Effects of glycosylated and non-glycosylated G-CSFs, alone and in combination with other cytokines, on the growth of human progenitor cells.

Two recombinant human granulocyte colony-stimulating factors (rHu G-CSF) are clinically available, a glycosylated (lenograstim) and a nonglycosylated from (filgrastim). Since there is accumulating evidence that glycosylation plays a role in the in vitro activity of the G-CSF molecule, we compared the biological potency of lenograstim and filgrastim on human hematopoietic progenitor cells by colony assay in semisolid medium and ex vivo expansion experiments. Leukapheretic products without further processing and CD34-positive purified cells were used as source of human progenitors. Lenograstim demonstrated greater capacity, to stimulate the colony growth of both, purified and CD34+ peripheral blood cells. This effect, which is evident especially at low doses of growth factor, seems not to be mediated by accessory cells. Whether these observations may have clinical relevance is still to be clearly assessed and further investigations are needed.

Breathing pattern in men during inspiratory elastic loads.

Breathing pattern was studied in men during inspiratory elastic load applied throughout breathing cycle (CL) or inspiration only (DL). VT decreased similarly under both loads: 40% during 1st loaded breath (1st), 25% after 1 min (min); so did Ti (15% at 1st, 25% at min); Te decreased by 35% under CL, 25% under DL, at both times. Under DL expiratory flow started after a lag of about 0.4 sec, required to raise alveolar pressure above atmospheric. In all subjects the inspiratory muscles activity increased at 1st and in 6 out of 8 the ventilatory response at min was essentially neurogenic. At 1st all subjects recruited expiratory muscles, decreasing FRC by 100--300 ml under DL' in most this phenomenon was negligible at min. Rate of decrease of inspiratory muscle pressure during period of zero flow under DL was proportional to end-inspiratory muscle pressure (Pmuse.i.) and to Pmuse.i./Ti. At beginning of expiration dPmus/dt was greater under DL: under this period difference of Pmus between CL and DL seems mainly due to muscle intrinsic properties.

Treatment of Cushing's syndrome with the long-acting somatostatin analogue SMS 201-995 (sandostatin).

Three patients with Cushing's disease and one patient with paraneoplastic hypercortisolism were treated for 24-49 days with the long-acting analogue of somatostatin, SMS 201-995, Sandoz (SMS), administered in increasing doses up to 400-1200 micrograms daily. In the three Cushing's patients during SMS treatment plasma ACTH displayed an initial rise and a subsequent decrease. The pattern of urinary free cortisol (UFC) tended to be opposite to that of ACTH. In one of these patients, UFC continued to decrease throughout the treatment, without becoming normal. In the patient with paraneoplastic hypercortisolism, SMS was associated with a progressive decrease, though not the normalization, of UFC and of ACTH and cortisol levels. The reciprocal changes of the ACTH and UFC levels observed in the three Cushing's patients receiving SMS suggest that the peptide may act temporarily by inhibiting glucocorticoid secretion. In view of the marked reduction of UFC recorded in 1 of the 3 Cushing's patients and in the patient with paraneoplastic Cushing's syndrome, administration of SMS seems worth trying in cases of ACTH-dependent hypercortisolism requiring medical treatment.

Use of somatostatin analog SMS 201-995 in medullary thyroid carcinoma.

We have studied seven subjects with medullary thyroid carcinoma. Each had elevated basal serum calcitonin (CT) levels following total thyroidectomy. After subcutaneous administration of 100 micrograms of SMS 201-995, blood samples were collected at 60-minute intervals for six hours. Two patients showed a marked decrease of CT levels (patient A: baseline 565 pg/mL, nadir 150 pg/mL; patient B: baseline 1,632 pg/mL, nadir 416 pg/mL). The other five patients showed no significant change in comparison with saline infusion. Two patients were treated with SMS 201-995 (300 micrograms/day) for 90 days. One of these patients responded to the acute SMS 201-995 test and had CT levels persistently 50% lower than pretreatment values during this 90-day period. The other patient, whose CT levels did not decrease during the acute test, had persistently high values during this 90-day period but had relief of watery diarrhea even after the therapeutic trial was discontinued.

In vitro effects of fructose-1,6-diphosphate on oxygen affinity and electrolyte equilibrium in human blood.

The in vitro effects of a solution of fructose-1,6-diphosphate on hemoglobin-oxygen affinity and electrolyte distribution between plasma and red cells were evaluated. Fructose-1,6-diphosphate increased intracellular pH and decreased extracellular pH. There were no shifts in Na+, K+, Ca++ and Cl- between plasma and red cells. Red cell content of 2,3-diphosphoglycerate remained unchanged, while P50 was reduced (as a consequence of the intracellular alkalosis). The therapeutical implications of these results are discussed.

Effect of sandostatin on CRF-stimulated secretion of ACTH, beta-lipotropin and beta-endorphin.

The influence exerted by somatostatin on the secretion of ACTH and opioid peptides has still to be clarified. To gain further information on this issue, we performed in 10 normal volunteers two CRF tests (100 micrograms i.v.) one of which was preceded by s.c. injection of 100 micrograms of the long-acting somatostatin analogue SMS 201-995 (Sandostatin, Sandoz) (SMS), given 30 minutes before CRF. Premedication with SMS markedly inhibited the response of beta-EP to CRF, leaving unchanged the response of beta-LPH, ACTH and cortisol; mean incremental areas of beta-EP were 199.8 +/- 49.31 (SEM) vs 532.9 +/- 95.91 pmol 120 min (P less than 0.01) in the CRF test with and without SMS, respectively. To interpret the selective inhibitory effect of SMS on CRF-stimulated beta-EP secretion, it can be hypothesized that: a) the action of SMS was confined to a population of pituicytes preferentially secreting beta-EP; b) SMS interfered with the processing of POMC inhibiting the formation of beta-EP; c) SMS acted on extrapituitary, possibly peripheral, sources of beta-EP. In conclusion, this study indicates that, in man, somatostatin selectively inhibits the CRF-induced secretion of beta-EP, but not that of ACTH and beta-LPH, by an action that may be exerted at pituitary or extrapituitary level. This is a further example of dissociated secretion of POMC-derived peptides.

Four year treatment with a long acting somatostatin analogue in a patient with Verner-Morrison syndrome.

The case is described of a woman with a Verner-Morrison syndrome of extreme severity, caused by an occult VIPoma. Administration of SMS 201-995 (Sandoz) (SMS) at the dose of 150 and subsequently of 250 micrograms daily, decreased plasma levels of vasoactive intestinal polypeptide (VIP) from about 500 to 100 pg/ml (highest normal limit 60 pg/ml). This was associated with complete regression of the diarrhea and normalization of serum potassium levels and hence with the return of the patient to a fully normal life. After 36 months of clinical remission, watery diarrhea recurred together with elevation of VIP plasma levels and appearance of liver metastases. Laparotomic exploration led to the removal of a pancreatic VIPoma and its liver secondarisms, which was followed by a second remission. Reappearance of the symptoms and development of new liver metastases 8 months later required reinstitution of SMS therapy, which allowed once again to control the clinical picture. Anterior pituitary function, assessed by dynamic testing, was unaffected by chronic SMS administration with the exception of the stimulated growth hormone secretion that was inhibited. Glucose tolerance and insulin secretion remained normal during treatment. Glucose intolerance ensued after pancreatectomy and was not worsened by reintroduction of SMS. Treatment with SMS may allow long-lasting remission of Verner-Morrison syndrome associated to VIPoma, though it does not arrest the progression of the tumor.

Effects of salmon calcitonin on the bone loss induced by ovariectomy.

We present the results of a 12-month clinical study assessing the effects of synthetic salmon calcitonin (sCT) on a group of fertile white women who had undergone ovariectomy for uterine fibromatosis. The study was performed to verify whether CT can prevent the loss of bone mass and the changes in calcium-phosphorus metabolism associated with acute estrogen deficiency. The study consisted of an initial double-blind phase of 6 months, followed by a 6-month open period. Treated patients were given 100 MRC U of synthetic salmon CT injected i.m. in the morning, every other day, starting on the 7th day after the operation and continued for 12 months. Control patients received a placebo injection for the first 6 months; subsequently, they too were treated with sCT i.m. every other day for 6 months at the same dose as the 12 month-treated group. All patients received 500 mg of elementary calcium p.o., b.i.d. Bone mineral content (BMC) was measured at the extreme distal radius of the nondominant arm by a dual photon bone densitometer which utilizes two radio nuclides, 241 Am and 125 I, with energies of about 60 and 30 KeV. Biochemical parameters of the calcium-phosphorus metabolism were also measured. After 12 months of study, no significant changes of BMC were observed in the 12 months sCT treated group, while control patients, treated 6 months after the ovariectomy, showed a significant decrease in BMC values.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of Activity of Docetaxel in Soft Tissue Sarcomas: Results of a Phase II Study of the Italian Group on Rare Tumors.

Purpose. The prognosis of advanced soft tissue sarcoma is poor, only a few drugs showing some activity with response rates around 15- 25%. Consequently drug development seems mandatory to improve treatment outcome. Following previous favourable EORTC experience, the Italian Group on Rare Tumors started a phase II study with docetaxel to confirm the activity of this drug in soft tissue sarcoma.Patients and methods. Thirty-seven patients with soft tissue sarcoma resistant to at least one anthracyclinecontaining regimen were enrolled in a phase II multicenter study evaluating docetaxel 100 mg/m(2) in a 1-h i.v. infusion q(3) weeks.Results.Thirty-seven patients were enrolled onto this phase II study and 36 were evaluable for response. Only one partial remission was observed [2.8% with 95% confidence interval (CI) 0.1- 16.2%]. Median progression-free and overall survival were 42 and 350 days, respectively. Neutropenia and leukopenia as well as cutaneous manifestations were the most common toxicities.Discussion. The results of this phase II study do not confirm a previous EORTC repor t on the activity of docetaxel in soft tissue sarcoma, but are consistent with other more recent phase II studies. The accumulated evidence does not justify the use of this drug in the management of patients suffering from this disease, resistant to anthracyclinecontaining regimens.