CLINICO-PATHOLOGICAL CORRELATION IN NEONATAL AUTOPSIES

Of the 253 neonates admitted to a neonate intensive care unit during the period Jan 91 to Sep 93, 43 neonates died. Autopsy was done in 23 of these (53%). The mean duration of stay of the neonates in the intensive care unit prior to death was 5.6 days (range 2 hours to 10 days). Antemortem diagnoses included asphyxia neonatorum (4), meconium aspiration syndrome (2), septicemia (5), prematurity (3), birth trauma (2), congenital anomalies (2), hypoxic ischemic encephalopathy (1), and non-specific diagnosis (4). There were 6 major autopsy findings that, if known prior to death, would have altered clinical management and might have resulted in cure or prolonged survival. There were 8 additional major findings that, if known prior to death, would not have altered management There were 14 minor findings related to major diagnoses but unrelated to the primary cause of death.KEY WORDS: Autopsy, Cause of death, Perinatal mortality     

Radiographic findings in tuberculosis of the calvarium

We reviewed the pattern of involvement of the calvarium by tuberculosis (TB) in five patients and the role of imaging in its management. Four patients presented with localised scalp swelling and one with generalized seizures. Radiographs revealed lucent lesions with minimal surrounding sclerosis in the frontal (2), parietal (2) and occipital (1) bones. CT showed lesions involving the entire thickness of the calvarium and accompanying contrast-enhancing soft tissue. The patient presenting with seizures had a ring-enhancing lesion in the parietal lobe in addition to the extra-axial lesions. Although radiographs in all cases demonstrated calvarial TB, CT showed the extent of the defect, involvement of adjacent soft tissues, and in one case an intra-axial lesion. Radiographs suffice for follow-up of these patients. Received: 23 July 1999 Accepted: 20 September 1999     

Factors affecting mechanism and kinetics of drug release from matrix-based oral controlled drug delivery systems

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies. Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems. Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.     

Spontaneous rupture of the liver upon revascularization during transplantation

Spontaneous rupture of the liver has been described in association with many benign and malignant conditions. We report, to our knowledge, the first case of spontaneous rupture of the liver upon revascularization, requiring total hepatectomy and portocaval shunt, followed by successful retransplantation. Routine pathological examination of the explanted liver failed to reveal the etiology of the rupture. However, electron microscopy demonstrated abnormal collagen in the hepatic arterial wall compatible with a collagen disorder such as Ehlers-Danlos type IV disease. We conclude that the donor liver had a previously undiagnosed collagen disorder. Review of the literature does not preclude the use of livers from donors with a history of connective tissue disorders. Based on our experience one should exercise caution when using livers from such donors. With a history of connective tissue disorder in an immediate family member, further tests should be performed in the donor to rule out a subclinical connective tissue disorder. In addition, a review of all patients reported thus far to have undergone total hepatectomy and portocaval shunt, followed by liver transplantation as a two-stage procedure is presented.     

Needle stick injuries among medical students

Questionnaires were distributed among 200 medical students regarding safety precautions observed while perfonning various invasive procedures during their clinical posting. Only 106 students responded with the completed questionnaire. The most common procedure performed by the students was drawing of blood, with an average frequency of 60.8 per month. Sixty-one per cent of the students reported being injured during the various procedures and only 3 5.5% of them used gloves. Resheathing the needle was responsible for causing injury to 69% of the students, which was significantly higher than injuries occurring while entry into the vein or withdrawing the needle (p<0.05).     

A PATHOLOGICAL STUDY OF BENIGN AND MALIGNANT TUMOURS OF SALIVARY GLANDS

Interest in the knowledge of salivary gland tumours is highlighted. A sample of 315 cases, collected over a period of 25 years in a busy pathology centre, is analysed both on total and individual aspects of tumours. The findings are compared to earlier works on the subject and also with contemporary literature.KEY WORDS: Pathological study, Salivary tumours     

Enhanced oral paclitaxel absorption with vitamin E-TPGS: Effect on solubility and permeability in vitro, in situ and in vivo

Solubility and permeability being important determinants of oral drug absorption, this study was aimed to investigate the effect of d--tocopheryl polyethylene glycol 1000 succinate (TPGS) on the solubility and intestinal permeability of paclitaxel in vitro, in situ and in vivo, in order to estimate the absorption enhancement ability of TPGS. Aqueous solubility of paclitaxel is significantly enhanced by TPGS, where a linear increase was demonstrated above a TPGS concentration of 0.1 mg/ml. Paclitaxel demonstrated asymmetric transport across rat ileum with significantly greater (26-fold) basolateral-to-apical (B–A) permeability than that in apical-to-basolateral (A–B) direction. Presence of P-glycoprotein (P-gp) inhibitor, verapamil (200 μM), diminished asymmetric transport of paclitaxel suggesting the role of P-gp-mediated efflux. TPGS showed a concentration-dependent increase in A–B permeability and decreased B–A permeability. The maximum efflux inhibition activity was found at a minimum TPGS concentration of 0.1 mg/ml, however, further increase in TPGS concentration resulted in decreased A–B permeability with no change in B–A permeability. Thus, the maximum paclitaxel permeability attained with 0.1 mg/ml TPGS was attributed to the interplay between TPGS concentration dependent P-gp inhibition activity and miceller formation. In situ permeability studies in rats also demonstrated the role of efflux in limiting permeability of paclitaxel and inhibitory efficiency of TPGS. The plasma concentration of [¹⁴C]paclitaxel following oral administration (25 mg/kg) was significantly increased by coadministration of TPGS at a dose of 50 mg/kg in rats. Bioavailability is enhanced about 4.2- and 6.3-fold when [¹⁴C]paclitaxel was administrated with verapamil (25 mg/kg) and TPGS, respectively, as compared to [¹⁴C]paclitaxel administered alone. The effect of verapamil on oral bioavailability of [¹⁴C]paclitaxel was limited relative to the TPGS, consistent with the in vitro solubility and permeability enhancement ability of TPGS. In conclusion, the current data suggests that the coadministration of TPGS may improve the bioavailability of BCS class II–IV drugs with low solubility and/or less permeable as a result of significant P-gp-mediated efflux.     

Quantitative assessment of the contribution of sodium‐dependent taurocholate co‐transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin,pitavastatin and fluvastatin

Hepatic uptake transport is often the rate‐determining step in the systemic clearance of drugs. The ability to predict uptake clearance and to determine the contribution of individual transporters to overall hepatic uptake is therefore critical in assessing the potential pharmacokinetic and pharmacodynamic variability associated with drug–drug interactions and pharmacogenetics. The present study revisited the interaction of statin drugs, including pitavastatin, fluvastatin and rosuvastatin, with the sodium‐dependent taurocholate co‐transporting polypeptide (NTCP) using gene transfected cell models. In addition, the uptake clearance and the contribution of NTCP to the overall hepatic uptake were assessed using in vitro hepatocyte models. Then NTCP protein expression was measured by a targeted proteomics transporter quantification method to confirm the presence and stability of NTCP expression in suspended and cultured hepatocyte models. It was concluded that NTCP‐mediated uptake contributed significantly to active hepatic uptake in hepatocyte models for all three statins. However, the contribution of NTCP‐mediated uptake to the overall active hepatic uptake was compound‐dependent and varied from about 24% to 45%. Understanding the contribution of individual transporter proteins to the overall hepatic uptake and its functional variability when other active hepatic uptake pathways are interrupted could improve the current prediction practice used to assess the pharmacokinetic variability due to drug–drug interactions, pharmacogenetics and physiopathological conditions in humans. Copyright © 2013 John Wiley & Sons, Ltd.