In vitro cytotoxicity of (-)-catechin gallate, a minor polyphenol in green tea.

The cytotoxicity of (-)-catechin gallate (CG), a minor polyphenolic constituent in green tea, towards cells derived from tissues of the human oral cavity was studied. The sequence of sensitivity to CG was: immortalized epithelioid gingival S-G cells>tongue squamous carcinoma CAL27 cells>salivary gland squamous carcinoma HSG cells>>normal gingival HGF-1 fibroblasts. Further studies focused on S-G cells, the cells most sensitive to CG. The response of the S-G cells to CG was dependent on the length of exposure, with midpoint cytotoxicity values of 127, 67 and 58muM CG for 1-, 2- and 3-day exposures, respectively. The sequence of sensitivity of the S-G cells to various green tea catechins was characterized as follows: CG, epicatechin gallate (ECG)>epigallocatechin gallate (EGCG)>epigallocatechin (EGC)>>epicatechin (EC), catechin (C). The cytotoxicity of CG, apparently, was not due to oxidative stress as it was a poor generator of H(2)O(2) in tissue culture medium, had no effect on the intracellular glutathione level, its cytotoxicity was unaffected by catalase, and it did not induce lipid peroxidation. However, CG did enhance Fe(2+)-induced, lipid peroxidation. CG-induced apoptosis was detected by nuclear staining, both with acridine orange and by the more specific TUNEL procedure. The lack of caspase-3 activity in cells exposed to CG and the detection of a DNA smear, rather than of discrete internucleosomal DNA fragmentation, upon agarose gel electrophoresis, suggest, possibly, that the mode of cell death was by a caspase-independent apoptotic pathway. The overall cytotoxicity of CG was similar to its epimer, ECG and both exhibited antiproliferative effects equivalent to, or stronger than, EGCG, the most abundant catechin in green tea.

Gallium nitrate for advanced Paget disease of bone: effectiveness and dose-response analysis.

OBJECTIVE: To evaluate whether a brief course of treatment with gallium nitrate can reduce biochemical parameters of accelerated bone turnover in patients with advanced Paget disease. DESIGN: Unblinded trial, decreasing dose schedules of gallium nitrate. SETTING: University hospital with primary orthopedic and metabolic bone disease specialty. PATIENTS: Ten patients with advanced Paget disease who had previously received conventional therapy consisting of calcitonin, etidronate, or mithramycin. INTERVENTIONS: Five patients were entered into each of three dose schedules: 2.5 mg/kg body weight per day by continuous intravenous infusion for 7 days; 0.5 mg/kg per day for 14 days by subcutaneous injection; and 0.25 mg/kg per day for 14 days by subcutaneous injection. Several patients were treated with different dose schedules. Patients were followed until relapse. RESULTS: Fifteen courses of treatment were administered to ten patients. Reductions in serum alkaline phosphatase and urinary hydroxyproline excretion were observed after treatment with each dose schedule. After treatment with high, intermediate, and low doses, the median maximum decreases in serum alkaline phosphatase activity were 49%, 39%, and 18%, respectively. The median maximum decreases in urinary hydroxyproline excretion were 50%, 52%, and 16%, respectively. The maximum decrease in urinary hydroxyproline excretion occurred within a median of 2 weeks from the start of treatment, whereas the maximum decrease in serum alkaline phosphatase activity occurred substantially later at a median of 6 weeks. All treatment schedules were well tolerated. Response duration was highly variable (range, 6 to 42 weeks). CONCLUSIONS: Short-term treatment with gallium nitrate can reduce biochemical parameters of disease activity in patients with advanced Paget disease of bone. Larger trials using low-dose intermittent treatment schedules are required to evaluate the safety and effectiveness of this therapy.

Medical therapy of osteoporosis.

Osteoporosis, defined as diminished bone mass, which predisposes the skeleton to fracture with minimal or no trauma, is a major health problem in the United States, affecting an estimated 20 million people. Achievement of peak bone mass in the first three decades of life through adequate nutrition and exercise is considered essential for prevention. Once osteoporosis is established as a disease entity, a variety of medical therapies have proven efficacy. Sex hormone replacement in the estrogen- or testosterone-deficient patient can maintain and in certain cases augment skeletal mass and reduce fracture incidence. The benefits of cyclical estrogen therapy are of limited duration and risks of accelerating the growth of established breast cancer have not been defined. The route of administration may affect the risk to benefit ratio of estrogen on cardiovascular disease morbidity and mortality. Calcitonin is effective in preserving bone mass for a short duration (18 months); the long-term effects, especially on fracture rate, are unknown. The benefits of a number of agents including vitamin D, thiazides, and bisphosphonates are unproven. Agents with apparent benefit, such as fluoride, can produce abnormal bone and may protect select regions (spine) while increasing the risk of fracture in others (hip). New and established medical treatments are evolving that provide hope for safer, more effective therapies.

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.