A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept.

A Right-First-Time approach is described for developing bona fide formulations for First-In-Human (FIH) to Proof-Of-Concept (POC) studies to meet an overarching goal of reduced project cycle time from IND to NDA (as short as four years). Bona fide formulations are tailor-made according to the drug's biopharmaceutical properties including solubility, permeability and stability. Solubilization techniques are used extensively to reduce oral absorption variability for most compounds.

Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules.

This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs.

Evaluation of abdominal wall strength after TRAM flap surgery.

Evaluation of abdominal wall function after transverse rectus abdominis musculocutaneous (TRAM) flap surgery has been mostly subjective. The purpose of this study was to measure abdominal wall strength objectively and to compare the results with the patient's performance of daily activities. Abdominal wall strength was objectively measured with the B200 IsoStation machine preoperatively and 1 year after TRAM flap breast reconstruction.

A comparison of the effects of streptozotocin, N-methylnitrosourea and alloxan on isolated islets of Langerhans.

Isolated normal rat islets were pre-incubated with Streptozotocin (STZ), N-methylnitrosourea (MNU) or alloxan for 5, 10, 30 or 60 minutes at 0 degree C or 37 degrees C, and then were washed and incubated at 37 degrees C for 60 minutes with glucose (16.7 mM). Suppression of the insulinotropic response to glucose during incubation required 10 minutes of pre-incubation with the nitrosoureas whose effects were directly related to concentration and were temperature dependent.

The characterization of phenazine methosulfate stimulated insulin secretion.

This investigation was initiated to characterize the stimulation of insulin secretion by phenazine methosulfate (PMS). Islets of Langerhans, isolated by the collagenase method from normal rats and rats pre-injected with either streptozotocin or 6-aminonicotinamide, were exposed to PMS under various experimental conditions and insulin secretion in response to PMS, glucose and pyridine nucleotides was determined. Insulin releasing action of PMS was dose-, time- and temperature-related, occurred in the absence of glucose, and was inhibited by epinephrine, but not by mannoheptulose.

Effect of diabetogenic nitrosourea on the activity of the pentose phosphate hunt in isolated islets.

The effect of streptozotocin (STZ) on the activity of the pentose phosphate shunt in islets was studied. Isolated rat islets were pre-incubated with glucose (1.7 mM) alone or with streptozotocin (STZ) or N-methyl-N-nitrosourea (MNU).

Pancreatic beta cell toxicity by streptozotocin anomers.

D-glucose in the pyranose (ring) form exists as two anomers. The alpha-anomer is more effective than the beta-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting beta-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxic moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of two anomers in the pyranose form.

Abnormalities in pelvic visceral nerves. A basis for neurogenic bladder in the diabetic Chinese hamster.

In order to determine whether bladder dysfunction and hydronephrosis in diabetic Chinese hamsters are associated with nerve pathology, the pelvic visceral nerves of diabetic and normal hamsters were examined with histochemical and electron microscopic techniques. Acetylcholinesterase activity was reduced in the nerves and on smooth muscle fibers in the urinary bladder of diabetic hamsters when compared to controls. Depression of enzyme staining was most marked in those hamsters with the most severe hydronephrosis.

Renal amyloidosis in KK mice that may be misinterpreted as diabetic glomerulosclerosis.

A normoglycemic, normoinsulinemic, "lean" phenotype KK mouse having a morphologically normal pancreatic islet had renal lesions reminiscent of diabetic glomerulosclerosis described in the literature for KK mice. Most of these animals also had splenomegaly. Using histochemical and ultrastructural methods, the renal and splenic lesions were demonstrated to be amyloidotic.