Six patients (21–50 years) with growth hormone deficiency and panhypopituitarism were given recombinant growth hormone, somatropin, 0.04–0.1 U·kg·body wt−1·day−1, for 12 months. All patients reported improved well-being with increased working capacity. Bone mineral density, as measured by single photon absorptiometry at two sites on the forearm, showed increased values in 5/6 patients after 12 months when measured at the most distal site (predominantly trabecular bone) and in 4/6 at the more proximal site (predominantly cortical bone). Five patients continued therapy for an additional year and after 18 months a significant increase in bone mineral density was seen at both the distal and proximal sites. The mean annual increase in bone mineral density was 12.0±0.6 (sem)% and 3.8±1.3% at the distal and proximal sites, respectively. In a growth hormone deficient control group without growth hormone therapy, the corresponding values were −2.4±0.6% and −1.9±0.4%, respectively. Lean body mass, estimated anthropometrically, increased significantly after 12 months and total body potassium, measured by whole body counting technique, increased in 4/6 patients. During growth hormone treatment, the IGF-1 values were above the mean values for age and 50% of the values were above the mean + 2 SD. B-glucose, P-insulin, serum IGF-2, procollagen-III peptide and phosphate increased and urea, creatinine and IGF-binding protein-1 decreased during treatment. The beneficial effects of growth hormone substitution, especially on bone mineral density, indicate that growth hormone substitution should be considered in all patients with hypopituitarism and growth hormone deficiency, irrespective of age.

Calcium homeostasis was longitudinally followed in serum and urine throughout normal pregnancy and the puerperium in 23 healthy women. From the 14th week of gestation, samples were obtained every fourth week until the 38th week. Post partum samples were obtained on the fifth day and after eight weeks. In the serum the total calcium decreased continuously during pregnancy. The ionized calcium and phosphate levels remained unchanged and within the reference interval for non-pregnant women. The alkaline phosphatase level progressively increased and high levels were found at term. The magnesium and hematocrit values remained below, whereas the calcitonin level remained just above the reference interval throughout pregnancy. The parathyroid hormone was low initially and increased towards term but within the reference interval. The urine excretion of calcium was constantly high, close to the upper reference limit, and renal function was slightly improved. At the last sampling eight weeks after delivery, all values were within normal limits for non-pregnant women. Calcium homeostasis is considerably changed during pregnancy and non-pregnant reference limits are not often valid.

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ABSTRACT:In the early drug discovery process, metabolic stability and cytochrome P450 inhibition are often used as an early selection tool to identify useful compounds for further development. The reliability of the data in this process is therefore crucial. In the present study, in vitro enzyme kinetic data were used to predict the in vivo clearance and drug-drug interaction potential of four well known CYP2C9 substrates (tolbutamide, fluvastatin, ibuprofen and diclofenac) that are frequently used as benchmark substances in screening programs. Quantitative predictions of hepatic clearance using the well stirred prediction model and CL int calculated from enzyme kinetic measurements were not useful. Including and excluding protein binding resulted in under-and overestimation, respectively, of in vivo clearance. The only predicted in vivo clearance that fell into the range of reported measured values was for fluvastatin when protein binding was not included. In an open, randomized, seven-armed, crossover study in healthy volunteers, tolbutamide, ibuprofen, and fluvastatin were investigated as inhibitors of the metabolism of diclofenac, and vice versa. None of the combinations was found to interact with each other in vivo. The in vitro drug-drug interaction potential was investigated by K i determinations of the same combinations. In contrast to clearance predictions, the interaction potential in vivo was best predicted when plasma protein binding was included in the various models used. This study points to the uncertainty in calculating in vivo kinetics from in vitro enzyme kinetic data. The in vitro metabolic screening can thus be questioned as a compound selection tool without a proven in vitro-in vivo correlation.