A dose-finding study of zoledronate in hypercalcemic cancer patients.

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.

[Sclerodermatomyositis. Apropos of 13 cases]. / Les sclérodermatomyosites. A propos de 13 observations.

13 cases of sclero (dermato)myositis are reported with cutaneous signs specific of dermatomyositis in 6 cases. Scleroderma was rather benign, without any visceral involvement. In contrast, myositis was much more severe that usually encountered in systemic sclerosis, threatening the vital prognosis and requiring aggressive therapeutic measures to be controlled. In 6 cases, the axial musculature was involved. Occurrence of each component was not simultaneous. No case was paraneoplastic. Antinuclear antibodies were present in all cases. Antibodies against soluble nuclear antigens, specifically found by others in sclerodermatomyositis, were absent. The very peculiar clinical spectrum of this syndrome associated with immunologic abnormalities, elsewhere described, confirm the individualization of sclerodermatomyositis.

[Acrosclerosis, Gougerot-Sjögren syndrome, myxedema and anti-centromere antibodies. 3 cases of this association]. / Acrosclérose, syndrome de Gougerot-Sjögren, myxoedème et anticorps anti-centromère. Trois cas de cette association.

The authors report three identical cases of the association of acrosclerosis with telangiectasis without calcinosis, Sjögren-Gougerot syndrome, myxoedema with antithyroid antibodies and anti-centromere antibodies. The association of these conditions one with another has already been published, but, to the authors' best knowledge, this is the first report of all of them grouped together in the same patients. With reference to the literature, the authors discuss the problems of individualization of the CRST syndrome and its varieties and the clinical significance of the presence of anti-centromere antibodies.

[Amyloidosis in adult Still's disease. Apropos of 2 cases]. / Amylose au cours de la maladie de Still de l'adulte. A propos de 2 observations.

Two cases of amyloidosis were observed in a personal series of 42 patients with the adult from of Still's disease. Two other cases have been previously reported in the literature. In the first case, amyloidosis occurred 18 months after the onset of the disease and involved the kidneys and gastrointestinal tract with a fatal outcome in 6 months. In the second case, renal amyloidosis was observed 4 years after the onset of Still's disease and progressed to renal failure in 7 months, necessitating chronic haemodialysis. These cases show that the adult form of Still's disease may rarely be complicated by amyloidosis, the prognosis of which is particularly poor.

[Controlled prospective study of clinical and biological thyroid parameters in rheumatoid polyarthritis]. / Etude prospective contrôlée des paramètres thyroïdiens cliniques et biologiques dans la polyarthrite rhumatoïde.

15 patients with rheumatoid arthritis (14 women and 1 man aged between 30 and 75 years) were compared to a control group of 12 women and 1 man (aged between 22 and 77 years) admitted to the rheumatology unit at the same time for benign diseases. Both groups were examined for: the presence of a goitre, family history and/or clinical hormonal dysfunction, the plasma levels of total cholesterol, free thyroxin (FT4), free triiodothyronine (FT3), before and 2 hours after 50 micrograms of thyrotropin IV, thyrostimulin half an hour before and one hour after thyrotropin and the levels of the antimicrosomal anti-thyroid antibodies and the anti-thyroglobulin antibodies. None of the patients with rheumatoid arthritis had any clinical hormonal dysfunction. However, 6 of the 15 patients presented a homogeneous goitre, 5 of these 6 patients had a family history of goitre and 2 had positive antibodies. In comparison with the control group, the 15 cases of rheumatoid arthritis had a significant decrease (m +/- sd) in the FT4 (13.20 +/- 2.50 pmol/l vs 15.60 +/- 2.47; p less than 0.02), FT3 (3.80 +/- 1.12 pmol/l vs 5.50 +/- 0.93; p less than 0.001) and a rise in the T3 with low thyrotropin (5.70 +/- 1.60 vs 8.50 +/- 1.50; p less than 0.001), while the levels of thyrostimulin and the thyrostimulin peak under thyrotropin were not modified.(ABSTRACT TRUNCATED AT 250 WORDS)

[Spinal cord compression in malignant plasmacytic diseases. Apropos of 6 cases]. / Compression médullaire des maladies plasmocytaires malignes. A propos de 6 observations.

Myeloma may be complicated or revealed by spinal cord compression. Out of 105 cases of myeloma admitted to this Department, 6 cases of spinal cord compression were observed, with a favourable outcome after treatment by laminectomy combined with radiotherapy. In 5 cases out of 6, spinal cord compression was either the presenting sign or occurred within the first months after diagnosis. Compression occurred in the thoracic cord in 5 cases, and in the lumbar cord in 1 case. The interval between the first symptom and diagnosis varied greatly (from a few hours to 1 year), as did the degree of paraplegia, which ranged from paraparesis to flaccid paraplegia. A favourable outcome occurs in most other reported cases, in contrast with spinal cord compression from metastases. Treatment (laminectomy-radiotherapy or both) remains controversial.

Effects of furosemide on extravascular diffusion, protein binding and urinary excretion of cephalosporins and aminoglycosides in rabbits.

We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).