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The effects of short-term thymic hormone administration on age-associated immune function were evaluated. Two groups of individuals greater than 65 years of age were treated for 30 days with thymic extracts (TP1) or placebo; before and after this treatment a panel of in vitro and in vivo parameters was determined according to a very rigorous experimental protocol. In most individuals, TP1 treatment was associated with an improvement in cutaneous delayed-type response to PPD. Moreover, an increase in a circulating T cell subpopulation bearing the CD45R surface antigen ("virgin" T cells), and in NK cell cytotoxic activity was also observed in some subjects. Finally, lymphocyte responsiveness to PHA tended to increase, while no effect on lymphocyte ability to produce IL-2 following mitogen stimulation was observed. These findings suggest that TP1 treatment may influence age-related alterations in immune function parameters in some subjects.

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We report the development and validation of three microbioassays for calcitonin based on calcitonin-induced inhibition of the activity of isolated osteoclasts. Having precisely quantified osteoclast motility, spreading and bone resorptive activity, we have applied stringent analytical procedures to define assay characteristics. We have found that the appropriately transformed responses significantly regress on log dose of the peptides. Furthermore, potency estimates obtained using calcitonins from three species (human, salmon and a synthetic analogue of eel calcitonin) have been found to be consistent with those obtained using conventional calcitonin bioassays. In addition, the assays are remarkably sensitive (detection limit 10(-15) M), highly specific and precise. We have determined plasma levels of bioactive calcitonin on samples from patients with medullary thyroid carcinoma; these are several-fold lower than those obtained using our routine calcitonin radioimmunoassay. Our study thus, forms the basis of an entirely new approach for the determination of 'biologically active' calcitonin, and we envisage that such target cell-specific assays could become useful microanalytical methods.

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A new cephalosporin, cefonicid (1 g) was given intramuscularly to six healthy volunteers 12 h after induction of skin suction blister. Serum and blister fluid were collected during a 24 h period. Antibiotic assay was made by a microbiological method. The data were analysed by a one-compartment kinetic model. Despite the high protein binding, cefonicid penetrated in microbiologically effective concentration into blister fluid. Blister fluid concentrations were higher than the serum concentrations at 24 h.

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Norfloxacin is an antibacterial drug chiefly eliminated by the kidney and therefore useful in the treatment of urinary tract infections. To study its pharmacokinetics in chronic renal failure, we administered a single oral dose of 400 mg to 14 patients and 6 controls with normal renal function. Patients were divided into three groups according to the severity of renal failure. Norfloxacin was measured in serum and urine by bioassay. Serum half-life in controls was 3.87 hours and prolonged to 5.85 hours in group I (creatinine clearance 80-45 ml/min), 7.25 hours (p less than 0.05) in group II (creatinine clearance 44-20 ml/min) and 8.34 hours (p less than 0.01) in group III patients (creatinine clearance less than 20 ml/min). A good linear correlation between the elimination rate constant and creatinine clearance (r = 0.79, p less than 0.01) has been found. Total urinary excretion in the 72 hour period after administration achieves 40.4% in controls, falls to 23.5% (p less than 0.05), 15.6% (p less than 0.01) and 8.2% (p less than 0.01) of administered dose in groups I, II and III, respectively. Similarly, urinary concentrations decrease in all patient groups with respect to controls. Our data show that effective urinary antibacterial concentrations of norfloxacin after 400 mg single oral dose were obtained even in patients with severe renal failure. In these patients systemic accumulation after repeated dose administration is a probable event. Therefore, dosage adjustment is advisable in patients with creatinine clearance less than 20 ml/min, although it will inevitably cause lower urinary concentrations.

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(Asu1,7) E-CT (carbocalcitonin-elcatonin) is the aminoasuberic analogue of eel calcitonin differing from the natural hormone in that an ethylene bridge replaces the disulphide bridge in position 1-7. This modification preserves the conformation of natural calcitonin but enhances the physical, chemical and biological stability of the molecule. This in its turn facilitates maximum purification of the product as well as enhancing its resistance to degradation both in vitro and in vivo. The specific activity of carbocalcitonin is equivalent to 5000 U.MRC/mg and it possesses all the pharmacological and clinical properties of natural calcitonins. It has the same hypocalcemic potency of eel or salmon calcitonin, superior to the human and porcine types. Carbocalcitonin has the typical pharmacological effects of the natural hormone on the kidneys, bone and gastrointestinal tract, the target organs of calcitonins. When injected into the cerebral ventricle of laboratory animals it was found to have an analgesic effect. In clinical terms (Asu1,7) E-CT gave good results when used in the treatment of hypercalcaemia and senile osteoporosis. Carbocalcitonin was also employed in conditions characterised by a high bone metabolism turnover such as Paget's disease, Sudeck's atrophy and immobilisation osteoporosis. Experiments to date have shown carbocalcitonin to be extremely interesting in terms of tolerability with very few side effects being noted. This may well be attributable to the greater stability conferred by the absence of the S-S bridge.

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The pharmacokinetics of ceftazidime were investigated in eight normal subjects and eight patients with ascites after intravenous administration of 1 g of the drug. Samples of blood and ascitic fluid were collected for 6 h after dosage, and urine samples were collected for 24 h. Pharmacokinetic data were calculated by using a one-compartment model. The apparent volume of distribution and half-life of elimination (t1/2 beta) in patients with ascites were approximately three times those in normal subjects. In contrast, renal clearance was greater in the normal subjects. With respect to ascites, the mean area under the concentration-time curve was 95.3 +/- 38.3 micrograms X h/ml. The mean ratio of the area under the concentration-time curve for ascitic fluid to that for plasma was 69.9% (+/- 38.2). These data show that ceftazidime rapidly diffuses into the peritoneal space, in which concentrations greater than 10 micrograms/ml were present for at least 6 h.

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Gx 258, a new phenylalkanoic acid derivative, was shown in animal tests to possess potent antiinflammatory, analgesic and antipyretic activity. Its antiinflammatory activity was not mediated via the pituitary-adrenal axis, since it was also effective in adrenalectomized rats. Since large doses of Gx 258, 9-83 times greater than those showing antiinflammatory activity, were required to produce gastrointestinal lesions in rats, Gx 258 appears to have a very good therapeutic index. Its therapeutic index as an antiinflammatory and analgesic agent was 2.3-20.5 times greater than that of the parent compound ibuprofen. Gx 258, like ibuprofen, inhibited the biosynthesis of prostaglandins in vitro.

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The pharmacokinetics and clinical efficacy of ceftazidime, a cephalosporin with activity against Pseudomonas aeruginosa, were studied in children with cystic fibrosis. Ceftazidime had high in vitro activity against P. aeruginosa strains isolated from our patients, with a mean MIC90 of 8 micrograms/ml. The first dose of 50 mg/kg IV of ceftazidime achieved serum concentrations of 40.8 +/- 19.7 micrograms/ml at one hour and 3.8 +/- 1 micrograms/ml at four hours after administration (mean values +/- SD). The MIC90 was exceeded by serum concentrations for up to three hours. The elimination of the drug from the blood followed a biexponential decay with an elimination half-life of 60.4 +/- 6.8 min and a total body clearance of 6.0 +/- 3.1 ml/min/kg. Renal clearance of the drug accounted for 75% of the total clearance; these are higher values than those reported for adults. Peak concentrations of ceftazidime in the sputum two hours after a single administration were 4.13 +/- 2.06 micrograms/ml; after seven and 14 days of treatment, sputum concentrations were significantly lower. Eleven children with acute pulmonary exacerbation were treated for 14 days with ceftazidime at a dose of 150 mg/kg/day (12 treatment courses). Significant clinical and radiologic improvements were obtained in nine of 12 patients. In six of 11 cases the P. aeruginosa count decreased by 10(4) CFU/ml. Ceftazidime was well tolerated, and no side effects appeared during treatment.

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Copper is clearly involved in experimental and human inflammation, as suggested by a large body of data, some of which obtained in our own laboratories. With the purpose to further investigate the role of copper in the inflammatory process, we have studied the development of carrageenan foot oedema and carrageenan pleurisy in rats treated with a copper-deficient diet according to the following schedule: (1) foot oedema in rats maintained on a 0.4 p.p.m. copper-deficient diet for 1 and 3 months; (2) foot oedema and pleurisy in rats maintained on a 0.2 p.p.m. copper-deficient diet for 1 month; (3) foot oedema and pleurisy in rats maintained on a 0.6-0.8 p.p.m. copper-deficient diet for 5 months. With these experiments we have shown an enhancement of the inflammatory reaction which, apparently, is both time and copper content dependent. The possibility that endogenous copper could play a key role in modulating the acute inflammatory process is discussed.

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The antiinflammatory activity of a topical preparation containing dextran sulphate and betamethasone 17-valerate was studied in comparison with that of the single active principles. In the rat carrageenan paw edema test, where compounds were applied topically as cream formulations, dextran sulphate alone was inactive but it greatly improved the antiinflammatory activity of betamethasone 17-valerate. The reported data indicate that dextran sulphate and betamethasone 17-valerate act synergistically in reducing the paw volume. Moreover, the drug combination administered s.c. demonstrated a statistically significant interaction, when compared with the single active principles, in reducing increased vascular permeability in the rat. The results are briefly discussed in relation to published clinical data.

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The development of two models of acute inflammation (carrageenan-induced foot oedema and pleurisy) was studied in rats after 1 month of a 0.2 p.p.m. copper-deficient diet and after 5 months of a 0.6-0.8 p.p.m. copper-deficient diet. A 'pro-inflammatory' effect of copper deficiency was observed with the 0.2 p.p.m. diet, whilst no effect was evident following the 0.6-0.8 p.p.m. copper deficient diet. These results are briefly commented upon.

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Adjuvant arthritis has been studied in young copper-deficient rats and a very strong inhibition of the disease following 60 days of deficient diet (0.4 ppm of copper) was found. No difference in lung prostaglandin synthesis and in rat stomach strip and colon reactivity to exogenous prostaglandins was noticed between controls and copper-deficient animals. These results are briefly discussed.

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Carrageenan-induced hind paw oedema has been studied in rats deprived of copper for different lengths of time. A common feature observed in normally fed and copper-deficient rats was the rise of serum copper levels occurring between 10 and 24 h after the injection of the irritant. After 1 month of copper-deficient diet no differences are seen in the oedema developed by controls and copper-deprived animals, while after 3 months the oedema developed by copper-deficient rats was significantly greater compared with the controls.

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