Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis.

BACKGROUND: Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). METHODS: Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h). RESULTS: 96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar. CONCLUSIONS: Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393.

Use of a combination formulation of bismuth, metronidazole and tetracycline with omeprazole as a rescue therapy for eradication of Helicobacter pylori.

BACKGROUND: Helicobacter pylori infection occurs in children and adults worldwide. Standard triple therapy of omeprazole, amoxicillin and clarithromycin (OAC) may not be optimal. AIM: To evaluate quadruple therapy with bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride, given with omeprazole in H. pylori infected subjects who failed previous OAC eradication therapy. METHODS: This was a multicenter, open-label, single-arm, multinational study. Helicobacter pylori-positive subjects who had failed ≥1 previous course of OAC therapy with or without up to three supplemental treatments in the previous year. Subjects were treated for 10 days with a combination formulation containing bismuth subcitrate potassium 140 mg, tetracycline hydrochloride 125 mg, and metronidazole 125 mg, three capsules four times daily (q.d.s.), and omeprazole 20 mg twice daily (b.d.). The primary endpoint was H. pylori eradication rate defined as one negative (13) C-urea breath test ≥28 days post-treatment. RESULTS: Helicobacter pylori eradication rates ranged from 93.2% to 93.8% in the intent-to-treat population (n = 49), and from 94.7% to 95.0% in the PP population (n = 40). No clinically meaningful differences were observed when analysed by country. Metronidazole resistance was observed in 16/49 (32.7%) subjects and clarithromycin resistance in 31/49 (63.3%) subjects. Thirty-three subjects (67.3%) reported 87 adverse events, and only one (2%) discontinued the study for an adverse event. CONCLUSIONS: A quadruple regimen of bismuth, metronidazole and tetracycline plus omeprazole produces a high eradication rate in subjects previously failing H. pylori eradication regimens. This bismuth-based regimen offers an effective option as rescue therapy.

A randomized, controlled study of the safety and efficacy of topical corticosteroid treatments of sunburn in healthy volunteers.

Topical glucocorticosteroids are frequently used for the treatment of sunburn despite the scarcity of randomized, double-blind controlled trials to support this indication. This randomized, intra-individually controlled trial compared the efficacy and safety of two topical glucocorticosteroids, 0.1% methylprednisolone aceponate milk (MPA) and 0.1% hydrocortisone 17-butyrate emulsion (HCB), for treatment of sunburn in 24 healthy volunteers of skin type III. After irradiation of the skin by simulated sunlight, treatments were blinded and randomly allocated to 36 cm2 test areas on both sides of the spine. Volunteers were treated twice daily for 7 days and assessed daily with 1-day follow-up. The untreated area was not blinded. Primary efficacy measures were sum score and sunburn reaction based on erythema, oedema, burning and itching. Secondary efficacy measures were physician's global assessment, individual signs/symptoms, colorimetry, dermatological improvement, and time to healing. Intra-individual comparisons were made. Differences in sum score were apparent on days 3-4 and significant on days 4-5 for corticosteroids compared with nontreatment. Treated areas had significantly lower sunburn reaction than untreated areas (P = 0.1% and P = 0.5% for MPA and HCB, respectively). Differences between treatments were not significant. Secondary efficacy measures were in line with these findings. None of the three adverse events reported were considered to be related to treatment. We conclude that MPA and HCB are safe and effective in the treatment of sunburn.

Do urea/ammonium lactate combinations achieve better skin protection and hydration than either component alone?

Twenty subjects with healthy skin were treated with the following formulations for two weeks: drug-free W/O vehicle, 5% ammonium lactate (CAS 52003-58-4) in W/O vehicle, 5% urea (CAS 57-13-6) in W/O vehicle, 3% ammonium lactate + 3% urea in W/O vehicle, 5% ammonium lactate + 5% urea in W/O vehicle. These formulations were applied in randomized order to 6 test areas on the forearms; one area was left untreated. Repetitive washings were additionally performed in the second treatment week. TEWL, stratum corneum water content (corneometry-determined electrical capacitance), and cutaneous blood flow (laser Doppler) were measured at baseline, day 7, and day 14. 5% urea and both ammonium lactate/urea combinations produced significant stratum corneum hydration and improved stratum corneum barrier function; there were no significant differences between these three treatments.

Inhibitory effect of 1alpha,25-dihydroxyvitamin D3 on allogeneic lymphocyte stimulation and Langerhans cell maturation.

1alpha,25-Dihydroxyvitamin D3 (calcitriol) has been shown to inhibit the proliferation of peripheral blood mononuclear cells induced by allogeneic Langerhans cells in a human mixed epidermal cell lymphocyte reaction. The potent antigen-presenting function of Langerhans cells is gained during culture. We tried to dissect the effect of calcitriol on lymphocyte proliferation and Langerhans cell maturation in a murine mixed epidermal cell lymphocyte reaction using unfractioned epidermal cells as a source for Langerhans cells. First, calcitriol was added upon setup of the mixed epidermal cell lymphocyte reaction using cultured epidermal cells as antigen-presenting cells, and this was found to inhibit the proliferation of lymphocytes in a time- and concentration-dependent manner. When calcitriol was added only during preculture of freshly isolated epidermal cells, the subsequent mixed epidermal cell lymphocyte reaction was also inhibited. In addition, the growth of keratinocytes and the production of granulocyte/macrophage colony-stimulating factor during preculture of epidermal cells was completely inhibited. Supplementation with this growth factor only partially restored the proliferative response of lymphocytes. These results suggest that calcitriol inhibits both the alloantigen-driven stimulation of naive T cell and Langerhans cells maturation. Further experiments with purified Langerhans cells are required to elucidate the mechanism of action of calcitriol on Langerhans cell maturation.

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3.

The biological active form of vitamin D3, 1,25-dihydroxyvitamin D3 (VD), regulates cellular growth and differentiation. This provides the hormone with an interesting therapeutic potential. However, hypercalcemia is a side effect, which is caused by VD's classical action, the regulation of calcium homeostasis. This made the need for VD analogues with selectively increased cell regulatory properties. Studies with 20-epi analogues pointed out the importance of the carbon-20 position and led to the development of 20-methyl derivatives of VD. In this report the biological properties of the compounds ZK161422 and ZK157202, which are 20-methyl- and 20-methyl-23-eneanalogues, respectively, have been analyzed in comparison with VD. Both compounds show about 2-fold lower affinity to the VD receptor (VDR) than VD. However, compared to VD, their antiproliferative effect is up to 30-fold higher on human peripheral blood mononuclear cells and even up to 300-fold higher on human breast cancer MCF-7 cells. Whereas the hypercalcemic effect for ZK157202 is also increased 10-fold, ZK161422 has the same calcium-mobilizing potency as VD. Moreover, ZK161422, but not ZK157202, showed preference for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding sites spaced by 9 nucleotides (IP9) rather than for activation from a response element formed by a direct repeat spaced by 3 nucleotides (DR3). This observation supports a model, in which promoter selectivity reflects the selectively increased antiproliferative effect of VD analogues.

1alpha,25-dihydroxyvitamin D3 rapidly inhibits fibroblast-induced collagen gel contraction.

1alpha,25-Dihydroxyvitamin D3 (1,25-D3) inhibits the proliferation of fibroblasts in vitro in monolayer culture. We investigated the effect of 1,25-D3 on normal murine and human fibroblasts cultured in collagen type I gels, which more closely resembles the in vivo situation in the dermis. In this culture system 1,25-D3 had no effect on fibroblast proliferation; however, the fibroblast-induced collagen gel contraction was inhibited in a time- and concentration-dependent manner in the nanomolar concentration range. 25-Hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were inactive. 1,25-D3 had no effect in fibroblasts lacking a functional vitamin D receptor. Pretreatment of fibroblasts in monolayer culture for 5 min was sufficient to trigger the inhibition of collagen gel contraction. Nifedipine increased collagen gel contraction and counteracted the effect of 1,25-D3. The inhibition of collagen gel contraction by 1,25-D3 is supposed to be mediated by the vitamin D receptor because a functional vitamin D receptor is required, and vitamin D metabolites with low affinity to the vitamin D receptor were inactive. Brief pretreatment of fibroblasts was sufficient to trigger the inhibitory effect of 1,25-D3, suggesting a nongenomic effect. A genomic mode of action could not be ruled out, however, because the inhibition was first measured after 24 h. The antagonism of the calcium channel antagonist nifedipine probably represents the sum of two opposite effects rather than supporting evidence for a nongenomic mode of action of 1,25-D3. In conclusion, 1,25-D3 has a specific and rapidly triggered inhibitory effect on fibroblast-induced collagen gel contraction.

Synthesis and biological activities of 8(14)a-homocalcitriol.

8(14)a-Homocalcitriol was synthesized and tested for its biologic activities. It exhibited a vitamin D agonist activity profile. The compound was bound to the pig intestinal receptor with an affinity slightly less than calcitriol, showed the same potency in inducing HL 60 cell differentiation and inhibition of keratinocyte proliferation as calcitriol, and was found to be approximately 10-fold less potent in inducing hypercalcemia and hypercalciuria after a single injection in normal rats.

Effects of calcipotriol (MC 903) and calcitriol after topical application on the skin of hairless rats. Much lower effect of calcipotriol on systemic calcium homeostasis.

Topical application of calcitriol or its analogs is a new approach for treating psoriasis, but may be limited by systemic calcitropic effects. Calcipotriol (MC 903) is a novel calcitriol analog with low calcitropic potency after systemic application. To compare the topical potency of calcitriol and calcipotriol we applied the two drugs on the right flanks of hairless rats for 10 days. In concentrations of 0.001-0.01 g/100 ml (ethanol) the two drugs are equally effective in inducing changes in the horny layer of the skin (increase in the amount of horny material that is able to be desquamated). This can be interpreted as a stimulation of terminal keratinocyte differentiation. However, only calcitriol caused a significant rise in the serum calcium concentration. In conclusion, calcitriol and calcipotriol seem to be equally effective after topical application on the skin of hairless rats, but calcipotriol has a much lower systemic calcium liability.