerance. RESULTS: Fifty-two consecutive patients, with a median age of 76 years (70-85), affected by locally advanced (35%), metastatic (54%) or recurrent (11%) NSCLC were enrolled. The overall best objective response was 3.8% CR, 19.2% PR, 32.7% SD, 23.1% disease progression and 21.2% not evaluable. Both drugs were well tolerated. The median TTP was 6 months (95% confidence limits 4-8), the median overall survival was 10 months (95% confidence limits 6-14) and the one-year survival rate was 42%. CONCLUSION: The planned sequential administration of GEM and VNR suggests that the TTP can be increased with the use of the 2 single agents in elderly patients with locally advanced or metastatic NSCLC.

Age Factors↗
PubMed2006

[Differences in serum retinol level between the breastfed and non-breastfed children aged 0 to 23 months].

OBJECTIVE: Some recent studies found that high prevalence of vitamin A deficiency in the breastfed children. This study aimed to understand the differences in serum retinol level between breastfed and bottle-fed children aged 0 to 23 months and the possible causes of low level of serum retinol for the breastfed children. METHODS: Data for children aged 0 to 23 months were extracted from a population-based cross sectional study for vitamin A nutrition status. Fluorescence method was used to measure the serum retinol. Mothers or caregivers were asked to answer a pre-designed questionnaire and socioeconomic status, peri-natal care, breastfeeding status, morbidity histories and other related factors were collected. Semi-quantitative food frequency questionnaire was used to investigate the child's dietary intake one week prior to the survey. Data were analyzed using SAS 8.1. RESULTS: Of 401 children aged 0 to 23 months, the breastfeeding rate was 50.37%. The means of the serum retinol level between bottle-fed (30.67 +/- 0.57) microg/dl and the breastfed children (27.60 +/- 0.56) microg/dl was significantly different (P < 0.01). The corresponding figures were (31.82 +/- 0.98) microg/dl and (29.46 +/- 0.96) microg/dl after adjustment for confounders, which also showed significant difference (P < 0.01). After stratified by age groups, the breastfeeding rates in the 0-, 6-, 12- and 18-months groups were 92.1%, 70.1%, 32.0% and 17.1%, respectively. We calculated the difference in means of the serum retinol level between the bottle-fed and breastfed children for each of four age groups, and the 95% confidence limits of the differences. The differences in means and the 95% confidence limits for 0-, 6-, 12- and 18-months group were 4.70 microg/dl (-2.52-1.92), 0.82 microg/dl (-2.32-3.95), 2.95 microg/dl (-0.68-6.58) and 6.05 microg/dl (2.34-9.77), respectively. After adjustment for confounders and covariates, the adjusted figures were 0.00 microg/dl (-7.18-7.19), 1.35 microg/dl (-1.76-4.45), 2.92 microg/dl (-0.82-6.65) and 4.26 microg/dl (0.71-7.81), respectively. The significant difference in means of serum retinol level was only found in the 18-months group before or after adjustments (P < 0.01 for both). The Cochrane-Atmitage chi square trend test showed that the breastfed children tended to have lower frequencies of complementary dietary intakes than that of the bottle-fed aged 12 months and above. CONCLUSIONS: The breastfed children aged 0 to 23 months had relative low serum retinol level while compared with the bottle-fed. However, the significant differences seemed to be only confined to those aged 18 months and above. Low level of vitamin A in breast milk and low frequent complimentary food supplements might have served as the potential for the differences.

Breast Feeding↗
PubMed1990

[Latin American regional reference materials for porcine heparin and bovine heparin].

In agreement with the Regional Programme of Reference Materials of the Panamerican Health Organization the Instituto Nacional de Farmacología y Bromatología of Buenos Aires designed a study for the calibration of a Reference Material for Heparin, porcine, mucosal and a Reference Material for Heparin, bovine, mucosal. The assay methods used in this study were those described in the United States Pharmacopeia XXI Ed and British Pharmacopoeia 1980, Addendum 1983. The overall combined potency estimates of both heparin in preparations relative to 4th Int.St. was 1633.83 UI/ampoule (95% confidence limits 1609.70-1657.96 UI/ampoule) for porcine heparin and 1332.31 UI/ampoule (95% confidence limits, 1302.31-1361.77 UI/ampoule) for bovine heparin. The assigned unitage was 1630 UI/ampoule for the porcine Reference Material and 1330 UI/ampoule for the bovine Reference Material.

Animals↗
PubMed1984

Sarcomas of soft tissues after Vietnam service.

Vietnam service and military service experiences of 281 men with sarcomas of soft tissues were compared in this epidemiologic study to a control group of men derived from driver's license files and matched on 5-year period of birth and ZIP code of residence. No direct association was found for service in Vietnam (odds ratio, 0.53; confidence limits, 0.21-1.31) or for any military service (odds ratio, 0.53; confidence limits, 0.37-0.76). A multivariate matched logistic regression analysis showed similar results for Vietnam service while controlling for military service. Results also were similar when the 130 cases who had died were compared to a second control group derived from death certificates. Finally, no significant associations were found for "Agent Orange" or other variables that might be related to herbicide exposure.

Adult↗
PubMed1988

An international study of mortality from achalasia.

Mortality associated with achalasia was studied in 28 populations from 26 countries. 829 deaths were reported in a total population of 754 million over periods ranging from 1 to 8 years. Standardised mortality rates (SMR) were calculated in comparison with the USA white population (SMR = 100; 95% confidence limits = 89-112). The highest mortalities were recorded in New Zealand (SMR = 259; 95% confidence limits 131-420) and the lowest in Spanish speaking countries such as Panama (SMR = 0; confidence interval 0-210) and Spain (SMR = 22; confidence interval 3-79).

Cause of Death↗
PubMed2003

Limits for the scaled average bioequivalence of highly variable drugs and drug products.

PURPOSE: To provide a rational procedure for establishing regulatory bioequivalence (BE) limits that can be applied in determinations of scaled average BE for highly-variable (HV) drugs and drug products. METHODS: Two-period crossover BE investigations with either 24 or 36 subjects were simulated with assumptions of a coefficient of variation of 10, 20, 30, or 40%. The decline in the fraction of accepted studies was recorded as the ratio of geometric means (GMR) for the two formulations was raised from 1.00 to 1.45. Acceptance of BE was evaluated by scaled average BE, assuming various BE limits, and, for comparison, by unscaled average BE. A procedure for calculating exact confidence limits in two-period studies is presented, and an approximate method, based on the linearization of the regulatory model, is applied. RESULTS: A mixed model is proposed for average BE. Accordingly, at low variabilities, the BE limit is constant, +/-BELo, generally log(1.25). Beyond a logarithmic, limiting, "switching" variability (sigma(o)), in the region of HV drugs, the approach of scaled average BE is applied with limits of +/-(BEL(o)/sigma(o)). It is demonstrated that the performance of the mixed model corresponds to these expectations. The effect of sigma(o), and of the resulting BE limits is also demonstrated. Scaled average BE, with all reasonable limits for HV drugs, requires fewer subjects than an unscaled average BE. In two-period studies, the exact and approximate methods calculating confidence limits yield very comparable inferences. CONCLUSIONS: Scaled average BE can be effectively applied, with the recommended limits, for determining the BE of HV drugs and drug products. The limiting, "switching" variability (sigma(o)) will have to be established by regulatory authorities.

Computer Simulation↗