Gliptin-induced bullous pemphigoid.

OBJECTIVES: Bullous pemphigoid (BP) is a rare, autoimmune, blistering disease in elderly patients that can be triggered by external factors including drugs. Drug-induced bullous pemphigoid (DIBP) does not always follow a self-limiting course after the withdrawal of the offending drug. Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins seem to be associated with a significant risk of inducing BP. CASE PRESENTATION: We report 2 cases of BP attributed to the DPP-4 inhibitor linagliptin. In both cases, the clinical manifestation was strongly suggestive of BP. The diagnosis was verified by histology and direct immunofluorescence (DIF). Linagliptin and all other possible drug triggers of BP were discontinued after consultation with an endocrinologist and a cardiologist. Systemic treatment of BP consisted of methylprednisolone and tetracycline. During the follow-up period, one of the patients suffered a fatal brain stroke while the other was managed with reduced doses of corticosteroids. CONCLUSION: The proper management of autoimmune bullous skin disorders in elderly patients includes a scrupulous assessment of plausible drug triggers. Systemic corticosteroids for treating severe cases of DIBP can worsen concomitant diseases which often necessitates multidisciplinary care.

Dietary supplements - use and safety perception: A study among hospitalized dermatology patients.

OBJECTIVES: Evidence suggests that the use of dietary supplements in patients with various disorders is growing. The study aims to examine the use of drug supplements in patients with dermatological disorders, regarding their type, the reasons and predictors of their use, and the safety beliefs and communication attitude of users. MATERIALS AND METHODS: A cross-sectional study of patients hospitalized in the Clinic of Dermatology and Venereology at the University Нospital in Stara Zagora, Bulgaria, was carried out from October 2018 to December 2019. Data were collected using a specially designed and validated questionnaire. Statistical analysis included the χ2-test, the Mann-Whitney U test, and logistic regression. RESULTS: Overall 348 patients (204 females and 144 males) were involved in the study. The patients who reported having used dietary supplements were 67% of the study population. Various combinations ranked first among the dietary supplement types, and vitamins/minerals presented a substantial part (75.9%). The majority of the patients (61.6%) used dietary supplements for more than one reason, mainly for organ-related disorders. Most of the respondents (76.4%) considered them to be completely safe. Higher education (OR = 1.91; CI: 1.14 - 3.19), being a non-smoker (OR = 1.81; CI:1.14 - 2.88), and sporting activities (OR = 1.71; CI: 1.03 - 2.83) increased the odds of using dietary supplements. CONCLUSION: The examined cohort of dermatology patients presented a dietary supplement user profile similar to the general population. The study confirmed that these products are considered to be safe by the majority of participants. Factors indicative of a healthy lifestyle and higher education were predictive for their use.

Serum concentrations of 25-OH vitamin D and the pro-inflammatory interleukins IL-17, IL-23, and IL-18 in patients with plaque psoriasis.

AIMS: The present study aimed to assess vitamin D status and serum concentrations of pro-inflammatory cytokines IL-17, Il-23, and IL-18 in patients with chronic plaque psoriasis and their association with various demographic and clinical characteristics. METHODS: The study was conducted during the autumn/winter period on 48 patients with chronic plaque psoriasis and 48 controls. Total serum 25(OH)D level was determined with Roche Elecsys® 2010 Vitamin D total assay. Commercial ELISA kits were used for quantifying the serum levels of IL-17A, IL-18, and IL-23. RESULTS: Serum 25(OH)D had a median value of 16.95 ng/mL (IQR 10.8-23.50) for patients with psoriasis and 18.80 ng/mL (IQR 15.45-25.85) for the control group (P=0.09). A moderate negative correlation was found between PASI score and 25(OH)D levels (rs=-0.34; P=0.02). The serum levels of IL-17 (P=0.001), IL-23 (P=0.01) and IL-18 (P=0.02) were significantly higher in the patient group compared to controls. IL-17 concentrations were higher in patients with moderate to severe psoriasis compared to patients with mild psoriasis (P=0.003). No significant correlations were detected between the serum concentrations of 25(ОH)D and IL-17, IL-23, and IL-18. CONCLUSION: It was confirmed that IL-17 serum level is associated with psoriasis severity. Measurement of 25(OH)D serum concentration can be useful in patients with moderate to severe psoriasis with or without comorbidities. A direct association between 25(OH)D serum concentration and the serum concentrations of IL-17, IL-23, or IL-18 was not identified in this study.

Metabolic Disorders Induced by Fructosedrinking Water Affect Angiotensin II-mediated Intestinal Contractility in Male Wistar Rats.

INTRODUCTION: The high-fructose diet in rats has been reported to cause metabolic disorders such as impaired fasting glucose levels, in-sulin resistance, dyslipidemia, and dysregulation of the renin-angiotensin system. This could lead to further complications, for instance, to the smooth muscle dysfunction. AIM: The present study aimed at developing fructose-induced metabolic perturbations in rats and the investigation of their impact on angiotensin II-induced smooth muscle intestinal motility. MATERIALS AND METHODS: Mature Wistar rats were randomly divided into two groups (9 rats per group): control group (drinking tap water) and fructose-drinking group (15% fructose, dissolved in tap water). At the end of the experimental period (11 weeks), the plasma levels of insulin, renin, angiotensin II and creatinine, as well as the lipid profile were assessed. Morphometric analysis and lipid index calculation were also performed. The contractile properties of ileum, colon and rectum were studied using stimulation with angiotensin II in the isolated tissue bath system. RESULTS: Our experiment showed that drinking 15% fructose solution induced dyslipidaemia accompanied by elevated lipid indexes as well as an increase in creatinine and renin plasma levels in the rats. CONCLUSIONS: Fructose drinking and consequently the developed metabolic disorders modified the Ang II-induced intestinal activity causing a gradual alteration in the distal direction with the rectum being the most strongly affected organ.

Adverse drug reactions and reactive oxygen species.

Adverse drug reactions represent a major source of morbidity in hospitalized- and outpatients. Adverse drug reactions may affect the function of any organ or system. Due to their clinical nonspecificity adverse drug reactions are often difficult to be recognized. The clinical manifestation, the type and severity of adverse drug reactions vary a great deal depending on patient- and drug-related factors. In recent years growing evidence has emerged implicating involvement of free radicals and reactive oxygen species in chronic degenerative diseases and in acute conditions, such as stroke and infection. The review focuses on the role of reactive oxygen species in the pathogenesis of drug-induced disease with special reference to hepatotoxicity, nephrotoxicity and allergic disease. The participation of reactive oxygen species in the development of adverse drug reactions induced by special drug classes (non-steroidal anti-inflammatory drugs, anti-infective agents, cytostatics) is described. Results from studies on animals and humans reveal the putative implication of oxidative stress in drug-induced disease states.

Preventing microalbuminuria in type 2 diabetes.

BACKGROUND: The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. METHODS: We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits). RESULTS: The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups. CONCLUSIONS: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

A prospective study of adverse drug reactions in a dermatology department.

The objective of this study was to evaluate the clinical pattern and risk factors for adverse drug reactions (ADRs) in patients hospitalized in a specialized dermatology department. A prospective study was conducted in the Clinic of Dermatology and Venereology in Stara Zagora for a 5-year period. ADRs were classified by type, severity and causality. Case-causality was scored according to Naranjo et al. (1981). A total of 1041 admissions were analyzed. ADRs occurred in 147 patients. Cutaneous reactions represented the most common ADRs followed by endocrine/metabolic, cardiovascular and gastrointestinal disorders. The prevalent clinical patterns of cutaneous ADRs were exanthematous and urticarial. ADRs were almost evenly distributed as type A and type B reactions. Drug classes most frequently responsible for ADRs were glucocorticosteroids (GLCs) and antiinfective agents. The factors significantly associated with ADRs were the use of GLCs (OR 11.11; 95% CI 6.69-18.43), antiinfective agents (OR 1.48; 95% CI 1.04-2.11) and older age. Patients hospitalized in a dermatology department may develop ADRs with multiorgan clinical presentation. The most important risk factors for ADRs in this sample of patients were the use of GLCs, antiinfective agents and older age. The study establishes a specific ADR risk profile of patients with dermatological disorders in a hospital setting.

Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.

BACKGROUND: In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. METHODS: We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic <90 mm Hg; n=169) or intensified (systolic/diastolic <130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat. FINDINGS: Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99). INTERPRETATION: In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial.

BACKGROUND: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS: The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS: 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION: In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Clinical relevance of drug-drug interactions in hospitalized dermatology patients.

BACKGROUND: Potential drug-drug interactions (DDIs) are known to be a risk factor for the development of adverse drug reactions (ADRs). Data on the occurrence of ADRs related to DDIs is scarce and comes from different groups of patients. OBJECTIVES: The aim of the study was to evaluate the frequency, nature and determinants of potential DDIs in hospitalized dermatology patients and assess their contribution for the development of ADRs. MATERIAL AND METHODS: A prospective observational study comprising all consecutive inpatients admitted to the Clinic of Dermatology and Venereology, University Hospital, Stara Zagora for the period March 2009 - August 2011 was carried out. Systemic medication was screened for potential DDIs using an electronic drug interactions checker. DDIs were then verified with Stockley's Drug Interactions and divided into "clinically important" and "clinically unimportant". ADRs were classified by clinical manifestation, type and severity. Causality was scored according to Naranjo et al. (1981). RESULTS: The study included 674 patients, 513 (76.1%) of them with established comorbidities. Totally, 504 potential DDIs were identified (441 "clinically important" and 63 "clinically unimportant") in 236 patients. Hypotension was the most common expected clinical presentation of the potential DDIs. The strongest predictor for the development of DDIs was the number of systemic drugs (OR 2.25, 95% CI 1.97-2.58). Overall 43 ADRs were recorded, 53.5% "type B" and 46.5% "type A" reactions, most commonly with cutaneous and cardiovascular manifestations. The development of ADRs was attributed to 13 DDIs (2.6% of all detected potential DDIs) in 10 of these cases (23.25%). CONCLUSIONS: Potential DDIs were frequent in hospitalized dermatology patients. The drug groups most commonly involved were cardiovascular drugs. The proportion of DDIs associated with the occurrence of ADRs was relatively low, but close monitoring of patients on multiple drug regimens is essential because these reactions may be severe.

Effect of trandolapril on regression of retinopathy in hypertensive patients with type 2 diabetes: a prespecified analysis of the benedict trial.

Background. The effect of angiotensin converting enzyme inhibitors (ACEi) on regression of retinopathy in type 2 diabetics is still ill defined. Methods. We compared the incidence of retinopathy regression in 90 hypertensive type 2 diabetics randomized to at least 3-year blinded ACEi with trandolapril (2 mg/day) or non-ACEi therapy who had preproliferative or proliferative retinopathy at baseline. Results. Over a median (interquartile range) follow-up period of 35.8 (12.4-60.7) months, retinopathy regressed in 27 patients (30.0%). Regression occurred in 18 of 42 patients (42.9%) on ACEi and in 9 of 48 (18.8%) on non-ACEi therapy (adjusted for predefined baseline covariates HR (95% CI): 2.75 (1.18-6.42), P = .0193). Concomitant treatment with or without Non-Dihydropyridine Calcium Channel Blockers (ndCCBs) did not appreciably affect the incidence of retinopathy regression. Conclusions. Unlike ndCCB, ACEi therapy may have an additional effect to that of intensified BP and metabolic control in promoting regression of diabetic retinopathy.

Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe drug reaction, most commonly to aromatic anticonvulsants with a delayed onset, variable clinical presentation and protracted course. The exact incidence of DRESS syndrome is not known because of the variability in clinical presentation, lack of strict diagnostic criteria and universally accepted nomenclature. We report four cases of DRESS syndrome associated with the use of carbamazepine. The clinical manifestation was similar: a maculopapular eruption progressing to exfoliative erythroderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes and liver injury (in 2 patients) were also observed. Assessment of causality using the Naranjo algorithm established a "probable" relationship with carbamazepine in three of the cases and a "possible" relationship in one case. Detection of DRESS syndrome is dependent on the exclusion of a variety of diseases with similar manifestations and may be delayed in time. DRESS syndrome is a potentially life-threatening multisystem adverse drug reaction, and accidental reexposure or drug provocation tests must be avoided.

Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial.

The Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients who were on immunosuppressive therapy with the cyclosporine microemulsion Neoral, mycophenolate mofetil (MMF) was not better than azathioprine in preventing acute rejection at 21 mo after transplantation and was 15 times more expensive. The MYSS Follow-up Study, an extension of MYSS, was aimed at comparing long-term outcome of 248 MYSS patients according to their original randomization to MMF (1 g twice daily) or azathioprine (75 to 100 mg/d). Primary outcome was estimated GFR at 5 yr after transplantation. Mean 5-yr GFR difference between azathioprine and mycophenolate was 4.67 ml/min per 1.73 m(2) (95% confidence interval [CI] -0.43 to 9.77 ml/min per 1.73 m(2); P = 0.07). GFR from month 6 (mean +/- SEM: 54.3 +/- 1.6 versus 53.9 +/- 1.5 ml/min per 1.73 m(2); P = 0.83) to month 72 after transplantation (49.5 +/- 2.2 versus 47.3 +/- 2.4 ml/min per 1.73 m(2); P = 0.50); GFR slopes (mean +/- SEM: -1.10 +/- 0.56 versus -1.23 +/- 0.31 ml/min per 1.73 m(2) per year; P = 0.83); and 72-mo patient mortality (4.0 versus 4.0% [P = 0.95]; HR 0.96; 95% CI 0.28 to 3.31; P = 0.95), graft loss (6.8 versus 6.1% [P = 0.82]; HR 0.89; 95% CI 0.32 to 2.46; P = 0.83), incidence of persistent proteinuria (25.0 versus 27.4%; P = 0.72), late (>6 mo after transplantation) rejections (25.3 versus 21.2%; P = 0.53), and adverse events were similar on azathioprine (n = 124) and MMF (n = 124), respectively. Outcomes in the two groups were comparable also among patients with or without steroid therapy, considered separately. In kidney transplantation, the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial.

For assessment of the independent renoprotective effect of BP control and angiotensin-converting enzyme inhibitor (ACEi) therapy, the relationships of baseline BP, BP reduction, and follow-up BP with the incidence of persistent microalbuminuria were evaluated in 1204 hypertensive patients who had type 2 diabetes and normoalbuminuria and were included in the BErgamo Nephrologic Diabetic Complications Trial (BENEDICT) study and were randomly assigned to 3.6 yr of treatment with the ACEi trandolapril (2 mg/d), the nondihydropyridine calcium channel blocker (ndCCB) verapamil SR (240 mg/d), their fixed combination Veratran (trandolapril 2 mg/d plus verapamil SR 180 mg/d), or placebo, plus other antihypertensive medications targeted at systolic/diastolic BP <130/80 mmHg. Follow-up (from month 3 to study end) systolic, diastolic, mean, and pulse BP and their reductions versus baseline--but not baseline BP--independently predicted (P < 0.001) the risk for microalbuminuria. In patients with follow-up BP above medians, ACEi significantly reduced the risk for microalbuminuria to levels that were observed among patients with BP below medians, regardless of ACEi treatment. The same trend was observed among patients with BP reductions below medians. ndCCB therapy did not independently affect microalbuminuria. Patients who were on Veratran had lower BP and less frequently received diuretics, beta blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACEi therapy both independently may prevent microalbuminuria. ACEi therapy is particularly effective when BP is poorly controlled, whereas ndCCB therapy is ineffective at any level of achieved BP. As compared with trandolapril, Veratran may help with achievement of target BP with less need for concomitant antihypertensive medications.

In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: insights from the MY.S.S. trial.

BACKGROUND: Target organs express antigens recognized directly by antigen-specific T cells, and their recognition is crucial to precipitate rejection. Then, the earliest T-cell activation is inhibited by cyclosporine A (CsA), the lowest would be the risk of rejection. Here, we aimed to assess this possibility in a large cohort of de novo kidney transplant recipients participating in an ongoing clinical trial, the Mycophenolate Steroid-Sparing (MY.S.S.) Trial. METHODS: Three-hundred-thirty-four patients entered the prospective, multicenter MY.S.S. trial. The main aim of the study was to assess the predictive value of serial evaluation of blood CsA trough concentration (C0) and 2-hour postdose drug (C2) levels alone or in combination, and to identify which is the critical posttransplant measurement to target CsA therapy in order to minimize the risk of acute rejection. A very large number of CsA trough (N= 2236) and C2 (N= 2128) measurements during the first 6 months postsurgery were available for analysis. Patients with delayed graft function were excluded. RESULTS: CsA trough levels measured at day 2 posttransplant were the strongest predictor of acute graft rejection over 6-month follow-up. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while for levels lower than 300 ng/mL, the risk of acute rejection was more than doubled. Higher levels failed to provide any further protection from graft rejection. CsA trough values predicted allograft rejection with an accuracy of 74%, while C2 levels considered alone had no predictive values at all. CONCLUSION: Findings that among serial daily measurements posttransplant those taken as early as at day 2 have by far the highest capacity to predict rejection episodes, underline the need of targeting CsA therapy very early posttransplant with the goal to modulate early enough T-cell activation at the interface between the recipient's blood and the graft where alloimmune response actually initiates.