A Novel Extravascular Input Function for the Assessment of Drug Absorption in Bioavailability Studies

Purpose. Flexible parametric models describing the input process after extravascular drug administration are needed for the assessment of absorption rate and the use of population methods in bioavailability and bioequivalence studies. Methods. The oral concentration-time curve modeled as the product of the input and disposition function in the Laplace domain was obtained by numerical inversion methods for parameter estimation. The utility of the inverse Gaussian input density was examined using bioavailability data of an extended-release dosage form. Measures of rate of absorption and the cumulative absorbed amount profile were defined in terms of the estimated model parameters. Results. Accurate estimation of absorption parameters was achieved by simultaneous fitting of the extravascular and intravascular data (describing the latter by a triexponential function). The new input function allowed a direct estimation of both extent of absorption and mean absorption time. Conclusions. The findings suggest that the inverse Gaussian density is a useful input function. Its flexibility may reduce the effect of model misspecification in parameter estimation. All parameters can be readily interpreted in terms of the absorption process.     

Blood flow, O2 extraction and O2 consumption along the rat small intestine

Differences in O2 delivery and consumption along the fed and fasted small intestine are described. Total wall blood flow was determined in sequential segments of small intestine from 5 to 6-month-old male, anesthetized Fischer 344 rats either 75-80 min before or after feeding, using radioactive microspheres. Oxygen saturation in submucosal arterioles and venules (50-60 micron diam) was determined throughout the intestine, using a microspectrophotometric technique. Venous O2 saturations showed considerable heterogeneity in all regions, and ranged from 0 to 77%. Arterial-venous O2 content differences (CaO2-CvO2) did not change along the fasted rat intestine, and averaged 8.2 ml O2/100 ml blood. However, CaO2-CvO2 followed a small proximal to distal gradient (proximal greater than distal) in the fed rats. Larger proximal to distal gradients (proximal greater than distal) occurred in both blood flow and O2 consumption in both groups. Feeding did not change intestinal average CaO2-CvO2. However, feeding induced a 53% increase in average O2 consumption, with the greatest increase (130%) occurring in the middle third of the intestine. Feeding induced a 42% increase in average blood flow, with the greatest increase (70%) occurring in the distal third of the intestine. The increased O2 used by the fed intestine was primarily provided by the increased blood flow. The O2 consumption gradient is assumed to reflect differences in mucosal mass along the intestine and/or differences in metabolic activity.     

Lobe of origin in the attribution of lung cancer to asbestos.

Lung cancer originates most commonly in the upper lobes in the general population but among workers with asbestosis it is most common in the lower lobes. Published data on lobar distribution were used to estimate the probabilities that lung cancer among asbestos workers is attributable to exposure to asbestos. This attribution varies directly with the relative risk. Critical values of the relative risk at which attribution of lung cancer to asbestos equalled its attribution to other causes, mainly smoking, were calculated. At a relative risk above 2.81 upper lobe cancers were more likely to be due to asbestos than not. For middle and lower lobe cancers, the critical relative risk was 1.55. These critical values were compared with published standardised mortality ratios reported for cohorts of workers with asbestosis. Since the ratios ranged from 6.3 to 9.1, the probability that lung cancer in such cases is due to asbestos is high regardless of lobe of origin. In many cohorts unstratified by the presence or absence of asbestosis the risk ratios are below one or both of these critical values. Since risk ratios are so high among workers with asbestosis, the ratios must be lower for workers without asbestosis than the overall ratios for unstratified cohorts. Therefore, the critical values may be useful in workers without asbestosis among such cohorts to estimate the upper limit of the probability that lung cancer in a given lobe is due to exposure to asbestos.     

Peroneal nerve palsy after early cast application for femoral fractures in children.

The incidence and contributing factors associated with post-casting peroneal nerve palsy were examined in a series of 110 consecutive pediatric femoral shaft fractures treated with early hip spica cast application. Four patients with peroneal nerve palsy were identified. All four had 90 degrees/90 degrees casts placed and underwent cast wedging for alignment. All palsies resolved with immediate cast removal. Other treatment options for certain femur fractures with significant initial shortening should be considered. We advise pre- and post-cast neurologic examination and avoidance of forceful distraction. Fracture manipulation, through wedging, should be delayed.     

The site of airway irritation during induction of anaesthesia

The aim of this investigation was to study the role of the nasal airway in mediating upper airway reflexes during induction of anaesthesia when the commonly used irritant inhalational anaesthetic agent enflurane is used. In a prospective randomised study, 40 ASA 1 & 2 day-case patients undergoing body surface surgery were recruited. Following intravenous induction using propofol, 20 patients received enflurane administered via a laryngeal mask airway (LMA), the anaesthetic vapour therefore bypassing the nasal airway. In the other group, 20 patients received enflurane anaesthesia administered using a face mask, the nasal airway therefore being exposed to inhalation anaesthetic. We were unable to demonstrate any significant (p < 0.05) differences between the two groups in relation to upper airway complications (cough, breath holding, laryngeal spasm, bronchospasm and excitement). Previous work has identified the nose as a possible important reflexogenic site for upper airway reflexes in humans during anaesthesia. We have been unable to demonstrate any difference in upper airway complications when the nasal airway was included or excluded from exposure to irritant anaesthetic vapours, when administered in a clinical setting.     

Adjunct therapies to bacterial sepsis in the neonate

Recent steps to prevent neonatal sepsis due to group B Streptococcal infection have lowered the attack rate from this organism, but may not have lowered overall sepsis rates. Mortality from sepsis stills remains between 20 and 40% and is probably so high due to the immunological immaturity of the newborn. Although antibiotics remain the mainstay for treatment, adjunctive therapies aimed at improving the immunological integrity of the neonatal patient have a role in treatment and may improve outcomes. We discuss several adjunctive therapies, along with the physiologic rationale for their use, and discuss an approach for their inclusion in therapy for neonatal sepsis.     

SAS amplification in soft tissue sarcomas.

Gene amplification is an important mechanism of increased gene expression in a number of human solid tumors. We have recently identified and cloned sequences from a novel DNA amplification unit in malignant fibrous histiocytoma. The amplified sequences are derived from chromosome 12q13-14 and encode a gene designated SAS (sarcoma amplified sequence). In the present study, a series of soft tissue sarcomas was studied to characterize further the phenomenon of SAS amplification. Seven of 22 (32%) malignant fibrous histiocytomas and three liposarcomas contained SAS amplification. Strikingly, all of the tumors with SAS amplification occurred in central sites (i.e., in the abdominal or inguinal regions) rather than in the extremities (i.e., in the arms of legs). These observations demonstrate that SAS amplification occurs with a significant frequency in mesenchymal tumors and is particularly associated with abdominal disease.