Calcium and vitamin D metabolism in sarcoidosis.

BACKGROUND: Sarcoidosis associated hypercalcemia (SAHC) may be secondary to excessive levels of 1,25-(OH)2 vitamin D3 produced by autonomous 1-alpha-hydroxylase activity within the granulomas.  The frequency, treatment, and consequences of hypercalcemia remain unclear. STUDY DESIGN AND METHODS: Two patient cohorts were studied.  In Cohort 1, the prevalence of hypercalcemia in 1606 sarcoidosis patients seen during a six year period was analyzed along with treatment and outcome. Cohort 2 consisted of  261 sarcoidosis patients with measured 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 levels. In forty patients, serial levels of 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 were measured at least three months apart without change in therapy. RESULTS: SAHC was identified in 97 of 1606 (6%) of patients studied and additional nine (0.6%) patients had primary hyperparathyroidism. Post treatment follow up was available in 86 SAHC patients. Hypercalcemia improved in >90% of patients, including eight patients treated solely with vitamin D supplement withdrawal. Renal insufficiency, documented in 41 (42%) of SAHC patients, improved with hypercalcemia treatment.  In 80% of Cohort 2 patients low 25-(OH) vitamin D3 levels were measured with only one patient having a low 1,25(OH)2 vitamin D3 level. Elevated 1,25(OH)2 vitamin D3 levels, which were measured in 11% of patients, were higher for those with a history of hypercalcemia. CONCLUSION: Sarcoidosis associated hypercalcemia, which is often accompanied by renal insufficiency, responds to treatment of sarcoidosis and withdrawal of vitamin D supplementation. Measurement of serum vitamin 1,25(OH)2 vitamin D3 appears to best evaluate vitamin D status in sarcoidosis patients.

Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat.

BACKGROUND: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. MATERIALS AND METHODS: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 µg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 µg/kg·h), were studied. Second, ROSE-010 (100, 200 µg/kg) Technosphere® powder was studied by inhalation. RESULTS: The baseline MMC cycle length was 17.5±0.8 min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 µg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7 min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39)amide. Insufflation of ROSE-010 (100, 200 µg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4 min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5 min, respectively. CONCLUSIONS: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment.

Aggressive osteoblastoma of the mandible closely simulating calcifying epithelial odontogenic tumor. Report of two cases with unusual histopathologic findings.

Aggressive osteoblastoma is a rare bone-forming neoplasm composed of prominent epithelioid cells that demonstrate locally invasive growth with a high rate of recurrence but no metastatic potential. Clinical, radiographic and pathologic features of mandibular aggressive osteoblastoma in a 21-year-old African-American male and a 12-year-old Caucasian female are presented. Both tumors were resected with wide surgical margins and neither patient had adjuvant radiation or chemotherapy. The patients showed no evidence of local recurrence or distant spread either clinically or radiographically after two years of follow-up. These tumors were composed of solid sheets of pleomorphic epithelioid cells, eosinophilic amorphous osteoid with foci of calcification, which closely simulated amyloid. Differentiation of this tumor from histologically similar calcifying epithelial odontogenic tumor and low-grade osteosarcoma proved difficult. Immunohistochemical study with osteocalcin confirmed the osteoblastic nature of these epithelioid cells.

Studies directed at the use of a parallel synthesis matrix to increase throughput in an in vivo assay.

Heparin is the anticoagulant of choice for hospitalized patients, but it is dosed only by injection because it is not absorbed following oral administration. We have discovered and prepared compounds (delivery agents) that facilitate the gastrointestinal absorption of heparin in rats, monkeys, and humans when given orally. We are currently developing a parallel synthesis approach to increase our delivery agent screening throughput in vivo. This approach has been used to produce micromolar quantities of compounds for testing in rats in a 5 x 5 parallel synthesis array. Using an amine benzoylation reaction sequence, 10 mixtures were prepared. These mixtures contained equal weight quantities of five N-substituted, non-alpha, amino acid delivery agents. Each of these mixtures was orally administered to rats in combination with heparin, and plasma clotting times (APTT) were measured to determine activity. Deconvolution of the data accurately identified the most active individual components. Independent synthesis of these compounds verified their activity. This parallel synthesis approach is an effective tool for the screening of oral heparin delivery agents and has increased screening throughput significantly.

Consensus workshop on the toxic effects of long-term PUVA therapy.

The possibility that there is an increased risk of melanoma in patients with psoriasis treated with psoralen-UV-A (PUVA) therapy has raised concern on the part of physicians and patients about the long-term safety of this treatment. In response to this concern, the National Psoriasis Foundation sponsored a workshop at which invited participants with expertise in PUVA therapy, psoriasis treatment, melanoma and nonmelanoma skin cancer, and epidemiological and clinical trials were asked to develop a consensus on the following 3 issues: the risk of long-term adverse effects of PUVA therapy with emphasis on nonmelanoma and melanoma skin cancer; the guidelines for physicians and patients for selection and use of PUVA therapy with consideration of the risk-benefit ratio of this treatment compared with the risk-benefit ratios of alternative treatments; and the directions for further evaluation of the long-term effects Of PUVA therapy.

The safety of etretinate as long-term therapy for psoriasis: results of the etretinate follow-up study.

BACKGROUND: Etretinate is an aromatic retinoid given orally to treat severe psoriasis, a chronic disease that often requires long-term therapy. OBJECTIVE: We assessed the safety of long-term therapy with etretinate for psoriasis. METHODS: This 5-year prospective study of a cohort of 956 patients with psoriasis treated with etretinate assessed the frequency of adverse events in relation to total use and in relation to the frequency of these events in control populations. RESULTS: Our data do not provide evidence for an increased risk of cardiovascular disease, cancer, diabetes, or inflammatory bowel disease in association with long-term etretinate use. Although some patients reported that joint problems improved with the use of etretinate, a greater number associated the use of etretinate with joint problems. CONCLUSION: With proper patient selection and monitoring, long-term etretinate therapy (up to 4 years) does not appear to be accompanied by a substantial increased risk of major adverse effects.

Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection.

The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.