Development and Stability Study of an Omeprazole Suppository for Infants.

BACKGROUND AND OBJECTIVE: Omeprazole is a proton pump inhibitor (PPI) that is used in acid suppression therapy in infants. In this study we aimed to develop a pediatric omeprazole suppository, with good physical and chemical stability, suitable for pharmaceutical batch production. METHODS: The composition of the suppository consisted of omeprazole, witepsol H15 and arginine (L) base. To achieve evenly distributed omeprazole suspension suppositories, the temperature, stirring rate, and arginine (L) base amount were varied. A previously validated quantitative high-performance liquid chromatography-ultraviolet method was modified and a long-term stability study was performed for one year. RESULTS: Evenly distributed omeprazole suspension suppositories were obtained by adding 100 mg arginine (L) base and pouring at a temperature of 34.7 °C and a stirring speed of 200 rpm. The long-term stability study showed no signs of discoloration and a stable omeprazole content between 90 and 110% over 1 year if stored in the dark at room temperature. CONCLUSION: We developed a pediatric omeprazole suppository. This formulation may provide a good alternative to manipulated commercial or extemporaneously compounded omeprazole oral formulations for infants. Clinical studies are needed to establish efficacy and safety in this young population.

Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia.

INTRODUCTION: Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor. OBJECTIVE: In this study, we evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH). METHODS: Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI >35 kg/m(2), and a serum total testosterone <10 nmol/l. All patients started on one tablet of 2.5 mg/week, with subsequent dose escalation every month until a serum total testosterone of 20 nmol/l was reached. ENDPOINTS: Psychological function, body composition, exercise capacity, and glucose, lipid, and bone metabolism. RESULTS: Thirty-nine patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1±10.1 to 59.2±6.1 pmol/l (P<0.001), and increased serum LH from 3.3±0.3 to 8.8±0.9 U/l (P<0.0001) and serum total testosterone from 8.6±0.7 to 21.5±1.3 nmol/l (P<0.0001). Significant effects on the predefined endpoints were not observed. CONCLUSION: Despite a marked rise in serum testosterone, low-dose aromatase inhibition had no somatic or psychological effects in men with OrHH.

Vitamin D absorption: consequences of gastric bypass surgery.

BACKGROUND: Severe vitamin D deficiency is a common finding in morbid obesity, and the incidence increases markedly after RYGB. Normalization of vitamin D levels after RYGB is difficult to achieve because the degree of surgery-induced malabsorption is not known. OBJECTIVE: To develop a test that quantifies the changes in intestinal cholecalciferol absorption induced by Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Absorption characteristics of cholecalciferol were studied in 14 morbidly obese, premenopausal women before and 4 weeks after laparoscopic RYGB. Serum cholecalciferol levels were measured at baseline and 1, 2, 3, and 14 days after a single oral dose of 50 000 IU solubilized cholecalciferol. RESULTS: Peak serum cholecalciferol levels were observed on day 1 in all patients. They were 26.6±3.7% lower after RYGB (P=0.02). Inter-individual variability was high. CONCLUSION: Peak cholecalciferol levels are reduced by about 25% after RYGB. Further analysis suggested that the timing of sampling in the current study was not optimal. This might have caused an underestimation of the true decrease in cholecalciferol absorption induced by RYGB.

Cholecalciferol loading dose guideline for vitamin D-deficient adults.

INTRODUCTION: Severe vitamin D deficiency is very common. Evidence-based guidelines for rapid correction with high-dose oral cholecalciferol are not yet available. OBJECTIVE: To develop a practical cholecalciferol loading dose regimen. MATERIALS AND METHODS: A total of 208 vitamin D-deficient subjects (serum 25-hydroxyvitamin D(3) (25-OHD(3)) level <50 nmol/l), aged 18-88 years, were treated with solubilized cholecalciferol, 50,000 IU/ml. They received either 25,000 IU every fortnight for 8 weeks (total dose 100,000 IU), 25,000 IU every week for 6 weeks (total dose 150,000 IU), or 25 000 IU every week for 8 weeks (total dose 200,000 IU). Blood samples were collected at baseline and 10 days after the final dose of cholecalciferol. Results Most patients were severely vitamin D deficient: 76% had a serum 25-OHD(3) level <30 nmol/l at baseline. Cholecalciferol in a cumulative dose of 100,000, 150,000, and 200,000 IU increased mean serum 25-OHD(3) level by 29 nmol/l (95% confidence interval (CI): 23-35 nmol/l), 43 nmol/l (95% CI: 36-50 nmol/l), and 69 nmol/l (95% CI: 64-75 nmol/l) respectively. The change in 25-OHD(3) (Delta25-OHD(3)) was related to the dose per kilogram body weight (R(2)=0.38, P<0.0001), and is described by the equation: Delta25-OHD(3)=0.025x(dose per kg body weight). CONCLUSION: The cholecalciferol loading dose required to reach the serum 25-OHD(3) target level of 75 nmol/l can be calculated as follows: dose (IU)=40x(75-serum 25-OHD(3))xbody weight.

Temazepam 10mg does not affect breathing and gas exchange in patients with severe normocapnic COPD.

BACKGROUND: Benzodiazepines can improve sleep quality, but are also thought to cause respiratory depression in patients with chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the effects of temazepam on indices of circadian respiratory function, dyspnea, sleep quality, and sleepiness in patients with severe COPD and insomnia. METHODS: In a double-blind, randomized, placebo-controlled, cross-over study in 14 stable patients with COPD (mean FEV(1) 0.99+/-0.3L) with insomnia, polysomnography with continuous transcutaneous capnography and oximetry, arterial gas sampling, hypercapnic ventilatory response, multiple sleep latency test, Epworth Sleepiness Scale, dyspnea and sleep visual analogue scales (VAS) were performed at baseline, after one week of temazepam 10mg at bedtime and after one week of placebo. RESULTS: Temazepam did not cause statistically significant changes in mean transcutaneous carbon dioxide tension during sleep compared to placebo (5.9+/-1.0 kPa vs. 6.3+/-1.4 kPa, p-value 0.27), nor in mean oxygen saturation (92+/-3% vs. 92+/-2%, p-value 0.31), nor in any of the other investigated variables, except for the total sleep time and sleep latency VAS, which improved with temazepam. CONCLUSIONS: One week usage of temazepam 10mg does not influence circadian respiratory function, dyspnea, and sleepiness in patients with stable, severe, normocapnic COPD and insomnia and it improves total sleep time and subjective sleep latency. However, this is a preliminary explorative study for assessing the feasibility to perform a larger study on this topic. The clinical implications of this study are very limited.

Cinacalcet for hyperparathyroidism in pregnancy and puerperium.

The efficacy and safety of various modes of medical treatment for primary hyperparathyroidism (PHPT) in pregnancy is largely unknown. This report describes two cases of PHPT in pregnancy that were temporarily treated with the calcimimetic cinacalcet. The first case was diagnosed in the 31st week of pregnancy. The patient was asymptomatic and had an albumin-corrected total calcium level (Ca(corr)) of 3.24 mmol/l. As serum calcium was only mildly elevated it was decided to postpone surgery to the postpartum period. Cinacalcet was started immediately after delivery to prevent a postpartum surge in serum calcium. The second patient presented with hypertension and symptomatic hypercalcemia (Ca(corr) 3.96 mmol/l) in the 32nd week of pregnancy. Surgery was postponed because of suspected pheochromocytoma. Treatment with a combination of cinacalcet and calcitonin reduced serum Ca(corr) to 3.0 mmol/l. This report describes the monitoring of mother and child, and explores the pros and cons of the use of calcimimetics during pregnancy and puerperium.

Tumor producing fibroblast growth factor 23 localized by two-staged venous sampling.

BACKGROUND: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia, renal phosphate wasting, suppressed 1,25-dihydroxyvitamin D production, and osteomalacia. It is caused by a usually benign mesenchymal tumor producing fibroblast growth factor 23 (FGF-23). Surgical excision of the tumor is the first choice of treatment because complete resection is curative. Unfortunately, localization often fails due to the small size of these neoplasms. According to the current standards, supportive care with oral phosphate and calcitriol is the only feasible option in such cases. CASE: In this report, we describe the diagnostic value of two-staged venous sampling to localize the FGF-23 secreting tumor in a case where conventional imaging failed. In addition, we examined the effect of dipyridamole on renal phosphate excretion, explored the efficacy of octreotide and calcitonin to suppress the FGF-23 production, and closely evaluated the hormonal changes following successful removal of the tumor. The latter observations indicate that calcitonin may be useful to suppress tumor-FGF-23 production and that FGF-23 may be a clinically relevant inhibitor of parathyroid hormone secretion in man.

Similar effects of rofecoxib and indomethacin on the incidence of heterotopic ossification after hip arthroplasty.

BACKGROUND: Although indomethacin is effective in preventing heterotopic ossification (HO) after primary total hip arthroplasty, side effects are frequently observed. In the last decade a new class of drugs--the COX-2 selective nonsteroidal anti-inflammatory drugs--has been developed. To investigate the effect of these COX-2 selective NSAIDs on heterotopic ossification (HO) after primary total hip arthroplasty (THA), we conducted a randomized controlled trial using either indomethacin or rofecoxib for 7 days. METHODS: 186 patients received either indomethacin 3 times daily, or rofecoxib twice, and 1 placebo, daily for 7 days. HO was graded according to the 1-year postoperative radiographs according to the Brooker classification. RESULTS: 12 of the 186 patients included discontinued their medication before the end of the trial due to side effects. The remaining 174 patients were included in the analysis. In the indomethacin group (n = 89), 77 patients (87%) showed no HO, 9 showed HO of grade 1 and 3 showed HO of grade 2 according to the Brooker classification. In the rofecoxib group (n = 85) 73 patients (86%) showed no ossification, 9 showed grade 1, and 3 showed grade 2. INTERPRETATION: The prophylactic effect of rofecoxib for 7 days in preventing heterotopic ossification after primary total hip arthroplasty is comparable to the effect of indomethacin given for 7 days. These results indicate that the development of HO follows a COX-2 pathway.

Cetrorelix suppression test to assess the source of androgen overproduction in postmenopausal hirsutism.

UNLABELLED: A 75-year-old woman presenting with recent onset hirsutism and severely elevated serum androgen levels was evaluated to assess the source of excessive androgen production. Commonly recommended hormonal stimulation and suppression tests, and the usually employed imaging techniques were non-diagnostic. In this report, we describe a new suppression test based on the use of the GnRH receptor antagonist, cetrorelix, to determine whether androgen production was LH-dependent. Cetrorelix, administered in a daily dose of 250 microg subcutaneously, suppressed serum LH within 24 h and reduced serum androgen levels to normal within 48-72 h, indicating that androgen overproduction was of ovarian origin. This diagnosis was confirmed by laparoscopic ovariectomy. CONCLUSION: The cetrorelix suppression test is a simple procedure that provides valuable information regarding the source of androgen excess in postmenopausal hirsutism.

Alternative splicing of cyclooxygenase-1 mRNA in the human iris.

In homogenates of the human iris, the nonsteroidal anti-inflammatory drug (NSAID) S(+)flurbiprofen has been reported to inhibit cyclooxygenase-1 (COX-1) 70-fold more potently than in human whole blood. We hypothesized that this difference may be due to alternative splicing of COX-1 mRNA in the human iris or in whole blood. In this study, we have identified a similar COX-1 splice variant (COX-1SV) in both tissues with comparable COX-1/COX-1SV expression ratios. Therefore, we conclude that the difference in IC(50) values of S(+)flurbiprofen towards COX-1 in the human iris and human whole blood is not related to differences in the occurrence of spliced COX-1.

99mTc-diflunisal and the human iris: topical application reveals localization.

Following the instillation of a drug into the eye, drainage mechanisms will commence at once. In this report, an attempt was made to assess the dynamics of an instilled nonsteroidal anti-inflammatory drug (NSAID), diflunisal, labeled with 1 MBq 99mTc followed by twenty minutes of scintigraphy. The results obtained with this labeled drug were compared with instillation of the same volume and activity of 99mTcO4-. Although the pertechnetate anion is an excellent and innocuous indicator for detecting the external lacrimal drainage system of the eye, it cannot visualize the internal structures. A clear scintigraphic difference was noted between labeled diflunisal and the pertechnetate anion. Scintigraphic activity surrounding the pupil of the eye provides evidence of visualization of the iris/ciliary body. This seems reasonable as the cyclooxygenase enzyme is located in this structure, and NSAIDs exert their mechanism of action via this complex. With this technology, visualization of some internal structures of the eye may be facilitated.