Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Tofacitinib versus etanercept or placebo in patients with moderate to severe chronic plaque psoriasis: patient-reported outcomes from a Phase 3 study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well-being; improvements in health-related quality of life (HRQoL) with etanercept in psoriasis are well documented. OBJECTIVE: To evaluate HRQoL with tofacitinib, vs. placebo or etanercept, in the Phase 3, randomized, placebo-controlled, non-inferiority, Oral-treatment Psoriasis Trial (OPT) Compare Study (NCT01241591). METHODS: Adults with moderate to severe chronic plaque psoriasis were randomized 3:3:3:1 to tofacitinib 10 or 5 mg twice daily (BID), etanercept 50 mg twice weekly or placebo, for 12 weeks. Patient-reported outcomes (PROs) included Dermatology Life Quality Index (DLQI), Itch Severity Item and Patient Global Assessment of psoriasis. RESULTS: At baseline, 83.4% (911/1092) of patients had a DLQI score ranging between 6 and 30, indicating a substantial burden of disease. By Week 12, 47.3%, 43.6% and 30.9% of patients in the tofacitinib 10 mg BID, etanercept and tofacitinib 5 mg BID groups, respectively, had a DLQI score of 0 or 1 (no effect of psoriasis on QoL) vs. 7.8% for placebo (all P < 0.0001). Tofacitinib significantly reduced itch vs. placebo (P < 0.05 both doses) and etanercept (P < 0.0001 both doses) within 1 day of starting treatment. Furthermore, reductions in itch were greater with tofacitinib 10 mg BID, vs. etanercept, at Weeks 2-12 (all time points P < 0.05). At Week 2, an Itch Severity Item score of 'little or no itch' was more frequent with tofacitinib 10 mg (68.6%) vs. etanercept (57.4%) and placebo (12.2%), and the PtGA response rate was significantly greater with tofacitinib 10 mg vs. placebo (P < 0.05). CONCLUSION: Oral tofacitinib provided significant improvements across multiple PROs by Week 12. Improvements with tofacitinib 10 mg BID were comparable to etanercept, and improvements in itch were greater and more rapid with tofacitinib 10 mg BID.

Degradation of paracetamol by advance oxidation processes using modified reticulated vitreous carbon electrodes with TiO(2) and CuO/TiO(2)/Al(2)O(3).

The degradation of paracetamol in aqueous solutions in the presence of hydrogen peroxide was carried out by photochemistry, electrolysis and photoelectrolysis using modified 100 pores per inch reticulated vitreous carbon electrodes. The electrodes were coated with catalysts such as TiO(2) and CuO/TiO(2)/Al(2)O(3) by electrophoresis followed by heat treatment. The results of the electrolysis with bare reticulated vitreous carbon electrodes show that 90% paracetamol degradation occurs in 4 h at 1.3 V vs. SCE, forming intermediates such as benzoquinone and carboxylic acids followed by their complete mineralisation. When the electrolysis was carried out with the modified electrodes such as TiO(2)/RVC, 90% degradation was achieved in 2 h while with CuO/TiO(2)/Al(2)O(3)/RVC, 98% degradation took only 1 h. The degradation was also carried out in the presence of UV reaching 95% degradation with TiO(2)/RVC/UV and 99% with CuO/TiO(2)/Al(2)O(3)/RVC/UV in 1 h. The reactions were followed by spectroscopy UV-Vis, HPLC and total organic carbon analysis. These studies show that the degradation of paracetamol follows a pseudo-first order reaction kinetics.

Effect of heat processing and storage time on migration of bisphenol A (BPA) and bisphenol A-diglycidyl ether (BADGE) to aqueous food simulant from Mexican can coatings.

Effects of heat processing and storage time (up to 70 days) on migration of bisphenol A (BPA) and bisphenol A-diglycidyl ether (BADGE) from can coatings into an aqueous food simulant were determined. Distilled water was canned in two types of Mexican cans: for tuna and for jalapeño peppers. Results showed that there is an effect of heat treatment on migration of both compounds. Storage time did not show any effect in BPA migration from tuna cans. There was an effect of storage time on BPA migration from jalapeño pepper cans. Results for BADGE migration were affected by its susceptibility to hydrolyze in aqueous simulants. BADGE concentration decreased, or was not detected, during storage in both types of cans. Migration levels for BPA and BADGE were within 0.6-83.4 and <0.25-4.3 microg/kg, respectively. Both were below European and Mercosur legislation limits. Other migrating compounds were detected, although no identification was performed.

Ciprofibrate versus gemfibrozil in the treatment of mixed hyperlipidemias: an open-label, multicenter study.

Mixed hyperlipidemia is a common risk factor for cardiovascular disease. The aim of this trial was to evaluate the efficacy and safety of ciprofibrate versus gemfibrozil for the treatment of patients with mixed hyperlipidemia carefully selected for similar lipid profiles. A total of 68 patients who had mixed hyperlipidemia after following an isocaloric American Heart Association (AHA) phase I diet for 4 weeks were included. The plasma lipid levels at the inclusion were low-density lipoprotein-cholesterol (LDL-C) > or = 130 mg/dL, cholesterol > or = 240 mg/dL, and triglycerides > or = 200 mg/dL. Patients were randomly assigned to receive ciprofibrate 100 mg/d or gemfibrozil 1,200 mg/d. At the end of the 8-week treatment period, efficacy and safety parameters were compared with baseline values. The primary efficacy parameters of the study were percentage changes in triglycerides and LDL-C from baseline. After 8 weeks, plasma triglyceride concentrations were decreased by 43.5% and 54% compared with baseline during ciprofibrate and gemfibrozil therapy, respectively (P <.001). High-density lipoprotein-cholesterol (HDL-C) concentrations were increased 20.8% and 19.3% during ciprofibrate and gemfibrozil, respectively (P <.001). Apoprotein B, cholesterol, and very-low-density lipoprotein-cholesterol (VLDL-C) concentrations were also improved by the study drugs (18.6%, 13.2%, and 30.9%, respectively, during ciprofibrate and 44%, 13.8%, and 14.4%, respectively, during gemfibrozil). Meanwhile, the effect of the drug was minimal on LDL-C. A significant decrease in non-HDL-C resulted from both treatments (19% and 19.5%, respectively, P <.05). The only statistically significant difference observed between treatments was the effects on fibrinogen concentration, a coronary risk factor. Ciprofibrate significantly decreased its concentration by 18.8%, fibrinogen was slightly increased during gemfibrozil treatment. No patient had a significant modification on any of the safety tests. In summary, ciprofibrate and gemfibrozil are well-tolerated and efficacious treatments for mixed hyperlipidemia. Significant reductions in triglycerides, non-HDL-C, and apolipoprotein B were achieved with both drugs. A significant fibrinogen reduction was obtained with ciprofibrate.

Clinical expression and SRY gene analysis in XY subjects lacking gonadal tissue.

In several syndromes genetic males lack gonadal tissue. A range of phenotypes are seen, which varies from complete female external genitalia to anorchic subjects with sexual infantilism. Differences in phenotypic expression depend on the stage at which testes degenerated during intrauterine development. Although most cases of these syndromes are sporadic, several instances of familial recurrence suggest a genetic origin. To help elucidate the source, we performed molecular analysis of the complete SRY gene open reading frame in two subjects with true agonadism and in two with anorchia. Our results add to previous findings indicating that molecular defects in SRY are not readily identified as a cause of these syndromes.

PCR-PRINS-FISH analysis of structurally abnormal sex chromosomes in eight patients with Turner phenotype.

According to cytogenetic analysis, about 50% of Turner individuals are 45,X. The remaining cases have a structurally abnormal X chromosome or are mosaics with a second cell line containing a normal or abnormal sex chromosome. In these mosaics, approximately 20% have a sex marker chromosome whose identity cannot usually be determined by classical cytogenetic methods, requiring the use of molecular techniques. Polymerase chain reaction (PCR), primed in situ labeling (PRINS), and fluorescence in situ hybridization (FISH) analyses were performed in 8 patients with Turner syndrome and 45,X mosaic karyotypes to determine the origin and structure of the marker chromosome in the second cell line. Our data showed that markers were Y-derived in 2 patients and X-derived in the remaining 6 patients. We were also able to determine the breakpoints in the two Y chromosomes. The use of cytogenetic and molecular techniques allowed us to establish unequivocally the origin, X or Y, of the marker chromosomes in the 8 patients with Turner phenotype. This study illustrates the power of resolution and utility of combined cytogenetic and molecular approaches in some clinical cases.

[Efficacy of clopidogrel as ADP-dependent platelet aggregation inhibitor. Study on individuals with coronary artery disease]. / Eficacia del clopidogrel como inhibidor de la agregación plaquetaria dependiente de ADP. Un estudio en individuos con enfermedad arterial coronaria.

Acetyl-salicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20 to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30 to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-derived antiplatelet-drug, with the same mechanism of action; reduces the expression of the glycoprotein IIb/IIIa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and lowers the incidence of adverse effects. In this study, we evaluated the effects of one daily dosis of 75 mg of clopidogrel on platelet function in 33 subjects with coronary artery disease. Before treatment and after the 6th and 12th week, the following parameters were evaluated: 5 microM-ADP and 20 micrograms/mL collagen-induced platelet aggregation, bleeding time and fibrinogen concentration. In basal and in the 6th and 12th week samples, ADP-induced platelet aggregation was 90.7% +/- 13.2, 54.6% +/- 23.2 and 49.2% +/- 23.7 respectively, that represents a significant reduction of 38.6% and 44.4%. Reduction of collagen-induced platelet aggregation was not significative. Plasmatic fibrinogen did not suffer variation during treatment. Bleeding time was significant prolonged from 4.1 minutes to 15.4 and 14.6 minutes (3.7-3.5 times compared with the test before treatment). There were no haemorrhagic complications, only digestive discomfort in fewer than 3% of patients. We concluded that clopidogrel is a safe and efficacious drug for patients, it efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time.

Bat-associated histoplasmosis in returning travelers: case presentation and description of a cluster.

Histoplasma capsulatum is a dimorphic fungus with the mycelial form producing spores that are readily airborne and able to reach small bronchi and alveoli. Isolation of the mycelial form of H. capsulatum in nature shows a striking correlation with moist, acidic soils, frequently contaminated with bird or bat excreta. Bats, but not birds, may be infected by H. capsulatum and may excrete the fungus in their feces. Skin test surveys show that the infectious agent is present worldwide in the areas between 45 degrees north and 30 degrees south of the equator. Clusters of cases may occur because of the disturbance of soil contaminated with H. capsulatum, or by visiting bat caves. Cave-associated histoplasmosis has been reported from the Americas, Africa, Oceania, and Africa. Recently, cave-associated histoplasmosis has been reported in travelers returning from Costa Rica and Peru. We report a cluster of cave-associated acute histoplasmosis that occurred in college students returning from Ecuador. Advice regarding histoplasmosis prevention should be given to travelers planning to visit bat-infested caves, and histoplasmosis should be considered in the differential diagnosis of febrile illness in returning travelers with a history of epidemiologic or geographic exposure.

[A molecular study of the delta-F508 mutation and genetic analysis of a sample of cystic fibrosis patients]. / Estudio molecular de la mutación delta-F508 y análisis genético de una muestra de pacientes con fibrosis quística.

The delta-F508 mutation was investigated in 39 index cases with cystic fibrosis (CF) using PCR-mediated site-directed mutagenesis. Eight patients were delta-F508 homozygous, 16 were delta-F508/unknown mutation compound heterozygous and 15 had unknown mutations in both alleles. Thus, delta-F508 was present in 41% of CF chromosomes and this frequency is lower than the observed among Northern European and North American Caucasians (70%), Southern Europe populations (50%) and Northern Mexico (59.1%). Age at present, age of onset of clinical data and age at diagnosis were lower in the group of delta-F508 homozygous, although the difference was not statistically significant. In this same group growth deficiency was more frequent than in the others. Among 84 brothers, 25 (28.9%) were affected. Pedigrees analysis showed that among 782 cousins, two were affected and in two families, other relatives born to non consanguineous parents had CF. These data suggest that, probably, the disease and heterozygous frequencies do not differ from the reported in Caucasians (1/2500 and 1/25 respectively). The low frequency of delta-F508 mutation could be due to the small size of the sample but it can also be explained by the heterogeneous genetic composition of the population living in Mexico or because a number of delta-F508 homozygous patients die at early ages without being diagnosed.

Frequency of delta F508 in a Mexican sample of cystic fibrosis patients.

This paper reports the frequency of the delta F508 mutation in a cohort of 50 Mexican patients with cystic fibrosis (CF). The mutation was detected by PCR mediated site directed mutagenesis. delta F508 was found in 39% of CF chromosomes, a frequency lower than that reported in Argentina and Spain. The high rate of CF cases who die undiagnosed, the ethnic origin of Mexican populations, and the limited number of cases studied could account for the low frequency of the delta F508 mutation found in this preliminary report.

[Isolation and partial characterization of phenoloxidase from apples (Malus domestica, var. Anna)]. / Aislamiento y caracterización parcial de la enzima fenoloxidasa de manzana (Malus domestica, var. Anna).

This study pursued the isolation and partial characterization of the enzyme polyphenoloxidase from apple (Malus domestica Anna variety), grown in the Hermosillo Coast (State of Sonora, Mexico). The effects of pH and temperature as well as its specificity towards substrates, and its behavior under conditions of hydrophobic chromatography, were studied. The enzyme was isolated from a residual powder obtained from ripe apples homogenized with cold acetone. The extract thus prepared was used to characterize the enzyme, and it showed an optimum pH of 5.36 and an optimum temperature of 35 degrees C. The substrate specificity proved to decrease from 4-methyl catechol, chlorogenic acid, catechol, and caffeic acid, to 3,4-dihydroxiphenyl alanine (DOPA). The enzyme resulted to be more thermostable (temperature range: 35 degrees C to 60 degrees C) than the rest of oxidases of plant origin. When the extract was eluted under conditions of hydrophobic chromatography separation, it appeared as a single peak resulting in a 300 fold purification. The phenolase activity characteristics found in the present study were similar to those observed in other apples from temperate climates; however, this particular polyphenoloxidase is more thermostable under natural conditions. This explains why apples of the Anna variety, at the high harvesting temperature, show a very fast formation of brown spots even when there is a minor damage. The content of compounds with phenolic group was high (1.16 g/100 g fresh weight). Further increase of the velocity of fruit enzymatic browning was due to this reason.

Hemorragia digestiva alta en Arequipa / Haemorrhage of the upper digestive tract in Arequipa

Los autores estudiaron a 200 pacientes con hemorragia digestiva en el Hospital Central del Sur-IPSS de Arequipa; 180 (90%) varones y 20 (10%) mujeres. Las causas más frecuentes fueron: úlcera duodenal (40%), lesiones agudas de mucosa gástrica (28%), úlcera gástrica (8%) y várices esofágicas (6.6%). En 12 pacientes (6%) la causa no fue definida. El consumo de alcohol o de antiinflamatorios estuvo frecuentemente asociado en los sujetos con lesiones agudas de mucosa gástrica 48/56. Recurrencia del sangrado se presentó en 61 pacientes, particularmente en los portadores de úlcera duodenal. El tratamiento médico fué eficaz en 164 (82%); 36 (18%) fueron sometidos a tratamiento quirúrgico, de ellos solo 5 (2.5%) de urgencia. La mortalidad estuvo relacionada con el diagnóstico de várices esofágicas 5/8.

The authors studies 200 patients with upper tract bleeding in the Hospital Central del Sur-IPSS of Arequipa: 180 (90%) men and 20 (10%) women. The most frequent causes were: duodenal peptic ulcer (40%), acute lesions of the gastric epithelium (28%), gastric peptic ulcer (8%), and varicose veins of the oesophagus (6.6%). In 12 patients (6%) the etiology was not encountered. Alcohol or antirrheumatic drug ingestion was frequently found in subjetcs with acute lesions of the gastric epithelium (45/56). Recurrent bleeding ocurred in 61 patients, especially in the duodenal peptic ulcer patients. The medical treatment was good in 164 (82%). 36 (18%) underwent surgical treatment, buy only 5 (2.5%) were emergency basid. Mortality was related to varicose veins 5/8.