In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.     

Retroperitoneal Laparoscopic Nephrectomy in Children

Retroperitoneal pediatric laparoscopic nephrectomy is described in 3 patients requiring 3 to 5 hours with an estimated blood loss of 10 to 60 cc. The children returned to school within 7 days postoperatively. Advantages of this procedure include the avoidance of intraoperative repositioning of the patient and easy conversion to an open lumbodorsal approach, if necessary; early laparoscopic visualization of the renal artery; applicability in cases of previous abdominal surgery, and avoidance of intraperitoneal adhesion.     

Phase II trial of Didemnin B in patients with advanced renal cell carcinoma

Summary Twenty-three patients with advanced renal cell cancer were treated with Didemnin B. One partial response was achieved (5%) in 21 evaluable patients. An allergic reaction was noted in four patients including one patient with anaphylaxis. Didemnin B is not recommended in the treatment of renal cell carcinoma.     

Identification of an early endosomal protein regulated by phosphatidylinositol 3-kinase

Phosphatidylinositol 3-kinases (PI 3-kinases) have been implicated in membrane trafficking in the secretory and endocytic pathways of yeast and mammalian cells, but the molecular mechanisms by which these lipid kinases operate are not known. Here we identify a protein of 170 kDa that is rapidly released from cell membranes in response to wortmannin, a potent inhibitor of mammalian PI 3-kinases. The amino acid sequence of peptides from p170 reveal its identity to early endosomal antigen (EEA) 1, an endosomal antigen with homology to several yeast proteins genetically implicated in membrane trafficking. Immunofluorescence analysis of 3T3-L1 adipocytes with antisera against p170/EEA1 reveal a punctate peripheral pattern that becomes diffuse in response to wortmannin. In vitro, p170/EEA1 binds specifically to liposomes containing PIns(3)P, suggesting that the effect of wortmannin on cells is due to inhibition of PIns(3)P production. Thus, p170/EEA1 may define a family of proteins that mediate the regulatory effects of 3′-phosphoinositides on membrane trafficking in yeast and mammalian cells.     

The Prospective Assessment of Autonomic Nerve Function by Pupillometry in Adolescents with Type 1 Diabetes Mellitus

The study aimed to compare the longitudinal assessment of autonomic nerve function by computerized infrared pupillometry and standard cardiovascular tests in adolescents with diabetes. Adolescents (n = 150) were assessed at two time points (T1 and T2). The median time interval between assessments was 1.5 (range 0.9–3) years. At T1 the median age was 14.5 (range 8.3–19.5) years and the median duration was 6.5 (range 1.1–16) years. The pupillary variables assessed included the resting pupil diameter, the maximum constriction velocity, and the reflex amplitude of constriction. Heart rate reflexes were assessed in response to deep breathing, the Valsalva manoeuvre, and on standing from a lying position (30/15 ratio). Between visits there was a significant decrease in maximum constriction velocity (6.0 mm s^?1 vs 6.3 mm s^?1, p = 0.0001) and resting pupil diameter (6.2 mm vs 6.3 mm, p = 0.001). At reassessment pupillary abnormalities increased from 32 (21 %) to 45 (30%), with 17 (54 %) of the initial abnormalities persisting. Adolescents with abnormally slow maximum constriction velocity compared to those with normal maximum constriction velocity had a higher glycated haemoglobin (HbA_1c%) at T2 (p = 0.02) and between assessments (p = 0.01). Cardiovascular test abnormalities did not increase between visits and the persistence of initial abnormalities was low (21 %). In summary, pupillometry appears a more sensitive test of autonomic nerve dysfunction in adolescents with diabetes than assessment of cardiovascular reflexes.     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

The effect of phencyclidine and DL-2-amino-5-phosphonovaleric acid on N-methyl-D-aspartic acid induced changes in extracellular concentration of dopamine and DOPAC in the rat neostriatum.

The effects of N-methyl-D-aspartic acid (NMDA) and phencyclidine (PCP) on extracellular levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat were studied using in vivo microdialysis. Intrastriatal infusion of NMDA produced a significant dose-dependent increase in extracellular DA and a decrease in concentrations of DOPAC. Whereas both 2-amino-5-phosphonovalerate (APV) and PCP antagonized the NMDA-induced increase in extracellular levels of DA, the effect on NMDA-induced changes in extracellular concentrations of DOPAC were different for the two compounds. The APV significantly attenuated the decrease in extracellular DOPAC produced by smaller concentrations of NMDA, whereas PCP did not prevent decrease in DOPAC produced by any concentrations of NMDA. Phencyclidine alone produced a dose-dependent increase in extracellular DA but had no effect on the extracellular concentration of DOPAC. This study demonstrated that PCP, at concentrations which did not produce an increase in extracellular DA, antagonized the effect of the NMDA on DA. The data also indicated that both APV and PCP antagonized the NMDA-evoked release of DA over a range of concentrations of NMDA, even though they did so by different mechanisms.