Serum free thiols predict cardiovascular events and all-cause mortality in the general population: a prospective cohort study.

BACKGROUND: Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress. Since serum free thiols are rapidly oxidized by reactive species, systemic oxidative stress is generally associated with reduced serum free thiol levels. Free thiols associate with favorable disease outcomes in many patient cohorts, and the current hypothesis is that oxidative stress might also play an important role in cardiovascular disease. In this study, we aimed to establish the role of serum free thiols in the general population by investigating their relationship with the risk of cardiovascular (CV) events and all-cause mortality. METHODS: Participants (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study from the general population were included. At baseline, serum levels of free thiols were quantified and adjusted to total protein levels. Protein-adjusted serum free thiol levels were studied for their associations with clinical and biochemical parameters, as well as with the risk of CV events and all-cause mortality. RESULTS: The mean protein-adjusted serum free thiol level was 5.05 ± 1.02 µmol/g of protein. Protein-adjusted serum free thiols significantly predicted the risk of CV events, even after adjustment for potential confounding factors (hazard ratio [HR] per doubling 0.68 [95% confidence interval [CI] 0.47-1.00], P = 0.048). Similarly, protein-adjusted serum free thiols were significantly predictive of the risk of all-cause mortality (HR per doubling 0.66 [95% CI 0.44-1.00], P = 0.050). Stratified analyses revealed lower HRs for subjects with a lower body mass index (BMI), without hypertension, and without diabetes. Conversely, HRs were lower in subjects with albuminuria. CONCLUSIONS: In this large population-based cohort study, serum free thiols significantly predicted the risk of CV events and all-cause mortality. Our results highlight the potential significance and clinical applicability of serum free thiols since they are amendable to therapeutic intervention.

Trend of relevant contact allergens of the feet in Spain over a period of 10 years.

INTRODUCTION: Allergic contact dermatitis (ACD) of the feet accounts for approximately 10% of all patch tested patients. OBJECTIVE: To study the clinical profile of patients with feet dermatitis and relevant contact allergens in Spain over a 10-year period. METHODS: Retrospective observational study of patients with suspected ACD from the GEIDAC (Spanish Research Group on Contact Dermatitis and Cutaneous Allergy) baseline series from eight hospitals in Spain between 2004 and 2014. The clinical data collected from each patient were age, sex, occupation, history of atopic dermatitis, and eczema location. RESULTS: A total of 450 cases clinically presented dermatitis affecting the feet; of these, 41% of were males and 5.6% were suspected to be of occupational origin. As much as 47% were diagnosed with ACD, 20% with atopic dermatitis/dyshidrotic eczema, and 5% with psoriasis. The "feet group" included statistically significantly more females in the age range of 21 to 60 years. The most frequent relevant contact allergens were potassium dichromate, cobalt(II) chloride, p-tert-butylphenol formaldehyde resin, mercapto mix, and mercaptobenzothiazole. CONCLUSIONS: ACD is the most frequent clinical diagnosis of feet dermatitis in our series. The most frequent allergens are similar to those published in other series of foot ACD in Europe and the trend has not changed in the studied decade.

Pesticide contact dermatitis in agricultural workers of Himachal Pradesh (India).

BACKGROUND: Common pesticides used in the region by agricultural workers may cause contact allergy. METHODS: Thirty agricultural workers with a history of pesticide exposure and dermatitis involving the face, neck, trunk or extremities, and 20 controls comprising 2 groups of 10 subjects each, group 1 with dermatitis and no exposure to pesticides, and group 2 with neither exposure to pesticides nor dermatitis, were patch tested with 10 pesticides commonly used in the region by use of the Finn Chamber method. RESULTS: The 30 patients, 20 of whom were male, aged 30-77 years, had dermatitis for 1 month to 18 years, with relapses and remissions. Seasonal exacerbation was present in 18 patients. Six patients attributed aggravation of their dermatitis to pesticide exposure, and 2 of these reacted positively to propiconazole. Positive patch test reactions to pesticides occurred in 10 patients, but not in controls. Thiuram was the commonest sensitizer (4 patients). Three patients were sensitized to propiconazole, and 2 patients reacted positively to metaldehyde. Formaldehyde, mercaptobenzothiazole, cypermethrin and isoproturon gave positive reactions in 1 patient each. CONCLUSION: The sensitizing potential of pesticides remains a concern. Apparently, pesticide contact dermatitis is more common than expected, but remains under-reported, as the implicated pesticides vary across regions and according to the crop patterns.

Effects of dalcetrapib in patients with a recent acute coronary syndrome.

BACKGROUND: In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS: We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS: At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).

UK rates of occupational skin disease attributed to rubber accelerators, 1996-2012.

BACKGROUND: Natural and synthetic rubbers containing rubber accelerators are well-known causes of allergic contact dermatitis (ACD). Latex contact urticaria (CU) has been widely reported, especially when powdered latex glove use was commonplace. Consequently, interventions to reduce latex exposure by altering glove manufacture were introduced. OBJECTIVE: This study aimed to analyse trends in UK-reported incidence of occupational skin disease associated with rubber accelerators. METHOD: We analysed cases reported to EPIDERM (part of The Health and Occupation Research network) of occupational ACD caused by natural and synthetic rubber products, between 1996 and 2012. RESULTS: For the studied period, a decreasing incidence of ACD associated with rubber products was found, with an average annual change of -1.2% [95% confidence interval (CI) -3.1 to 0.7]. The number of cases of latex CU (n = 580) significantly declined. The number of cases of ACD caused by mercapto mix and mercaptobenzothiazole (n = 177) and thiuram mix (n = 603) also declined. Reports of ACD associated with carba mix and its constituents (n = 219) increased significantly, by an average annual percentage of 10.1% (95%CI: 6.1-14.2). Twenty-six cases of ACD caused by rarer rubber compounds were identified, highlighting skin disease attributable to less widely recognized chemicals. CONCLUSIONS: These data show a falling reported incidence of occupational ACD attributed to rubber chemicals, but within this a significant rise attributable to the constituents of the carba mix. Clinicians should recognize the changing diversity of chemicals used in rubber manufacturing, and consider including carba mix in their baseline series and testing beyond this in suspect cases to avoid false-negative results.

Essential role of the cytochrome P450 enzyme CYP2A5 in olfactory mucosal toxicity of naphthalene.

Naphthalene (NA), a ubiquitous environmental pollutant that can cause pulmonary and nasal toxicity in laboratory animals, requires cytochrome P450 (P450)-mediated metabolic activation to cause toxicity. Our recent study using a Cyp2f2-null mouse showed that CYP2F2 plays an essential role in NA-induced lung toxicity, but not in NA-induced nasal toxicity. The aim of this study was to determine whether mouse CYP2A5, abundantly expressed in nasal olfactory mucosa (OM) and the liver, but less in the lung, plays a major role in the bioactivation and toxicity of NA in the OM. We found, by comparing Cyp2a5-null and wild-type (WT) mice, that the loss of CYP2A5 expression led to substantial decreases in rates of NA metabolic activation by OM microsomes. The loss of CYP2A5 did not cause changes in systemic clearance of NA (at 200 mg/kg, i.p.). However, the Cyp2a5-null mice were much more resistant than were WT mice to NA-induced nasal toxicity (although not lung toxicity), when examined at 24 hours after NA dosing (at 200 mg/kg, i.p.), or to NA-induced depletion of total nonprotein sulfhydryl in the OM (although not in the lung), examined at 2 hours after dosing. Thus, mouse CYP2A5 plays an essential role in the bioactivation and toxicity of NA in the OM, but not in the lung. Our findings further illustrate the tissue-specific nature of the role of individual P450 enzymes in xenobiotic toxicity, and provide the basis for a more reliable assessment of the potential risks of NA nasal toxicity in humans.

Cytotoxic Effects of a Novel Thialo Benzene Derivative 2,4-Dithiophenoxy-1-iodo-4-bromobenzene (C18H12S2IBr) in L929 Cells.

The aim of this study was to compare the cytotoxic effects of a newly synthesized thialo benzene derivative 2,4-dithiophenoxy-1-iodo-4-bromobenzene (C18H12S2IBr) and a well-known antifungal agent, fluconazole, in L929 cells. L929 cells were treated with 250, 500, or 1000 µg/mL of C18H12S2IBr and with the same doses of fluconazole. Cytotoxicity tests including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, and protein content were compared. Glucose and lactate concentrations were measured to determine alterations in metabolic activity. Apoptosis was investigated by TUNEL test and results were supported with survivin enzyme-linked immunosorbent assay. Treatment with C18H12S2IBr resulted in a concentration-dependent cytotoxicity as indicated by MTT, LDH leakage assay, and decreased protein concentration. The loss of cell viability and the increased LDH leakage in 500 µg/mL and 1000 µg/mL C18H12S2IBr and fluconazole groups indicated cell membrane damage and necrotic cell death. In all groups, metabolic activities were altered but apoptosis was not induced. We have previously investigated lower doses of C18H12S2IBr; there was no cytotoxicity in L929 cells. In this study, higher doses caused cytotoxicity and alterations in metabolic activity . When we consider the similar results obtained from fluconazole and especially the lowest dose of C18H12S2IBr, this newly synthesized compound may be a good alternative antifungal agent.

Community health assessment following mercaptan spill: Eight Mile, Mobile County, Alabama, September 2012.

CONTEXT: In 2008, a lightning strike caused a leak of tert-butyl mercaptan from its storage tank at the Gulf South Natural Gas Pumping Station in Prichard, Alabama. On July 27, 2012, the Alabama Department of Public Health requested Centers for Disease Control and Prevention epidemiologic assistance investigating possible health effects resulting from airborne exposure to mercaptan from a contaminated groundwater spring, identified in January 2012. OBJECTIVE: To assess the self-reported health effects in the community, to determine the scope of the reported medical services received, and to develop recommendations for prevention and response to future incidents. DESIGN: In September 2012, we performed a representative random sampling design survey of households, comparing reported exposures and health effects among residents living in 2 circular zones located within 1 and 2 miles from the contaminated source. SETTING: Eight Mile community, Prichard, Alabama. PARTICIPANTS: We selected 204 adult residents of each household (≥ 18 years) to speak for all household members. MAIN OUTCOME MEASURES: Self-reported mercaptan odor exposure, physical and mental health outcomes, and medical-seeking practices, comparing residents in the 1- and 2-mile zones. RESULTS: In the past 6 months, 97.9% of respondents in the 1-mile zone and 77.6% in the 2-mile zone reported mercaptan odors. Odor severity was greater in the 1-mile zone, in which significantly more subjects reported exposures aggravating their physical and mental health including shortness of breath, eye irritations, and agitated behavior. Overall, 36.5% sought medical care for odor-related symptoms. CONCLUSIONS: Long-term odorous mercaptan exposures were reportedly associated with physical and psychological health complaints. Communication messages should include strategies to minimize exposures and advise those with cardiorespiratory conditions to have medications readily available. Health care practitioners should be provided information on mercaptan health effects and approaches to prevent exacerbating existing chronic diseases.

Early proactive monitoring of DNA-thioguanine in patients with Crohn's disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers.

BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction. AIM: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn's disease (CD). METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months. RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/µg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/µg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively). CONCLUSION: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.

Exploring the role of oxidative stress and the effect of N-acetylcysteine in thiopurine-induced liver injury in inflammatory bowel disease: A randomized crossover pilot study.

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N-acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N-acetylcysteine decreased myeloperoxidase concentrations (33.6-24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S-methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2-isoprostanes (101-157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N-acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine-induced increase of serum liver tests.

Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD.

Thiopurines have been used in inflammatory bowel disease (IBD) for >30 years, and measurements of both thiopurine methyltransferase (TPMT) and thiopurine (TP) metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), have been readily available. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Committee on Inflammatory Bowel Disease thought it appropriate to review the present indications for use of TPMT and TP metabolite testing. Substantial evidence demonstrates that TP therapy is useful for both Crohn disease and ulcerative colitis. Review of the existing data yielded the following recommendations. TPMT testing is recommended before initiation of TPs to identify individuals who are homozygote recessive or have extremely low TPMT activity, with the latter having more reliability than the former. Individuals who are homozygous recessive or have extremely low TPMT activity should avoid the use of TPs because of concerns for significant leukopenia. TMPT testing does not predict all cases of leukopenia and has no value to predict hypersensitivity adverse effects such as pancreatitis. Any potential value to reduce the risk of malignancy has not been studied. All individuals taking TPs should have routine monitoring with complete blood cell count and white blood cell count differential to evaluate for leukopenia regardless of TPMT testing results. Metabolite testing can be used to determine adherence with TP therapy. Metabolite testing can be used to guide dose increases or modifications in patients with active disease. Consideration would include either increasing the dose, changing therapy or for those with elevated transaminases or an elevated 6-MMP, using adjunctive allopurinol to help raise 6-thioguanine metabolites and suppress formation of 6-MMP. Routine and repetitive metabolite testing has little or no role in patients who are doing well and taking an acceptable dose of a TP.

Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial.

AIMS: High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538). METHODS AND RESULTS: Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo). CONCLUSION: The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.

HEC-cysteamine particles: influence of particle size, zeta potential, morphology and sulfhydryl groups on permeation enhancing properties.

Within this study, the influence of particle size and zeta potential of hydroxyethyl cellulose-cysteamine particles on permeation enhancing properties was investigated. Particles were prepared by four different methods namely ionic gelation, spray drying, air jet milling and grinding. Particles prepared by grinding were additionally air jet milled. All particles were characterized in terms of particle size and zeta potential. The transport of fluorescein isothiocyanate-dextran 4 (FD4) across Caco-2 cell monolayers in the presence of these particles and the decrease in transepithelial electrical resistance (TEER) was evaluated. The cytotoxic effect of the particles was investigated using resazurin assay. Nanoparticles displaying a zeta potential of 3.3 ± 1.3 mV showed the highest enhancement of FD4 transport among all particles with a 5.83-fold improvement compared to buffer only. Due to the larger particle size, particles generated by grinding exhibited a lower capability in opening of tight junctions compared to smaller particles generated by air jet milling. In addition, the results of the transport studies were supported by the decrease in the TEER. All particle formulations tested were comparatively non-cytotoxic. Accordingly, the zeta potential and particle size showed a significant impact on the opening of tight junctions and hence could play an important role in the design of hydroxyethyl cellulose (HEC)-cysteamine-based nano- and micro-particles as drug delivery systems.

Safety of CETP inhibition.

PURPOSE OF REVIEW: Cholesteryl ester transfer protein (CETP)-inhibiting drugs effectively raise HDL cholesterol. In 2007, the CETP inhibitor torcetrapib unexpectedly showed increased fatality and cardiovascular events, possibly related to increased blood pressure and aldosterone levels caused by torcetrapib. Since then, novel CETP inhibiting drugs have been investigated. This review will discuss the safety of the CETP-inhibiting drugs. RECENT FINDINGS: The novel CETP inhibitors dalcetrapib, evacetrapib and anacetrapib did not show harmful effects on blood pressure or aldosterone levels. Ultrasound brachial artery flow-mediated vasodilation, carotid MRI and (18)F-fluordeoxyglucose PET imaging studies, showed that dalcetrapib therapy had neither harmful nor beneficial effects on endothelial function, atherosclerosis progression, or vessel wall inflammation. Recently, the clinical endpoint study investigating dalcetrapib was announced to be terminated early, after the second interim analysis showed that dalcetrapib lacked clinically meaningful efficacy. SUMMARY: Dalcetrapib, evacetrapib and anacetrapib did not show the harmful effects on aldosterone and blood pressure that were exhibited by torcetrapib, indicating that CETP inhibition is well tolerated. So far CETP inhibition did not show beneficial effects on clinical outcome. The phase III study with anacetrapib will give final answers on whether CETP inhibition can reduce cardiovascular events.

Sulfhydryl compound levels are associated with ATO-induced side effects in acute promyelocytic leukemia patients.

OBJECTIVE: The remarkable effect of arsenic trioxide (ATO) was verified, but side effects are generally observed in acute promyelocytic leukemia (APL) patients, especially leukocytosis and hepatotoxicity. Our aims are to study predictors and reduce ATO-induced side effects without inhibiting efficacy. METHODS: Sulfhydryl in ATO-treated APL patients was detected by the Spectra Max M5 microplate reader. And patients were divided into high and low sulfhydryl groups according to median sulfhydryl concentration. The onset time of leukocytosis and the peak value of WBC were compared . Correlations between hepatotoxicity indicators and sulfhydryl concentrations were analysed. RESULTS: The concentration of sulfhydryl before treatment was significantly higher in the high sulfhydryl group. Leukocytosis ((7.0 ± 5.5) vs. (14.6 ± 8.5) day) and the peak value of WBC occurred earlier in the low sulfhydryl group ((10.8 ± 5.9) vs. (19.3 ± 5.5) day) than in the high group, and the peak value was significantly lower in the low sulfhydryl group ((24.04 ± 15.05) × 109/L) than in the high group ((42.95 ± 25.57) × 109/L). The elevated liver enzymes were smaller in the higher sulfhydryl group between time points before treatment and the treatment one week later (ΔALT 66.57 vs. 9.85 U/L, ΔAST 59.52 vs. 17.76 U/L), as between time points before treatment and peak value. There was a negative correlation between sulfhydryl and elevated liver enzymes. CONCLUSIONS: Higher sulfhydryl compounds contribute to ameliorating ATO-induced leukocytosis and hepatotoxicity in APL patients. The low sulfhydryl before treatment can advance the onset of leukocytosis. For patients with higher sulfhydryl in the early stage, close monitoring of liver enzymes is warranted instead of prophylactic applying any hepatoprotective intervention, to maintain ATO efficacy.

Usefulness and pitfalls of MAA SPECT/CT in identifying digestive extrahepatic uptake when planning liver radioembolization.

PURPOSE: Identifying gastroduodenal uptake of (99m)Tc-macroaggregated albumin (MAA), which is associated with an increased risk of ulcer disease, is a crucial part of the therapeutic management of patients undergoing radioembolization for liver tumours. Given this context, the use of MAA single photon emission computed tomography (SPECT)/CT may be essential, but the procedure has still not been thoroughly evaluated. The aim of this retrospective study was to determine the effectiveness of MAA SPECT/CT in identifying digestive extrahepatic uptake, while determining potential diagnostic pitfalls. METHODS: Overall, 139 MAA SPECT/CT scans were performed on 103 patients with different hepatic tumour types. Patients were followed up for at least 6 months according to standard requirements. RESULTS: Digestive, or digestive-like, uptake other than free pertechnetate was identified in 5.7% of cases using planar imaging and in 36.6% of cases using SPECT/CT. Uptake sites identified by SPECT/CT included the gastroduodenal region (3.6%), gall bladder (12.2%), portal vein thrombosis (6.5%), hepatic artery (6.5%), coil embolization site (2.1%) as well as falciform artery (5.0%). For 2.1% of explorations, a coregistration error between SPECT and CT imaging could have led to a false diagnosis by erroneously attributing an uptake site to the stomach or gall bladder, when the uptake actually occurred in the liver. CONCLUSION: SPECT/CT is more efficacious than planar imaging in identifying digestive extrahepatic uptake sites, with extrahepatic uptake observed in one third of scans using the former procedure. However, more than half of the uptake sites in our study were vascular in nature, without therapeutic implications. The risk of coregistration errors must also be kept in mind.

Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk.

AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality.

No clinically relevant drug-drug interactions when dalcetrapib is co-administered with a monophasic oral contraceptive (Microgynon® 30).

UNLABELLED: Dalcetrapib, a cholesteryl ester transfer protein modulator, under development to increase high-density lipoprotein cholesterol and potentially decrease cardiovascular risk, will potentially be co-prescribed to women on oral contraceptive (OC). OBJECTIVE: Assess the effect of dalcetrapib on the pharmacokinetics and ability to suppress ovulation of Microgynon® 30, a representative monophasic OC. MATERIALS AND METHODS: A single-center, randomized, open-label, two-period crossover study in healthy women receiving monophasic OC. Subjects received Microgynon® 30 (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) once daily for 21 days followed by 7 treatment-free days (run-in period), then were randomized to Microgynon® 30 daily for 21 days with or without dalcetrapib 900 mg daily for Day 1 - 14. Plasma ethinylestradiol and levonorgestrel were measured on Day 14, and luteinizing hormone, follicle stimulating hormone, progesterone and estrogen from Day 11 - 14. The primary endpoint plasma exposure (AUC0-24 and Cmax) on Day 14 was evaluated for ethinylestradiol and levonorgestrel. Safety was monitored throughout. RESULTS: 30 subjects were randomized. The exposure of ethinylestradiol and levonorgestrel was similar when Microgynon® 30 was administered with or without dalcetrapib; for ethinylestradiol the geometric mean ratio %, (90% confidence interval (CI)) for AUC0-24 and Cmax were 92 (86 - 98) and 105 (95 - 115) and for levonorgestrel 92 (88 - 96) and 93 (87 - 99), respectively. Concentrations of luteinizing hormone, follicle stimulating hormone, estrogen and progesterone were comparable between treatments. CONCLUSIONS: Dalcetrapib has no clinically relevant effect on the pharmacokinetics of ethinylestradiol and levonorgestrel. Contraceptive efficacy of Microgynon® 30 is not anticipated to be compromised by co-administration of dalcetrapib.

Thiol-Functionalized Cellulose-Grafted Copper Oxide Nanoparticles for the Therapy of Experimental Colitis in Swiss Albino Mice.

Ulcerative colitis (UC) is a chronic inflammatory disease, which deleteriously affects the lower end of the gastrointestinal tract, i.e., the colon and the rectum. UC affects colonic inflammatory homeostasis and disrupts intestinal barrier functions. Intestinal tissue damage activates the immune system and collectively worsens the disease condition via the production of various cytokines. Ongoing therapeutics of UC have marked limitations like rapid clearance, extensive first-pass metabolism, poor drug absorption, very low solubility, bioavailability, etc. Because of these restrictions, the management of UC demands a rational approach that selectively delivers the drug at the site of action to overcome the therapeutic limiting factors. Metallic nanoparticles (NPs) have good therapeutic efficacy against colitis, but their uses are limited due to adverse effects on the biological system. In this study, we have used biocompatible thiol-functionalized cellulose-grafted copper oxide nanoparticles (C-CuI/IIO NPs) to treat UC. The metal NPs alleviated the colitis condition as evidenced by the colon length and observed physical parameters. Analysis of histopathology demonstrated the recovery of the colon architecture damaged by dextran sulfate sodium-induced colitis. Treatment with C-CuI/IIO NPs reduced the disintegration of goblet cells and the retainment of sulfomucin. Significant downregulation of inflammatory markers like MPO activity, as well as levels of nitrite and TNF-α, was found following C-CuI/IIO NP treatment. The observations from the study suggested that intrarectal treatment of colitis with cellulose-based C-CuI/IIO NPs successfully combated the intestinal inflammatory condition.