Calcitriol (1,25-dihydroxycholecalciferol) enhances mast cell tumour chemotherapy and receptor tyrosine kinase inhibitor activity in vitro and has single-agent activity against spontaneously occurring canine mast cell tumours.

Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.

Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis).

A potential negative side effect of intermittent parathyroid hormone (PTH) therapy to treat osteoporosis is the loss of cortical bone concomitant with increased cancellous bone mass. We addressed this issue by studying the effects of PTH on whole-body, axial, and appendicular bone mass in an animal model with haversian cortical bone remodeling. Ovariectomized, young adult female cynomolgus monkeys were assigned to placebo (n = 9) or PTH groups (n = 10). The PTH group received 10 microg/kg synthetic human PTH(1-34) peptide by subcutaneous injection, 3 days/week for 6 months, and the placebo group received vehicle. Multiple endpoints of bone mass, strength, and turnover in the axial and appendicular skeleton were assessed, including dual-energy X-ray absorptiometry (DEXA), quantitative computed tomography (qCT), analysis of serum (calcium, phosphorus, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase) and urinary (calcium and creatinine) biomarkers, histomorphometry, and biomechanical testing. Compared with placebo-treated animals, PTH-treated monkeys had no change in whole-body bone mass, but a 6.7% increase in spinal areal bone mineral density (aBMD) was observed. Cortical bone mass measured by qCT at appendicular sites was not affected by PTH treatment, but there were significant increases in cancellous bone mass in the proximal tibia, and a similar trend in the distal radius. Small, transient increases in serum and urinary calcium were observed, but there were no treatment-related effects on other biochemical endpoints. Increased bone formation rate (BFR/BV) in the midradius and midfemur was accompanied by a nonsignificant increase in midfemur porosity. Increased vertebral cancellous bone volume (BV/TV) was associated with greater trabecular and interstitial thickness with no effect on wall thickness. Increases in bone strength were observed in both axial (vertebral maximum stress and load at fracture) and appendicular (femoral neck fracture load) skeleton. Together, these results indicate that PTH therapy in the cynomolgus monkey results in a net gain of spinal and appendicular cancellous bone mass with no adverse effect on cortical bone.

Vitamin D in the prevention and treatment of prostate cancer.

Current approaches to the management of prostate cancer include surgery, radiation therapy, or hormonal manipulation either individually or in combination. With an increase in understanding of the etiology and natural history of prostate cancer, the influence of dietary factors on the disease is becoming more evident. There have been a number of studies in this regard that have demonstrated a relationship between prostate cancer and numerous dietary constituents including vitamins. The fat-soluble vitamins A and D have both been found to affect the growth of prostate cancer in preclinical experiments. Of the two, vitamin D has been the focus of greater attention in recent years, and there are indications that it may be useful both in the prevention and treatment of prostate cancer. This article reviews the current literature in this area to determine if treatment with vitamin D would be a viable management alternative for the patient described in the case study.

Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production.

Asthma may respond to dietary modification, thereby reducing the need for pharmacologic agents. This study determined the effectiveness of n-3 polyunsaturated fatty acid (PUFA) ingestion in ameliorating methacholine-induced respiratory distress in an asthmatic population. The ability of urinary leukotriene excretion to predict efficacy of n-3 PUFA ingestion was assessed. After n-3 PUFAs in ratios to n-6 PUFAs of 0.1:1 and 0.5:1 were ingested sequentially for 1 mo each; patient respiratory indexes were assessed after each treatment. Forced vital capacity (FVC), forced expiratory volume for 1 s (FEV1), peak expiratory flow (PEF), and forced expiratory flow 25-75% (FEF 25-75) were measured along with weekly 24-h urinary leukotriene concentrations. With low n-3 PUFA ingestion, methacholine-induced respiratory distress increased. With high n-3 PUFA ingestion, alterations in urinary 5-series leukotriene excretion predicted treatment efficacy. Elevated n-3 PUFA ingestion resulted in a positive methacholine bronchoprovocation dose change in > 40% of the test subjects (responders). The provocative dose to cause a 20% reduction (PD20) in FEV1, FVC, PEF, and FEF25-75 values could not be calculated because of a lack of significant respiratory reduction. Conversely, elevated n-3 PUFA ingestion caused some of the patients (nonresponders) to further lose respiratory capacity. Five-series leukotriene excretion with high n-3 PUFA ingestion was significantly greater for responders than for nonresponders. A urinary ratio of 4-series to 5-series leukotrienes < 1, induced by n-3 PUFA ingestion, may predict respiratory benefit.

Effect of treatment for 3 months with human parathyroid hormone 1-34 peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis).

Clinical data suggest that PTH may increase cancellous bone mass at the expense of cortical bone in human beings. In this study, the effects of PTH on whole body, axial and appendicular bone mass were studied in an animal model with Haversian cortical bone remodelling. Ovariectomized, young adult, female cynomolgus monkeys were assigned to Placebo (n = 9) or PTH groups (n = 10). The PTH group received 10 micrograms/kg synthetic human PTH(1-34) peptide by SC injection, 3 days/week for 3 months and the Placebo group received vehicle. Spinal and whole body bone mass were measured by DXA, and proximal tibia, distal radius and mid-radius bone mass were measured by quantitative computed tomography (QCT) at baseline and 3 months. Small, transient increases in serum calcium were observed 4 hours after injection with PTH. Compared to placebo-treated animals, PTH-treated monkeys had no change in whole body bone mass, but a 5% increase in spinal bone mineral density. Cortical bone mass measured by QCT at appendicular sites was not affected by PTH treatment, but there were significant increases in cancellous bone mass in the proximal tibia, and a similar trend in distal radius. PTH stimulated dramatic bone gain in the lumbar spine and at appendicular trabecular bone sites during three months' treatment. There was no evidence of cortical bone loss during the same period.

Diagnosis and treatment of patients with gastroesophageal reflux and noncardiac chest pain.

Patients with noncardiac chest pain frequently have some evidence of gastroesophageal reflux. Yet there are few formal studies on the treatment of what appears to be reflux-related chest pain. The purpose of this study was to evaluate the effectiveness of intensive antireflux therapy in patients with noncardiac chest pain and gastroesophageal reflux and to determine whether patients who will respond to this therapy can be identified through routine esophageal testing. Thirteen patients with noncardiac chest pain and evidence of gastroesophageal reflux were treated with intensive antireflux therapy featuring high-dose ranitidine. Chest pain symptoms were scored from 0 (none) to 4 (severe) at entry into the study and at 8 weeks. Mean symptom scores were 2.9 +/- 0.3 at entry and 0.7 +/- 0.3 at 8 weeks. All patients had improvement, including those with a normal endoscopic or barium study (nine patients) and those for whom earlier standard antireflux therapy had failed (seven patients). Only one patient had a positive acid perfusion test, and only seven had any correlation of chest pain and reflux episodes during ambulatory monitoring. We concluded that many patients with noncardiac chest pain have gastroesophageal reflux, including those for whom an empiric trial of standard antireflux therapy fails. More aggressive antireflux therapy often leads to improvement in symptoms. Diagnostic studies requiring strict correlation of chest pain symptoms and reflux episodes are insensitive methods of determining which patients will respond to antireflux therapy.

31P-nuclear magnetic resonance studies of the effect of recombinant human interleukin 1 alpha on the bioenergetics of RIF-1 tumors.

The effect of a single injection of human recombinant interleukin 1 alpha (IL-1 alpha) on s.c. RIF-1 tumors in mice was studied by in vivo 31P nuclear magnetic resonance spectroscopy. Spectra were obtained before and up to 24 h after IL-1 alpha. At 2, 4, 6, and 8 h after IL-1 alpha injection, RIF-1 tumors exhibited a reduction in bioenergetic status compared to untreated controls. The Pi to beta-nucleoside triphosphate and the phosphomonoester to beta-nucleoside triphosphate ratios increased, while the phosphocreatine to Pi and phosphodiester to phosphomonoester ratios decreased. Tumor blood flow, estimated by 86RbCl uptake, decreased within 30 min after IL-1 alpha treatment. Minimum perfusion was detected at 4 h, with recovery between 6 and 12 h after IL-1 alpha treatment. Histological sections of the RIF-1 tumors revealed intravascular congestion by 2 h, extravascular hemorrhage by 4 h, and necrosis by 12 h after treatment with IL-1 alpha. The time course of bioenergetic changes in RIF-1 tumors determined by 31P-NMR spectroscopy was found to parallel the reduction and subsequent recovery of tumor blood flow.

Unsuspected pernicious anemia in a patient with sickle cell disease receiving routine folate supplementation.

Although the issue of folate supplementation in sickle cell anemia remains controversial, routine supplementation has become common. The major drawback to indiscriminate folate therapy is the potential of masking findings of vitamin B12 (cobalamin) deficiency. This has been dismissed as a problem in sickle cell anemia because of the generally young age of the patients. However, because young blacks, especially women, are at higher risk for developing pernicious anemia than whites, sickle cell anemia and pernicious anemia can be expected to coexist occasionally. In this article we describe such a patient and recommend that routine folate supplementation should not be given in sickle cell anemia before determining the vitamin B12 status.