Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response.

Heat and a variety of other stressors cause mammalian cells and tissues to acquire cytoprotection. This transient state of altered cellular physiology is nonproliferative and antiapoptotic. In this study, male Wistar rats were stress conditioned with either stannous chloride or gallium nitrate, which have immunosuppressive effects in vivo and in vitro, or heat shock, the most intensively studied inducer of cytoprotection. The early stages of inflammation in response to topical suffusion of mesentery tissue with formyl-methionyl-leucyl-phenylalanine (FMLP) were monitored using intravital microscopy. Microvascular hemodynamics (venular diameter, red blood cell velocity [Vrbc], white blood cell [WBC] flux, and leukocyte-endothelial adhesion [LEA]) were used as indicators of inflammation, and tissue levels of inducible Hsp70, determined using immunoblot assays, provided a marker of cytoprotection. None of the experimental treatments blocked decreases in WBC flux during FMLP suffusion, an indicator of increased low-affinity interactions between leukocytes and vascular endothelium known as rolling adhesion. During FMLP suffusion LEA, an indicator of firm attachment between leukocytes and vascular endothelial cells increased in placebo and gallium nitrate-treated animals but not in heat- and stannous chloride-treated animals, an anti-inflammatory effect. Hsp70 was not detected in aortic tissue from placebo and gallium nitrate-treated animals, indicating that Hsp70-dependent cytoprotection was not present. In contrast, Hsp70 was detected in aortic tissues from heat- and stannous chloride-treated animals, indicating that these tissues were in a cytoprotected state that was also an anti-inflammatory state.

A review of clinical trials of therapies for osteoporosis using fracture as an end point.

As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.

Effect of calcium citrate supplementation on urinary calcium oxalate saturation in female stone formers: implications for prevention of osteoporosis.

In 14 women aged 37-68 y with a history of renal calcium calculi, bone densities were 12.0% below those of age-matched control subjects at the L2-4 lumbar spine (P = 0.007) and 6.4% less at the femoral neck (P = 0.095). A low-oxalate diet was supplemented with 1 g Ca/d as citrate. In 6 mo, plasma 1,25(OH)2D concentrations fell from 53.2 +/- 18.8 to 41.9 +/- 15.2 ng/L (P = 0.02) and parathyroid hormone from 39.1 +/- 17.0 to 30.8 +/- 12.5 ng/L (P = 0.02). Calcium oxalate saturation was 2.15 +/- 1.38 at baseline, 2.27 +/- 1.00 at 1 mo, and 2.06 +/- 1.57 at 6 mo. The increase in urinary calcium at 1 mo from 4.411 +/- 1.87 to 6.514 +/- 2.82 mmol/24 h (P = 0.01) was offset by a parallel increase in citrate excretion from 2.909 +/- 1.45 to 3.455 +/- 1.34 mmol/24 h (P = 0.03). Calcium citrate supplementation did not increase the lithogenicity of the women in this protocol.

A review of calcium preparations.

There are more than a dozen commonly prescribed calcium supplements and hundreds of different formulations commercially available. Numerous factors need to be considered when selecting a calcium preparation. Physical properties such as solubility, interference from coingested medications or foodstuffs, dosage, and timing can all affect the bioavailability of calcium. Medical conditions such as lactose intolerance, impaired gastric acid secretion, and high risk profile for kidney stone formation may impact on selection of a calcium supplement. This article will review the available literature and make general recommendations for the optimal use of calcium preparations.

Steroid-induced osteoporosis.

Prolonged administration of glucocorticoids causes accelerated loss of bone, which leads to osteopenia and an increased incidence of fractures. The clinical presentation of cortisol excess is one of progressive demineralization, primarily of trabecular bone, resulting in fractures of the vertebral bodies and ribs. Bone dissolution is greatest during the initiation of steroid therapy and can result in the loss of up to 20 per cent of trabecular bone in the first year. Bone loss slows with prolonged therapy; cortical bone is relatively spared so that appendicular skeleton fractures are not typically a part of this syndrome. The rate of bone loss is greatest in those individuals who have high bone remodeling rates. Histologically, one finds decreased trabecular volume and increased bone resorption with an increase in osteoclast number and activity, along with decreased bone formation and mineralization rate. Adjuvant medical therapies that block accelerated bone resorption may protect against steroid-induced osteoporosis.

Effect of gallium on bone mineral properties.

Gallium nitrate is biologically active in blocking bone resorption in vitro as well as in vivo. Administration of gallium nitrate to growing rats results in a dose-dependent accumulation of low levels of gallium in bone that is associated with specific changes in the mineral properties of bone. To elucidate in greater detail the changes induced by gallium, the properties of whole and density-fractionated bone samples from control and gallium-treated rats were examined. These studies showed that short-term treatment with gallium nitrate caused an increase in bone calcium and phosphate content. Devitalized bone powder from the gallium-treated rats was less soluble in acetate buffer and less readily resorbed by monocytes. Density fractionation analyses demonstrated that the largest proportion (76% by weight) of powdered metaphyseal bone particles from rats had a density of less than 2.15 g/cc. Following short-term treatment (14 days) with gallium nitrate (45 mg/kg body weight), a significant increase in the relative proportion of more dense bone (greater than or equal to 2.15 g/cc) was observed (24% for the control vs. 39% for the gallium-treated rats, P less than 0.01). In the diaphyseal samples, the largest proportion (88% by weight) of the bone powder had a density of greater than or equal to 2.15 g/cc. After short-term treatment with gallium, a slight decrease in mean diaphyseal particle density was observed. Measurement of calcium accretion with 45Ca in the gallium-treated rats demonstrated increased specific activity in the metaphyseal bone samples, densities = 2.0, 2.1, 2.15, and 2.25 g/cc; the difference was significant only for the 2.25 g/cc fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin.

STUDY OBJECTIVE: To determine whether gallium nitrate therapy is superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia. DESIGN: Randomized, double-blind comparison of active treatments. SETTING: Comprehensive cancer center. PATIENTS: One hundred ninety-eight consecutive hypercalcemic events in 164 patients screened for entry. ELIGIBILITY CRITERIA: hospitalization and intravenous hydration for at least 2 days; persistent elevated serum calcium levels of 2.99 mmol/L or greater (adjusted for serum albumin); serum creatinine levels of 221 mumol/L or less; no cytotoxic chemotherapy, radiation, or mithramycin within the preceding 7 days or during study; no concurrent use of aminoglycoside antibiotics; life expectancy greater than 4 weeks; lymphoma and parathyroid carcinoma excluded. Patients were stratified by histologic type of tumor (epidermoid or nonepidermoid). Fifty patients were randomized and treated. INTERVENTIONS: Gallium nitrate 200 mg/m2 body surface area for 5 days by continuous intravenous infusion, or salmon calcitonin 8 IU/kg body weight every 6 hours for 5 days by intramuscular injection. Patients randomized to receive gallium nitrate received sham injections of saline to simulate calcitonin; patients randomized to receive calcitonin received 1000 mL 5%-dextrose solution to simulate gallium nitrate. MEASUREMENTS AND MAIN RESULTS: All patients were evaluable. Eighteen of twenty-four patients who received gallium nitrate achieved normocalcemia compared with 8 of 26 patients who received calcitonin for an observed difference of 44% (95% confidence interval, 19% to 69%; P = 0.002). Median duration of normocalcemia before other cytotoxic or hypocalcemic therapy was 6 days for patients treated with gallium nitrate compared with 1 day for patients treated with calcitonin (P less than 0.001). Median duration of normocalcemia regardless of intercurrent treatment and without adjustment for serum albumin was 11+ days for patients treated with gallium nitrate and 2 days for patients treated with calcitonin (P less than 0.01). Mean daily fluid intake and mean daily dose of furosemide were similar in both treatment groups. No additional benefit was seen in 9 patients randomized to receive calcitonin who incidentally received corticosteroids. CONCLUSIONS: Gallium nitrate therapy is highly effective and superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia.

Gallium nitrate for acute treatment of cancer-related hypercalcemia: clinicopharmacological and dose response analysis.

Current treatment of cancer-related hypercalcemia is limited by agents of limited effectiveness or excessive toxicity. Gallium nitrate is a new drug which both inhibits bone resorption and increases calcium content of bone. We have now treated 39 episodes of hypercalcemia with gallium nitrate administered as a continuous i.v. infusion for 5-7 days at 3 daily dose levels (100 and 200 mg/m2, and 50 mg/m2 by brief infusion followed by 150 mg/m2). Nadir calcium values were significantly lower (9.2 +/- 1.5 mg/dl) for patients who received the highest dose relative to patients who received the lowest dose (10.5 +/- 1.6 mg/dl, P less than 0.001). While the actual percentage of patients who achieved normocalcemia was higher at the highest dose relative to the lowest dose (86 versus 60%), this difference was not statistically significant. Mean serum concentration of inorganic phosphorous declined significantly for all patients from 2.9 +/- 0.86 mg/dl at base line to 1.8 +/- 0.66 mg/dl (P less than 0.001). Pharmacokinetic studies suggested that a threshold plasma gallium concentration of approximately 1 microgram/ml must be attained to achieve acute normalization of elevated serum calcium levels. Steady-state plasma gallium levels were attained after 48 h; there was no evidence of drug accumulation in plasma after 2 days. Effects on serum creatinine concentration were negligible, and there were no other toxic reactions. These data confirm preclinical experiments which suggested that inhibition of bone resorption by gallium nitrate is dependent upon the dose and duration of drug exposure. We conclude that gallium nitrate is effective treatment for cancer-related hypercalcemia. The drug is now being evaluated against standard treatment in a randomized, double-blind trial.

Clinical study of a new antimetastatic compound, Nafazatrom (Bay g 6575). Effects on platelet consumption and monocyte prostaglandin production in patients with advanced cancer.

Nafazatrom (Miles Laboratories, West Haven, CT) is a potent inhibitor of metastasis in several animal model systems. The compound is active whether cancer cells are injected intravenously or are allowed to spontaneously metastasize from established tumors. Before studying the antimetastatic effects of Nafazatrom in a long-term randomized clinical trial, the authors conducted a preliminary study to evaluate its toxicity as well as its effects on certain parameters hat have been associated with the biology of metastasis. Since the interaction of platelets, monocytes, and tumor cells may be important for metastasis formation, the authors serially evaluated plasma levels of factors secreted from activated platelets (beta-thrombo-globulin and platelet factor 4) that are inversely correlated with platelet survival. Products of arachidonate metabolism from monocytes were also measured since Nafazatrom is known to modulate prostaglandin production. Thirty-one patients received doses of Nafazatrom ranging from 75 to 1500 mg/m2 orally three times a day. The dose was escalated every 2 weeks. There was no toxicity at any dose level. No major antitumor responses were observed. There was no consistent change in levels of platelet factors either within individual patients or for the population as a whole. Although Nafazatrom (20 microM) decreased tritiated arachidonate incorporation into peripheral blood monocytes from normal subjects in vitro, this effect was not seen in patients treated with the drug. Release of 3PGE2 and 3HETE from cultured monocytes was also not altered by treatment with Nafazatrom. It was concluded that Nafazatrom is safe and well-tolerated up to total doses of 4500 mg/day. The data suggest that the antimetastatic activity of Nafazatrom in vivo is mediated by mechanisms other than by a decrease in platelet consumption or by modulation of arachidonate metabolism by monocytes.

Metabolic effects of gallium nitrate administered by prolonged infusion.

Gallium nitrate was recently found to be effective treatment for resistant cancer-related hypercalcemia. In vitro and in vivo experiments have suggested that the drug directly inhibits calcium resorption from bone; however, the overall effects of gallium nitrate on calcium balance were unknown. We have completed metabolic balance studies in four patients who received this drug by prolonged infusion. All patients were in positive calcium balance while receiving the drug. Each patient also showed a substantial decrease in urinary calcium excretion. Serum phosphorus decreased in all four patients. There was no change in phosphorus, sodium, chloride, or magnesium balance or in creatinine clearance. We conclude that prolonged infusions of gallium nitrate reduce urinary calcium excretion and that the hypocalcemic effect of this drug is primarily due to inhibition of calcium resorption from bone. Thus, the drug may prove useful in reducing accelerated bone resorption in patients with bone metastases or chronic cancer-related hypercalcemia.