Biomedical subjects

A Laor

Publications and source records attributed to A Laor.

At least 19 recordsLinked to original sources

PubMed2003

Evaluation and refinement of the environmental stress index for different climatic conditions.

The purpose of this study was to evaluate the recently constructed environmental stress index (ESI) for a large database comprising various climatic conditions. Data analysis of measurements from 19 locations revealed a high correlation between ESI and the wet bulb globe temperature (WBGT) index for each database. Validity from statistical analysis, including optimization procedures, slightly changed the ESI constants as follows: ESI = 0.62Ta - 0.007RH + 0.002SR + 0.0043(Ta x RH) - 0.078(0.1 + SR)(-1) where: Ta = ambient temperature (degrees C); RH = relative humidity (%); and SR = solar radiation (w x m(-2)). The refined ESI and the WBGT index were applied to databases of more than 125,000 measurements for each variable: Ta, RH, SR, black globe temperature (Tg), and wet bulb temperature (Tw). For each database, the ESI was then successfully correlated with the WBGT (P < 0.05, R2 > or = 0.899). We conclude that the refined ESI, which is constructed from fast response and commonly used weather sensors (Ta, RH, SR), is a potential index to serve as an alternative to the WBGT for heat category assessment.

Acclimatization↗

PubMed2001

Neck circumference as a simple screening measure for identifying overweight and obese patients.

OBJECTIVE: There are numerous methods of assessing overweight and obesity. We undertook an observational study to test a method of identifying overweight or obese patients solely by measuring the circumference of the neck. RESEARCH METHODS AND PROCEDURES: A test sample and a second validation sample included 979 subjects (460 men and 519 women), who visited a family medicine clinic in a southern Israeli urban district for any reason between the randomly chosen months of January and September 1998. Main outcome included neck, waist, and hip circumferences; body mass index (BMI); and waist:hip ratio measures. RESULTS: Pearson's correlation coefficients indicated a significant association between neck circumference (NC) and: BMI (men, r = 0.83; women, r = 0.71; each, p < 0.0001), age (men, r = 0.33; women, r = 0.36; each, p < 0.0001), weight (men, r = 0.7; women, r = 0.81; each, p < 0.0001), waist circumference (men, r = 0.86; women, r = 0.85; each, p < 0.0001), hip circumference (men, r = 0.62; women, r = 0.56; each, p < 0.0001), and waist:hip ratio (men, r = 0.66; women, r = 0.87; each, p < 0.0001). NC > or=37 cm for men and > or =34 cm for women were the best cutoff levels for determining the subjects with BMI > or =25.0 kg/m(2) using the receiver output curve analysis. In the validation unrelated group, the test characteristics were excellent with 98% sensitivity, 89% specificity, and 94% accuracy for men, and 100% sensitivity, 98% specificity, and 99% accuracy for women. NC > or =39.5 cm for men and > or =36.5 cm for women were the best cutoff levels for determining the subjects with BMI > or =30 kg/m(2) using the receiver output curve analysis. In the validation unrelated group, the test characteristics were excellent with 93% sensitivity, 90% specificity, and 91% accuracy for men, and 93% sensitivity, 98% specificity, and 97% accuracy for women. DISCUSSION: NC measurement is a simple and time-saving screening measure that can be used to identify overweight and obese patients. Men with NC <37 cm and women with NC <34 cm are not to be considered overweight. Patients with NC > or =37 cm for men and > or =34 cm for women require additional evaluation of overweight or obesity status.

Anthropometry↗

PubMed2001

Term infants with fetal growth restriction are not at increased risk for low intelligence scores at age 17 years.

OBJECTIVE: To assess the long-term cognitive outcome of small for gestational age (SGA) compared with appropriate for gestational age (AGA) infants. DESIGN: Data from the Jerusalem Perinatal Study was matched with information from the army draft medical board. SGA and severe SGA were defined as birth weight below the 10th and 3rd percentiles for gestational age, respectively. A multiple linear regression analysis was performed to control for clinical, perinatal, and socio-demographic confounding variables. SUBJECTS: A cohort of 13,454 consecutive singleton term infants born between 1974 and 1976. MAIN OUTCOME MEASURE: IQ at age 17 years. RESULTS: SGA infants had lower adjusted mean +/- SE IQ scores compared with their AGA peers: 102.2 +/- 0.9 versus 105.1 +/- 0.7 (P <.0001) for males and 102.5 +/- 0.9 versus 103.9 +/- 0.7 (P <.015) for females. SGA was not associated with lower academic achievements compared with AGA. CONCLUSION: After controlling for multiple confounders, being born SGA at term is associated with slightly lower intelligence test scores at age 17 years. However, the clinical significance of the small difference is not evident in academic achievements.

Adolescent↗

PubMed2000

A new blue light-emitting phototherapy device: a prospective randomized controlled study.

OBJECTIVE: To evaluate the efficacy of a new phototherapy light source with a narrow luminous blue spectrum. The device, made with high-intensity gallium nitride light-emitting diodes (LEDs), was compared with conventional phototherapy at similar light intensities. SETTING: Two university-affiliated community hospitals in Jerusalem. DESIGN: Prospective open randomized study. PARTICIPANTS: Sixty-nine jaundiced, but otherwise healthy, term infants who met the entry criteria for phototherapy set by the American Academy of Pediatrics' Practice Parameter. MAIN OUTCOME MEASURES: The duration of phototherapy and the rate of decrease in total serum bilirubin (TSB) concentration. RESULTS: The mean TSB concentrations at initiation and termination of treatment did not differ between newborns receiving LED and those receiving conventional phototherapy. The duration of phototherapy and the rate of decrease in TSB concentration were not statistically different in the 2 groups. The average rate of decrease in TSB after adjustment by a linear regression analysis for confounding factors was -3.16 micromol/L/h (95% confidence limits -4.81, -1.51) in newborns receiving LED phototherapy compared with -2.19 micromol/L/h (-3.99, -0.40) in those treated with conventional phototherapy (P <.14). No side effects were noted in any of the newborns. CONCLUSIONS: The blue gallium nitride LED device is as effective as conventional phototherapy and is readily accepted by nursing staff. Future LED phototherapy devices can provide much higher irradiance, and thus greater efficacy, and offer a new highly versatile approach to the treatment of jaundice.

Bilirubin↗

PubMed1999

X-Rays from the Highly Polarized Broad Absorption Line QSO CSO 755.

We present results from a BeppoSAX observation of the broad absorption line (BAL) QSO CSO 755, which was observed as part of our program to investigate the X-ray properties of highly polarized BAL QSOs. CSO 755 is clearly detected by the BeppoSAX Medium-Energy Concentrator Spectrometers, making it the highest redshift (z=2.88) and most optically luminous (MV=-27.4) BAL QSO seen in X-rays. It is detected in several energy bands including the rest-frame 21-39 keV band, but we are able to place only loose constraints upon its X-ray spectral shape. Our X-ray detection is consistent with the hypothesis that the BAL QSOs with high optical continuum polarization tend to be the X-ray brighter members of the class. We examine a scattering interpretation of a polarization/X-ray flux connection, and we discuss the data needed to prove or refute such a connection. We also discuss a probable ROSAT detection of CSO 755. The observed-frame 2-10 keV flux from BeppoSAX (1.3x10-13 ergs cm-2 s-1) is high enough to allow X-Ray Multimirror Mission spectroscopy, and studies of iron K-line emission should prove of particular interest if a large amount of scattered X-ray flux is present.

Journal Article↗

PubMed1999

Nutritional status of children with solid tumors.

BACKGROUND: The purposes of the study were to evaluate prospectively the nutritional status of children with solid tumors who were receiving chemotherapy, to find the most sensitive parameter of protein energy malnutrition, and to determine whether the stage of disease and aggressiveness of chemotherapy have any influence on nutritional status. METHODS: Fifty patients were followed prospectively from the time of diagnosis throughout chemotherapy. Serum albumin, prealbumin, and weight were measured at the time of diagnosis and before each course of chemotherapy. RESULTS: At diagnosis, only 2.7% of patients had albumin levels < 3.5 g/dL whereas 36% had prealbumin levels below the normal limit. All patients showed a weight increment of 81 g/day (P = 0.0001), an albumin increment of 0.001 U/day (P = 0.0001), and a prealbumin increment of 0.044 U/day (P = 0.0407). The change in prealbumin values was much more prominent (10-fold higher) in children age < 2 years. Changes in albumin values were not statistically significant by stage of disease but the increment of prealbumin did show statistical significance, which was most prominent in patients with Stage IV disease CCG (children's cancer group classification ) (P = 0.0003). The intensity of chemotherapy had no influence on changes in weight or albumin levels. However, it did influence changes in prealbumin levels, which were most pronounced in the group receiving high dose chemotherapy. CONCLUSIONS: Based on the results of the current study, the authors believe prealbumin is the most powerful test overall with which to evaluate the nutritional status of children with solid tumors both at the time of diagnosis and throughout chemotherapy.

Adolescent↗

PubMed1999

Predicting the risk of jaundice in full-term healthy newborns: a prospective population-based study.

OBJECTIVE: The need to recognize infants that are at high risk for developing significant jaundice is apparent in the era of routine early discharge. The aim of the present study was to prospectively determine the ability to predict severe hyperbilirubinemia in term healthy newborns (defined as total serum bilirubin of > 10.0 mg/dl at day 2, > 14.0 mg/dl at day 3, and > 17.0 mg/dl at days 4 and 5 of life). DESIGN: Prospective study of 1177 healthy term newborns. SETTING: Two university-affiliated community hospitals in Jerusalem. RESULTS: Using a multiple logistic regression analysis, neonatal jaundice was best predicted (p < 0.0001) by day 1 serum bilirubin (adjusted odds ratio of 3.1 [per mg/dl] [95% confidence limits of 2.4 to 4.1]) and by a change in serum bilirubin from the first to the second day of life (2.4 [per mg/dl] [1.9 to 3.0]). Maternal blood type 0 (2.9 [1.5 to 5.8]), age (1.1 [per year] [1.0 to 1.2]), schooling (0.8 [per year] [0.7 to 0.9]), and full breastfeeding (0.4 [0.2 to 0.9]) were also associated with jaundice (p < 0.005). Other factors considered in the regression model but not found to be significantly related to jaundice included maternal ethnic origin, smoking, hypertension, diabetes mellitus, intranatal administration of oxytocin, meperidine, anesthesia, premature rupture of the membranes, parity, newborn sex, birth weight, gestational age, presentation. Apgar scores, blood type, hematocrit, cephalohematoma, and history of jaundice in other siblings. A model for predicting neonatal jaundice based on the above factors had a sensitivity of 81.8%, a specificity of 82.9%, a false positive rate of 80.2%, and a false negative rate of 1.1%. CONCLUSION: Individual risk assessment on discharge in association with day 1 total serum bilirubin is of value in identifying infants at greater risk for neonatal jaundice.

Bilirubin↗

PubMed1999

Can gender differences during exercise-heat stress be assessed by the physiological strain index?

A physiological strain index (PSI) based on rectal temperature (Tre) and heart rate (HR) was recently suggested to evaluate exercise-heat stress. The purpose of this study was to evaluate PSI for gender differences under various combinations of exercise intensity and climate. Two groups of eight men each were formed according to maximal rate of O2 consumption (VO2 max). The first group of men (M) was matched to a group of nine women (W) with similar (P > 0.001) VO2 max (46.1 +/- 2.0 and 43.6 +/- 2.9 ml. kg-1. min-1, respectively). The second group of men (MF) was significantly (P < 0. 001) more fit than M or W with VO2 max of 59.1 +/- 1.8 ml. kg-1. min-1. Subjects completed a matrix of nine experimental combinations consisting of three different exercise intensities for 60 min [low, moderate, and high (300, 500, and 650 W, respectively)] each at three climates (comfortable, hot wet, and hot dry [20 degrees C 50% relative humidity (RH), 35 degrees C 70% RH, and 40 degrees C 35% RH, respectively]). No significant differences (P > 0.05) were found between matched genders (M and W) at the same exposure for sweat rate, relative VO2 max (%VO2 max), and PSI. However, MF had significantly (P < 0.05) lower strain than M and W as reflected by %VO2 max and PSI. In summary, PSI applicability was extended for exercise-heat stress and gender. This index continues to show potential for wide acceptance and application.

Adult↗

PubMed1999

The physiological strain index applied to heat-stressed rats.

A physiological strain index (PSI) based on heart rate (HR) and rectal temperature (Tre) was recently suggested to evaluate exercise-heat stress in humans. The purpose of this study was to adjust PSI for rats and to evaluate this index at different levels of heat acclimation and training. The corrections of HR and Tre to modify the index for rats are as follows: PSI = 5 (Tre t - Tre 0). (41.5 - Tre 0)-1 + 5 (HRt - HR0). (550 - HR0)-1, where HRt and Tre t are simultaneous measurements taken at any time during the exposure and HR0 and Tre 0 are the initial measurements. The adjusted PSI was applied to five groups (n = 11-14 per group) of acclimated rats (control and 2, 5, 10, and 30 days) exposed for 70 min to a hot climate [40 degrees C, 20% relative humidity (RH)]. A separate database representing two groups of acclimated or trained rats was also used and involved 20 min of low-intensity exercise (O2 consumption approximately 50 ml. min-1. kg-1) at three different climates: normothermic (24 degrees C, 40% RH), hot-wet (35 degrees C, 70% RH), and hot-dry (40 degrees C, 20% RH). In normothermia, rats also performed moderate exercise (O2 consumption approximately 60 ml. min-1. kg-1). The adjusted PSI differentiated among acclimation levels and significantly discriminated among all exposures during low-intensity exercise (P < 0.05). Furthermore, this index was able to assess the individual roles played by heat acclimation and exercise training.

Acclimatization↗

PubMed1998

Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine.

While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Adult↗

PubMed1998

Macrosomia does not predict overweight in late adolescence in infants of diabetic mothers.

OBJECTIVE: To determine the predictive value of macrosomia for overweight later in adult life in infants of diabetic mothers. DESIGN: Data from the computerized records of the Jerusalem Perinatal Study were matched to measurements made at age 17 obtained from the military draft medical examination records. PARTICIPANTS: 10,891 infants born in Jerusalem between November 1974 and February 1976. MAIN OUTCOME MEASURES: Macrosomia based on 90th percentile birth weight for gestational age and overweight defined as the 90th percentile for body mass index at age 17. RESULTS: Diabetes was diagnosed in 87 (0.8%) of the mothers. Thirty-one (35.6%) of the infants of the diabetic mothers were macrosomic compared to 1012 (9.4%) of the siblings of nondiabetic mothers (p < 0.001). At 17 years of age 10.3% vs. 9.4% of the siblings of diabetic vs. nondiabetic mothers were overweight (p > 0.05). The rate of adolescent overweight in macrosomic vs. nonmacrosomic subjects was 12.3% vs. 9.7% (p < 0.01) in siblings of nondiabetic mothers, and 16.1% vs. 7.1% (p > 0.05) for diabetic mothers. The sensitivity and specificity, in diabetic mothers, of macrosomia for overweight at age 17 was 44.4% and 66.7%, respectively. The positive and negative predictive value of macrosomia for overweight at age 17 was 16.1% and 92.9%, respectively. CONCLUSIONS: The risk of adolescent overweight was significantly increased among macrosomic infants, although this trend did not reach statistical significance in the smaller group of infants born to diabetic mothers. Macrosomia among infants of diabetic mothers had little predictive value for overweight in late adolescence.

Adolescent↗

PubMed1998

The outcome of twin pregnancies after IVF.

It has been suggested that the high rates of prematurity, low birth weight, perinatal morbidity and mortality in in-vitro fertilization (IVF) infants are due to the increased frequency of multiple gestations in this population. The aim of our study was to test this hypothesis by comparing the outcome of IVF twins with that of twins born after spontaneously conceived pregnancies. The perinatal outcome of 40 IVF twins was compared with that of 80 control twins, matched for maternal age, parity and ethnic origin. IVF twins had a higher rate of prematurity (P = 0.03), their mean birth weight was significantly lower (P < 0.01) and the frequency of very low birth weight infants was much higher (P < 0.003). There was no neonatal mortality in the control group, whereas four IVF twins died (P < 0.01). Neonatal morbidity was significantly greater in IVF twins (P < 0.05). Oxygen therapy and mechanical ventilation were administered more frequently to IVF twins (P < 0.007 and P < 0.05). We conclude that twins conceived by IVF are at a significantly higher risk for prematurity and associated neonatal morbidity and mortality than spontaneously conceived twins.

Adult↗

PubMed1998

Comparison of sodium bicarbonate, Carbicarb, and THAM during cardiopulmonary resuscitation in dogs.

OBJECTIVES: During cardiopulmonary resuscitation (CPR), elimination of CO2 was shown to be limited by low tissue perfusion, especially when very low perfusion pressures were generated. It has therefore been suggested that sodium bicarbonate (NaHCO3), by producing CO2, might aggravate the hypercarbic component of the existing acidosis and thereby worsen CPR outcome. The objectives of this study were to evaluate the effects of CO2 producing and non-CO2 producing buffers in a canine model of prolonged ventricular fibrillation followed by effective CPR. DESIGN: Prospective, randomized, controlled, blinded trial. SETTING: Experimental animal research laboratory in a university research center. SUBJECTS: Thirty-eight adult dogs, weighing 20 to 35 kg. INTERVENTIONS: Animals were prepared for study with thiopental followed by halothane, diazepam, and pancuronium. Ventricular fibrillation was electrically induced, and after 10 mins, CPR was initiated, including ventilation with an FIO2 of 1.0, manual chest compressions, administration of epinephrine (0.1 mg/kg every 5 mins), and defibrillation. A dose of buffer, equivalent to 1 mmol/kg of NaHCO3, was administered every 10 mins from start of CPR. Animals were randomized to receive either NaHCO3, Carbicarb, THAM, or 0.9% sodium chloride (NaCl). CPR was continued for up to 40 mins or until return of spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: Buffer-treated animals had a higher resuscitability rate compared with NaCl controls. Spontaneous circulation returned earlier and at a significantly higher rate after NaHCO3 (in seven of nine dogs), and after Carbicarb (six of ten dogs) compared with NaCl controls (two of ten dogs). Spontaneous circulation was achieved twice as fast after NaHCO3 compared with NaCl (14.6 vs. 28 mins, respectively). Hydrogen ion (H+) concentration and base excess, obtained 2 mins after the first buffer dose, were the best predictors of resuscitability. Arterial and mixed venous Pco2 did not increase after NaHCO3 or Carbicarb compared with NaCl. CONCLUSIONS: Buffer therapy promotes successful resuscitation after prolonged cardiac arrest, regardless of coronary perfusion pressure. NaHCO3, and to a lesser degree, Carbicarb, are beneficial in promoting early return of spontaneous circulation. When epinephrine is used to promote tissue perfusion, there is no evidence for hypercarbic venous acidosis associated with the use of these CO2 generating buffers.

Animals↗

PubMed1997

Size at birth, maternal nutritional status in pregnancy, and blood pressure at age 17: population based analysis.

OBJECTIVE: To assess the effect of size at birth, maternal nutrition, and body mass index on blood pressure in late adolescence. DESIGN: Population based analysis of birth weight corrected for gestational age, mother's weight before pregnancy and weight gain in pregnancy, obtained from the Jerusalem perinatal study, and blood pressure and body mass index at age 17, available from military draft records. SETTING: Jerusalem, Israel. SUBJECTS: 10,883 subjects (6684 men and 4199 women) born in Jerusalem during 1974-6 and subsequently drafted to the army. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures measured at age 17 and their correlation with birth weight, size at birth, mother's body mass index and weight gain during pregnancy, and height and weight at age 17. RESULTS: Systolic and diastolic blood pressures were significantly and positively correlated with body weight, height, body mass index at age 17, and with mother's body weight and body mass index before pregnancy, but not with birth weight or mother's weight gain in pregnancy. CONCLUSION: Variables reflecting poor intrauterine nutrition, including low maternal body mass index before pregnancy, poor maternal weight gain in pregnancy, and being born small for gestational age, were not associated with a higher blood pressure in late adolescence.

Adolescent↗

PubMed1997

Bleeding predictors in factor-XI-deficient patients.

Bleeding in factor-XI-deficient patients is mainly injury-related. Parameters influencing bleeding particularly in patients with minor factor XI deficiency have not been defined. We utilized a logistic regression model to analyze parameters influencing bleeding tendency in subjects from 45 families with factor XI deficiency. Bleeding manifestations were documented in 58% of 26 homozygous or doubly heterozygous factor-XI-deficient patients, in 20% of 46 heterozygous factor-XI-deficient patients and in 9% of 47 family members with a normal factor XI genotype. Odds ratios for bleeding in homozygotes or double heterozygotes were 13 and in heterozygotes 2.6 with 95% confidence intervals of 3.8-45 and 0.8-9.0, respectively. Bleeding correlated negatively with factor XI level (r = -0.36, P = 0.0001) with major factor XI deficiency being a strong predictor of bleeding (P = 0.011). Minor factor XI deficiency and blood group O slightly contributed to bleeding. Although factor VIII and factor XI levels were correlated (r = 0.48, P = 0.0001), levels of factor VIII and von Willebrand factor were not predictors of bleeding. Bleeding was more common following operative procedure involving mucosal membranes (P < 0.01). The designed model enabled prediction of bleeding manifestations with an overall accuracy of 78% and 82% in heterozygotes.

Case-Control Studies↗

PubMed1996

Heat acclimation: cardiovascular response to hot/dry and hot/wet heat loads in rats.

Body temperature, blood pressure (BP) and heart rate (HR) of rats before and after acclimation to heat were studied in chronically cannulated sedentary conscious rats in different hot environmental conditions [hot/dry: 40 degrees C, 20% relative humidity (RH) and hot/wet: 35 degrees C, 70% RH]. During exposure to heat stress, acclimated rats showed an attenuated increase in colonic temperature (Tc) compared to non-acclimated rats. Concomitantly, an abrupt decrease in HR, delayed and attenuated elevation in mean arterial BP and improved cardiac efficiency were recorded. Differences were observed upon exposure to the hot/wet and hot/dry climates: the hot/dry climate imposed a greater physiological burden than the hot/wet climate. The data suggest that for sedentary rats dry heat produces a greater load than humid heat. Thus, the conventional heat load indices do not apply universally but have a thermoregulatory pattern specificity.

Acclimatization↗

PubMed1996

Myopia in neurofibromatosis type 1.

We studied the prevalence of myopia in 17-year-old Israeli military recruits with neurofibromatosis type 1 (NF1). Twenty-four percent of the youngsters with neurofibromatosis had myopia, compared to 19% of the controls; this difference was statistically significant (P < 0.03). The recruits with NF1 had a slightly lower IQ, fewer years of education, and lower height and weight than the controls. Thus, these factors, which have been reported to be associated with myopia, did not significantly influence the high prevalence of myopia in the neurofibromatosis subjects. A high prevalence of myopia seems to be an additional feature of NF1.

Adolescent↗

PubMed1995

Criteria to assess in vivo performance of sustained release products: application to diltiazem formulations.

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.

Adult↗