What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review.

BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.

Highly effective treatment with tacrolimus ointment in an adolescent with oral graft-versus-host disease.

CASE: We report a case of acute oral graft-versus-host disease in an adolescent, which was successfully treated with tacrolimus 0.1% ointment. CONCLUSION: Although tacrolimus ointment is not licensed for the indication of oral GvHD, this case report provides preliminary evidence for a potential effectiveness of using tacrolimus in case of failure when GvHD is resistant.

Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin.

OBJECTIVE: To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug. METHODS: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. RESULTS: Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter. CONCLUSIONS: The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.

The pharmacokinetic properties of topical levocabastine. A review.

The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.

Effect of dipyridamole on the formation of 6-oxo-prostaglandin F1 alpha by the rat isolated aorta and ram seminal vesicle microsomes.

1 Dipyridamole (1 and 10 muM) enhanced the production of 6-oxo-prostaglandin F1 alpha by rat aortic tissue. 2 Dipyridamole (5 to 40 muM) did not influence the PGI2-synthetase activity in ram seminal vesicle microsomes whereas, in concentrations ranging from 100 to 200 muM, it reduced the metabolism of exogenously added arachidonic acid. The latter effect may be due to an inhibition of the cyclooxygenase.

Modulation of prostacyclin biosynthesis by calcium entry blockers and extracellular calcium.

The influence of variations in the availability of extracellular Ca2+ and of Ca2+-entry blockers on prostacyclin production by mesothelial cells in culture was studied. The Ca2+-entry blockers nifedipine and verapamil suppressed the basal, as well as the thrombin-, bradykinin-, and ionophore A23187-stimulated biosynthesis by about 50-60%, but high concentrations were required and the inhibition was never complete. Basal prostacyclin formation was unaffected by a Ca2+-poor buffer, but showed 50% reduction in the Ca2+-free buffer. Although the thrombin-stimulated prostacyclin formation was not significantly influenced by a Ca2+-poor or a Ca2+-free buffer, prostacyclin release stimulated by A23187 and bradykinin was diminished in the presence of these modified incubation media; the reduction of bradykinin stimulated biosynthesis was rather small (30%). These results suggest that the Ca2+ from intracellular stores is sufficient for half maximal stimulation of the phospholipases involved in the biosynthetic pathway of prostacyclin and that--depending on the nature of the stimulus--different phospholipases are activated with varying requirements for free Ca2+.

Safety and pharmacokinetics of the neuroprotective drug lubeluzole in patients with ischemic stroke.

A total of 22 patients with acute ischemic stroke participated in two randomized, single-masked, placebo-controlled studies that evaluated the safety and pharmacokinetics of single escalating intravenous doses of lubeluzole. The first dose of study medication in all patients was given within 6 hours of the first sign of stroke onset. In the first study, 6 patients received a single 1-hour intravenous infusion of 5 mg of lubeluzole; 4 of these patients received an additional 10-mg dose 3 to 4 days later. Two additional patients received placebo. In the second study, 4 patients received a single 1-hour infusion of 10 mg of lubeluzole, and 2 patients received placebo. After a safety evaluation of the second study, 6 additional patients received 15 mg of lubeluzole, and 2 other patients received placebo. Lubeluzole had no clinically relevant effects on any cardiovascular variable compared with placebo. The majority of adverse experiences were mild to moderate and resolved during treatment. No unexpected electroencephalogram abnormalities were observed, and no evidence of epileptiform discharges was found in any of the patients. At the end of the infusion, plasma lubeluzole concentrations decayed biphasically, with mean distribution half-lives of 46.3 to 101.0 minutes and mean terminal half-lives of 20.8 to 27.7 hours. Comparisons of the dose-normalized value of the individual plasma concentrations at the end of the infusion and the total area under the curve from time 0 to infinity suggested that lubeluzole exhibited linear kinetics over the dose range evaluated in patients with ischemic stroke. In the small number of patients studied, lubeluzole's favorable safety profile was demonstrated by the lack of clinically relevant effects on cardiovascular variables and by neurologic examination and clinical laboratory findings.

Relationship between prostacyclin biosynthesis and cyclic AMP in cultured rabbit mesothelial cells.

Calcium ionophore A23187 (10 microM) as well as thrombin (10 U/ml) stimulated the biosynthesis of prostacyclin in cultured rabbit mesothelial cells; in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (Mix, 1 mM) the cyclic AMP (cAMP) content was also elevated. Both effects were inhibited by indomethacin (28 microM). Exogenous prostacyclin elicited by itself a clear enhancement of intracellular cAMP. An increased cAMP content was also obtained with isoproterenol (10 microM), whose activity was antagonized by propranolol (10 microM). These two products however, had no effect on the prostacyclin release. In all these experiments, inhibition of phosphodiesterase with Mix, was necessary to obtain detectable cAMP levels. In the presence of Mix, the stimulation of prostacyclin production by A23187 and thrombin was significantly lower as compared to the stimulation in the absence of Mix. Our results suggest that increased prostacyclin biosynthesis results in adenylate cyclase stimulation. This rise in intracellular cAMP in the presence of Mix, is accompanied by a downward regulation of further prostacyclin production.

Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole.

STUDY OBJECTIVE: To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-beta-cyclodextrin under fasting versus postprandial conditions. DESIGN: Open-label, two-way, randomized, crossover study. SETTING: Janssen Research Foundation, Belgium. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. MEASUREMENTS AND MAIN RESULTS: The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0-infinity and AUC0-24 hrs) were also significantly higher under fasting than under postprandial conditions. CONCLUSIONS: Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.

Effects of formoterol (Oxis Turbuhaler) and ipratropium on exercise capacity in patients with COPD.

Although long-acting inhaled beta 2-agonists improve various outcome measures in COPD, no double-blind study has yet shown a significant effect of these drugs on exercise capacity. In a randomized, double-blind, placebo-controlled, crossover study, patients received formoterol (4, 5, 9, or 18 micrograms b.i.d. via Turbuhaler), ipratropium bromide (80 micrograms t.i.d. via pMDI with spacer), or placebo for 1 week. Main endpoint was time to exhaustion (TTE) in an incremental cycle ergometer test. Secondary endpoints were Borg dyspnoea score during exercise, lung function, and adverse events. Thirty-four patients with COPD were included, mean age 64.8 years, FEV1 55.6% predicted, reversibility 6.1% predicted. All doses of formoterol, and ipratropium significantly improved TTE, FEV1, FEF25-75%, FRC, IVC, RV and sGAW compared with placebo. A negative dose-response relationship was observed with formoterol. Ipratropium increased time to exhaustion more compared with formoterol, 18 micrograms, but not with formoterol, 4.5 and 9 micrograms. No changes in Borg score were found. There was no difference in the adverse event profile between treatments. In conclusion, 1 week of treatment with formoterol and ipratropium significantly improved exercise capacity and lung function compared with placebo. However, a negative dose-response relation for formoterol was unexpected and needs further investigation.

Pharmacokinetics of lubeluzole (Prosynap) after single intravenous doses in healthy subjects.

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.

The pharmacokinetics of oral itraconazole in AIDS patients.

To test the hypothesis that absorption of orally administered itraconazole may be reduced in patients with the Acquired Immunodeficiency Syndrome (AIDS), 8 patients with AIDS were given two 100 mg capsules of itraconazole for 15 days. Plasma levels were measured by HPLC hourly for the first 8 h following ingestion, then at 24, 48, 72 and 96 h on days 1, 8 and 15. Peak plasma levels occurred after approximately 4 h. Mean peak plasma concentrations were 446 +/- 196 and 530 +/- 214 ng mL-1 at days 8 and 15. The area under the curve over 24 h (AUC0-24) was 2105 +/- 1241, 7679 +/- 3838 and 8748 +/- 4385 ng mL-1 h for days 1, 8 and 15, respectively. Steady-state was achieved after one week of dosing. There was no evidence of hepatotoxicity and one patient stopped itraconazole due to a rash. It may be concluded that the absorption of oral itraconazole capsules is reduced in AIDS patients, by a factor of approximately 50%, when compared with normal volunteers. AIDS patients may require higher doses of itraconazole than used in non-AIDS patients to achieve comparable plasma levels.

The prevalence and natural history of pituitary hemorrhage in prolactinoma.

CONTEXT: Incidental pituitary hemorrhage, without full pituitary apoplexy, is a recognized radiological finding, but little information exists on its clinical behavior, with most reports describing surgically treated macroprolactinoma or nonfunctioning adenoma. OBJECTIVE: Our aim was to characterize the prevalence, natural history, and risk factors associated with pituitary hemorrhage in a large clinic prolactinoma population. DESIGN: The design consisted of a retrospective analysis of a clinic population. SETTING: The setting was a tertiary endocrine center in a large teaching hospital. PATIENTS: We studied three hundred sixty-eight patients with prolactinoma. The presence of hemorrhage was documented on magnetic resonance imaging. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence, risk factors, and natural history of pituitary hemorrhage. RESULTS: Pituitary hemorrhage was found in 25 patients, giving an overall prevalence of 6.8%, and was significantly higher in macroprolactinoma (20.3%) compared to microprolactinoma (3.1%, P < .0001). Three patients had classical pituitary apoplexy. The majority of patients in the hemorrhage group had macroprolactinomas (16/25 [64%]) and were women (22/25 [88%]). The proportion of women with macroprolactinoma was higher in the hemorrhage group (14/16 macroprolactinomas [87.5%]) than in the nonhemorrhage group (36/63 macroprolactinomas [57.1%], P = .02). The majority of pituitary hemorrhages (92%) were treated conservatively with dopamine agonist therapy for hyperprolactinemia. Eighty-seven percent of patients had complete resolution of their hemorrhage within 26.6 ± 23.3 (mean ± SD) months. The presence of macroprolactinoma (odds ratio 9.00 [95%CI 3.79-23.88], P < .001) and being female (odds ratio 8.03 [95%confidence interval 1.22-52.95], P = .03) were independently associated with hemorrhage. CONCLUSIONS: These data show that incidental hemorrhage in prolactinoma is not uncommon. It is more likely to occur in macroprolactinoma, where 1 in 5 develop hemorrhage, and is particularly common in women with macroprolactinoma. The majority are asymptomatic and resolve spontaneously.

The effect of the leukotriene receptor antagonist zafirlukast on neurokinin A-induced bronchoconstriction in patients with asthma--A comparison with leukotriene D4 induced broncoconstriction.

The bronchoconstriction caused by inhaled neurokinin A (NKA) in patients with asthma is indirect. The mediators involved in NKA-induced bronchoconstriction are unknown. Studies with various H1 receptor antagonists were negative, making an important contribution of histamine unlikely. To study the role of cysteinyl leukotrienes in neurokinin A-induced bronchoconstriction, we performed a randomised, double-blind, cross-over, placebo controlled trial in 12 patients with mild to moderate asthma. Zafirlukast and matching placebo were given orally, 40 mg the evening before and 40 mg the morning of assessment. In one period NKA was administered, in the other period leukotriene D4 (LTD4). Increasing concentrations of NKA and LTD4 were inhaled from a 30 L bag, after nebulization via a Mallinckrodt nebuliser. The difference between log10PC20LTD4 after treatment with placebo or zafirlukast was highly significant (p<0.0001). A trend was observed towards a difference between log10PC20 neurokinin A after treatment with placebo or zafirlukast (p=0.0741). The dose ratio for the neurokinin A provocation was 4.4 and for the LTD4 provocation 67.7. In conclusion, zafirlukast had a large inhibitory effect on LTD4-induced bronchoconstriction, but offered only limited protective effect against neurokinin A-induced bronchoconstriction. We suggest that leukotrienes play a limited role in the bronchoconstrictor effect of neurokinin A in patients with asthma.

Effects of dexamethasone on prostacyclin biosynthesis in rabbit mesothelial cells.

We investigated whether glucocorticoids reduce the formation of arachidonic acid metabolites in a non myeloid cell type, the mesothelial cell, which is functionally and embryologically related to the vascular endothelial cell and which forms almost exclusively prostacyclin from arachidonic acid. Preincubation of rabbit mesothelial cells with 2.5 microM dexamethasone suppressed basal as well as bradykinin- or thrombin-stimulated prostacyclin biosynthesis. In further experiments bradykinin was selected as stimulus. The inhibition by dexamethasone was dose-dependent between 0.025 and 2.5 microM. The minimum contact period required for expression of this effect was 30 min and after a contact period of 60 to 120 min the inhibition reached a maximum, but was never complete. After 240 min, sufficient activity was secreted in the extracellular medium for inhibition of the prostacyclin formation in untreated cells. Experiments with cycloheximide were somewhat confused by its direct effects on prostacyclin biosynthesis, but still suggested that the anti-prostacyclin effect of dexamethasone required de novo protein biosynthesis. Our experiments indicate that glucocorticoids induce the formation of lipocortin-like factor(s) in non-phagocytic mesothelial cells, thereby suppressing the formation of prostacyclin, their main arachidonic metabolite.

Dexamethasone and prostacyclin biosynthesis by serosal membranes of the rabbit peritoneal cavity.

The effect of 2.5 microM dexamethasone on prostacyclin biosynthesis in isolated peritoneal serosa of the rabbit was studied. Pretreatment with dexamethasone for 90 min or more led to suppression of the subsequent prostacyclin biosynthesis in the absence of dexamethasone. This inhibition and the formation of extracellular non dialysable inhibitors were dependent on protein biosynthesis. These results indicate that glucocorticoids can partly suppress prostacyclin biosynthesis, probably via formation of lipocortin-like activity.

Paradoxical response to itraconazole treatment in a patient with onychomycosis caused by Microsporum gypseum.

A Columbian patient presented with a rare type of onychomycosis caused by Microsporum gypseum. Oral treatment with itraconazole formulation (Funazol) available in Columbia failed to improve the nail alteration. The fungitoxic effect of itraconazole was assessed on the M. gypseum strain cultured from the nail of the patient by using the method of culture of fungi on cyanoacrylate skin surface strippings (CSSS). In addition, a comparative evaluation of the oral bioavailability of itraconazole was made in volunteers after intake of Funazol and Sporanox. In the ex vivo bioassay on CSSS, topical itraconazole proved to be highly active against M. gypseum. After oral intake, however, the itraconazole bioavailability of Funazol relative to Sporanox averaged only 3.5%. Antifungal pulse therapy with Sporanox, 400 mg daily for 1 week per month for 4 months, cured the patient. This study shows that itraconazole is hardly or not absorbed from the oral formulation Funazol. Both the oral bioavailability and consequently therapeutic efficacy of the genuine drug (Sporanox) are highly superior.