Add-on effects of Chinese herbal medicine external application (FZHFZY) to topical urea for mild-to-moderate psoriasis vulgaris: Protocol for a double-blinded randomized controlled pilot trial embedded with a qualitative study.

Psoriasis vulgaris is a chronic dermatological disease with a high global prevalence. It significantly reduces patients' quality of life and is associated with a substantial economic burden. Conventional therapies for mild-to-moderate psoriasis are often associated with insufficient long-term symptomatic relief and side effects. Chinese herbal medicine (CHM) is commonly used for psoriasis management. A CHM formula, namely Fu zheng he fu zhi yang (FZHFZY), has shown promising treatment effects in clinical practice when used as a bath therapy. However, its efficacy and safety has not been evaluated by a rigorous randomized controlled trial (RCT). Therefore, we designed a double-blinded pilot RCT embedded with a qualitative study on CHM formula FZHFZY plus topical urea for mild-to-moderate psoriasis vulgaris to advance the evidence development and practice of CHM external application for psoriasis. This will be a mixed-method design consisting of a pilot RCT and a qualitative study. The pilot RCT is a two-arm, parallel, placebo-controlled, double-blinded trial. Sixty eligible participants will be randomized at a 1:1 ratio to receive eight weeks' treatment of either FZHFZY plus 10% urea cream, or placebo plus 10% urea cream, with 12-week follow-up visits after the treatment phase. The CHM or placebo will be administered externally as a bath therapy. Outcome measures include trial feasibility, efficacy and safety. The primary efficacy outcome will be Psoriasis Area Severity Index (PASI). Secondary efficacy outcomes include Physician Global Assessment, PASI-75, PASI-50, Body Surface Area, Dermatology Life Quality Index, Skindex-16, itch visual analogue scale and relapse. The qualitative study will be conducted to collect participants' feedback on CHM external application and their experience with the pilot RCT. This study will advance the evidence-based clinical practice of using CHM for psoriasis vulgaris and then to support translation of findings into clinical practice in the future. Trial registration number: ChiCTR2200064092.

Efectividad de la administración de urea para el tratamiento de la hiponatremia en la insuficiencia cardiaca / Effectiveness of urea administration for the treatment of hyponatremia in heart failure

Objetivos Valorar la eficacia y la seguridad de la urea en pacientes con hiponatremia e insuficiencia cardiaca (IC). Métodos y resultados Se trata de un estudio observacional retrospectivo analítico de pacientes con IC e hiponatremia (Na+ <135mmol/l). Se incluyeron 49 pacientes tratados con urea y 47 pacientes que no recibieron urea, todos ellos bajo tratamiento estándar (según práctica clínica habitual) de la IC, con seguimiento en el hospital Álvaro Cunqueiro de Vigo entre enero de 2013 y mayo de 2022. En el estudio se evaluó la normalización de los niveles de sodio (Na >135mmol/l). La natremia al inicio del tratamiento con urea oral era de 127±5,22mmol/l, a las 24horas el sodio era de 128±2,47 (p<0,009) y la media el día de la normalización fue de 135,19±4,23mmol/l (p<0,005). Los días de media para conseguir la normalización del sodio fueron 5,03±2,37. La uremia al inicio del tratamiento con urea era de 73±46,93mg/dl y la media el día de la normalización del Na+ fue de 116,05±63,64mg/dl (p<0,002). La dosis media de urea oral fue 22,5g/día. No se observaron efectos adversos relevantes, ni cambios en cuanto a las cifras de creatinina. Conclusiones El tratamiento con urea oral añadido al tratamiento estándar, durante cortos periodos de tiempo, es seguro y eficaz para corregir la natremia en pacientes con IC hipervolémica con hiponatremia.

Objectives To assess the efficacy and safety of urea in patients with hyponatremia and heart failure (HF). Methods and results This is a retrospective observational analytical study of patients with HF and hyponatremia (Na+ <135mmol/L). Forty-nine patients treated with urea and 47 patients who did not receive urea, all under standard treatment (according to usual clinical practice) for HF, were included and followed up at Álvaro Cunqueiro Hospital in Vigo (Spain) between January 2013 and May 2022. The study evaluated the normalization of sodium levels (Na >135mmol/L). The initial natremia at the start of oral urea treatment was 127±5.22 mmol/L, at 24h the sodium level was 128±2.47 (P<.009), and the mean on the day of normalization was 135.19±4.23mmol/L (P<.005). The average number of days to achieve sodium normalization was 5.03±2.37 days. The initial uremia at the start of urea treatment was 73±46.93mg/dL, and the mean on the day of Na+ normalization was 116.05±63.64mg/dL (P<.002). The average oral urea dose was 22.5g/day. No relevant adverse effects were observed, nor were there significant changes in creatinine levels. Conclusions Oral urea treatment, when added to standard treatment for short periods of time, is safe and effective in correcting natremia in patients with hypervolemic HF with hyponatremia. (AU)

Transition to glycerol phenylbutyrate for the management of urea cycle disorders: clinical experiences.

BACKGROUND: Urea cycle disorders (UCDs) are a group of rare inborn diseases caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. The most common biochemical feature is elevated blood ammonia levels, which can be toxic at high levels, especially to the brain and may manifest as encephalopathy if left untreated. Glycerol phenylbutyrate (GPB) is currently approved for use in the USA and Europe for patients of all ages with UCD who cannot be managed with protein restriction and/or amino acid supplementation alone. This article presents the author's experience in different exemplary settings and depicts the most efficient management of UCDs with GPB. CASE PRESENTATION: Six patient histories are described. 4 had OCT, one citrullinemia, and one argininosuccinic aciduria. Treatment with GPB was started between 2 days and 14 years of age. Before GPB, one patient had not been treated, 4 had received sodium phenylbutyrate (NaPB), and one Na benzoate. CONCLUSIONS: Overall, treatment with GPB was followed by a relevant metabolic improvement, resulting in better therapeutic compliance, reduced hospitalization, and improved quality of life.

Protective effect of activated charcoal against progression of chronic kidney disease: A randomized clinical study.

Chronic kidney disease (CKD) is a non-reversible and progressive disease affecting the kidneys, significantly impacting global public health. One of the complications of chronic kidney disease is impaired intestinal barrier function, which may allow harmful products such as urea to enter the bloodstream and cause systemic inflammation. This study aimed to investigate whether supplementation with activated charcoal could reduce uremic toxins in patients with end-stage renal disease (ESRD). The study was a randomized clinical trial conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Governorate. Eighty-two patients with ESRD on regular hemodialysis were enrolled, with 15 patients receiving oral supplementation with activated charcoal in addition to standard care and 13 patients receiving only standard care. Blood samples were collected at baseline and after eight weeks, and several biomarkers were measured, including estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. The results showed a significant reduction in both serum urea and serum phosphorus levels after eight weeks of oral-activated charcoal treatment. However, the other biomarkers were not affected by the treatment. In conclusion, the use of oral-activated charcoal for eight weeks in Iraqi patients undergoing maintenance hemodialysis improved urea and phosphorus levels.

Citrulline in the management of patients with urea cycle disorders.

BACKGROUND: Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. RESULTS: Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions. CONCLUSIONS: This study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations.

Oral Urea Supplementation in the Treatment of Acute Hyponatremia among Hospitalized Adults: A Systematic Review.

Hyponatremia is the most common electrolyte disturbance among hospitalized adults. Oral urea is currently recommended in Europe in the treatment of chronic hyponatremia; no published systematic review investigating oral urea for acute hyponatremia among hospitalized adults exists. An oral urea supplement became available in the United States in 2016. This was a systematic review investigating the use of oral urea in the treatment of acute hyponatremia among hospitalized adults. Pubmed, CINAHL, Scopus, Web of Science, and Cochrane databases were searched for studies published between 1998 and 2021. Risk of bias was assessed using the ROBINS-I tool; strength of the evidence was assessed using GRADE criteria. Changes in serum sodium and measures of safety and tolerance were reported. Eight studies were identified that met inclusion criteria, which included a total of 296 patients. Seven studies were retrospective. All studies found an increase in serum sodium levels associated with oral urea supplementation. Side effects were minimal; one patient discontinued urea due to a side effect (dysgeusia). Urea dose/duration varied among the studies. Based on the serious risk of bias and GRADE criteria, the strength of the evidence was considered low. Oral urea supplementation was associated with increases in serum sodium concentrations among hospitalized adults with hyponatremia, and appears to be safe and well tolerated in this population. Prospective controlled trials are needed to establish the efficacy, comparative effectiveness, and potential cost savings of this therapy.Key teaching pointsHyponatremia is associated with negative clinical outcomes among hospitalized adults.Oral urea is now available in the United States, and is currently recommended in Europe to treat chronic hyponatremia.This systematic review shows that oral urea supplementation may be associated with increases in serum sodium levels among hospitalized adults with hyponatremia, and appears safe and well-tolerated; however, the studies reviewed here are at high risk of bias and the available evidence is of low quality, making any recommendation drawn from this data weak.Prospective controlled trials are needed to establish the efficacy, comparative effectiveness, and potential cost savings of oral urea supplementation for hyponatremia.

Impact of insufficient doses of medications on Helicobacter pylori eradication: a retrospective observational study.

BACKGROUND AND AIMS: The doses of medications may influence the success of Helicobacter pylori (H. pylori) eradication. This real-world observational study aimed to explore the impact of insufficient doses of medications prescribed for the bismuth-containing quadruple therapy (BQT) regimen on successful H. pylori eradication. METHODS: We retrospectively screened the patients who were diagnosed with H. pylori infection and received BQT regimens for H. pylori eradication at our department between January 2017 and July 2020. The rate of successful H. pylori eradication was compared according to the doses of medications prescribed. Standard doses were defined according to the clinical guidelines. RESULTS: Overall, 1054 patients were included. The rate of successful H. pylori eradication was 78.2% (824/1054). Among them, proton pump inhibitors (PPIs) and antibiotics were prescribed at insufficient doses in 37.0% (390/1054) and 6.7% (71/1054) of patients, respectively. Furthermore, pantoprazole (98.7% [385/390]) was the most common type of PPIs prescribed at insufficient doses, and nitroimidazoles (85.9% [61/71]) were the most common type of antibiotics prescribed at insufficient doses. Among the patients receiving colloidal bismuth pectin (CBP) (200 mg tid) and standard-dose antibiotics, the rate of successful H. pylori eradication was lower in insufficient-dose PPIs group than standard-dose PPIs group (78.1% [271/347] versus 82.6% [438/530], P = 0.095). Among the patients receiving CBP (200 mg tid) and standard-dose PPIs, the rate of successful H. pylori eradication was significantly lower in insufficient-dose antibiotics group than standard-dose antibiotics group (37.8% [14/37] versus 82.6% [438/530], P < 0.0001). Among the patients receiving CBP 200 mg tid, the rate of successful H. pylori eradication was significantly lower in patients receiving both PPIs and antibiotics at insufficient doses than those at standard doses (46.4% [13/28] versus 82.6% [438/530], P < 0.0001). CONCLUSION: Among the BQT regimens, PPIs and/or antibiotics, especially pantoprazole and metronidazole, are often prescribed at insufficient doses, compromising the success of H. pylori eradication. ABBREVIATIONS: H. pylori, Helicobacter pylori; UBT, urea breath test; DPM, disintegrations per minute; BQT, bismuth-containing quadruple therapy; PPI, proton pump inhibitor; CBP, colloidal bismuth pectin; qd, once daily; bid, twice daily; tid, three times daily; qid, four times daily.

Protective mechanism of traditional Chinese medicine guizhi fuling pills against carbon tetrachloride-induced kidney damage is through inhibiting oxidative stress, inflammation and regulating the intestinal flora.

BACKGROUND: Chemical or drug-induced kidney damage has been recognized as a critical cause of kidney failure. The oxidative stress, inflammation, and imbalance of intestinal flora caused by carbon tetrachloride (CCl4) play a fundamental role in chronic kidney damage. Guizhi Fuling pills (GZFL) is a traditional formula consisting of five traditional Chinese medicinal herbs, which can promote blood circulation and improve kidney function. The underlying mechanisms of GZFL improving kidney damage are not fully understood yet. AIM: The current study aimed to explore the effects of GZFL on CCl4-induced kidney damage and intestinal microbiota in mice. METHODS: Male ICR mice were intraperitoneally administered with 20% CCl4 (mixed in a ratio of 1:4 in soybean oil) twice a week, for 4 weeks to induce kidney damage. Creatinine (CRE), urea nitrogen, antioxidant enzymes, and inflammatory cytokines were measured and the histology of the kidney, jejunum, and colon examination to assess kidney and intestinal damage. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) family members, nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in kidney tissues, and the tight junction proteins in colonic tissues were detected by Western blot. The gut microbiota was analyzed through 16S rRNA gene sequencing. RESULTS: GZFL treatment decreased the serum CRE and urea nitrogen levels. Moreover, GZFL reduced the levels of pro-inflammatory cytokines and increased antioxidant enzyme activities in kidney and colonic tissues. GZFL improved the kidney, jejunum, and colon histology. Furthermore, GZFL inhibited the expressions of NLRP3, ASC, and cleaved-Caspase-1, while Nrf2, HO-1, NQO1, GCLM, and tight junction proteins were increased. The dysbiosis of intestinal microbiota improved after GZFL treatment. CONCLUSIONS: This study showed that GZFL could improve kidney damage, which might be mainly via the integrated regulations of the Nrf2 pathway, NLRP3 inflammasome, and composition of intestinal microbiota.

Assessment of the efficacy, skin acceptability and cosmetic quality of an adjuvant cream based on 40% urea and amino-inositol in the treatment of mild psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease with a multifactorial genesis. Structural changes are encountered in psoriasis and skin barrier function is impaired. Tight junctions (TJs) play a key role in skin barrier dysfunction. Loss of profilaggrin or filaggrin leads to changes in the stratum corneum and consequent loss of water and the development of xerosis. METHODS: We carried out an observational study to evaluate the efficacy, skin acceptability and cosmetic qualities of a cream formulation, based on 40% urea and amino-inositol, in the treatment of mild psoriasis in the absence of other associated cosmetic/pharmacological treatments. All parameters were evaluated before (T0) and after 4 weeks (T4). Efficacy assessment was based on both clinical evaluation and photographic documentation. RESULTS: The results showed significant clinical improvement (-64.18% PASI, -57.11% BSA, -61.84% Plaque Score, -41.86% PGA and -76.34% VAS -77.5 DLQI) in 4 weeks of treatment. No significant side effects were reported. Similarly, the degree of satisfaction with the product and adherence to its use were particularly satisfactory among patients. CONCLUSIONS: The tested product was found to be a promising, effective adjuvant treatment in patients with mild psoriasis, and was also useful in reducing itchy symptoms, the impact on quality of life, as well as significantly reducing the clinical signs of psoriasis.

Effects of Helichrysum Psudoplicatum supplementation on pruritus intensity, fatigue, quality of life and anorexia in hemodialysis patients: a randomized, double-blind placebo-controlled trial.

OBJECTIVES: Anorexia, fatigue and pruritus are common complications of hemodialysis (HD) patients. Today, the use of medicinal plants is more than synthetic drugs due to their safety. Therefore, we designed a randomized controlled clinical trial to evaluate the effects of Helichrysum psudoplicatum (H. psudoplicatum) supplementation on biochemical parameters, pruritus intensity, fatigue, quality of life and anorexia in HD patients. METHODS: This randomized, double-blind, placebo-controlled trial was performed on 50 subjects with, aged 55-65 years old. HD patients were randomly divided into two groups. Intervention group received 250 mg/day of H. psudoplicatum supplement capsule for 6 weeks (n=25), and the placebo group was given placebo capsule for the same time duration and dosage (n=25). The serum concentrations of urea, creatinine, albumin and hemoglobin were measured enzymatically methods. Anorexia, pruritus intensity, quality of life the dialysis patients with pruritus and fatigue score was measured using a Simplified Nutritional Appetite Questionnaire (SNAQ), Numerical rating scale (NRS), Fatigue severity scale (FSS) and ItchyQoL questionnaire, respectively. Shapiro-Wilk and independent-samples t-test or Mann-Whitney test were used for the analysis of the data. RESULTS: The results showed that the H. psudoplicatum supplementation significantly improved the pruritus intensity, quality of life the dialysis patients with pruritus and fatigue in HD patients, for 6 weeks (p<0.001). However, it did not significantly effect on the anorexia, albumin, hemoglobin, urea, creatinine, arm circumference, and body mass index (p>0.05). CONCLUSIONS: According to the results of this study, H. psudoplicatum supplementation can be effective as an adjunct therapy to improve pruritus intensity, quality of life, fatigue and relative improvement of anorexia in HD patients.

Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity. PATIENTS AND METHODS: Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks. RESULTS: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks. CONCLUSIONS: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03212625).

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin.

Introduction: Parkinson's disease psychosis (PDP) may affect up to 60% of patients with Parkinson's disease over the course of their disease, and is associated with poor prognosis, including increased risks of mortality and nursing home placement. PDP treatments have been limited to off-label use of atypical antipsychotics, most of which pose risks of worsened motor symptoms and other potential adverse events (AEs) due to their dopamine receptor blockade and additional off-target receptor affinities. Pimavanserin is a highly selective 5-HT2A inverse agonist and poses no known risks for worsening of parkinsonism or other off-target receptor AEs. Pimavanserin is the first and only medication approved for PDP treatment. Areas covered: This review covers estimated prevalence, clinical characteristics, diagnostic criteria, and risk factors for PDP; the hypothetical progression of PDP; management of PDP including use of antipsychotics; pharmacology and clinical trial data on pimavanserin; and expert opinion on PDP treatment. The NLM/PubMed database was searched for papers using the search terms of "PDP" AND "treatment" AND "pimavanserin" for the last 10 years. Expert opinion: The recent insights into PDP pathophysiology and approval of the only medication specifically to treat PDP are key advances that should improve the recognition, diagnosis, and management of PDP.

Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants.

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry.

BACKGROUND: The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE). OBJECTIVES: To report comprehensive follow-up data from the CARPE registry. PATIENTS AND METHODS: We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively. RESULTS: Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased. CONCLUSIONS: Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema.

Ear drops for the removal of ear wax.

BACKGROUND: Ear wax (cerumen) is a normal bodily secretion that can become a problem when it obstructs the ear canal. Symptoms attributed to wax (such as deafness and pain) are among the commonest reasons for patients to present to primary care with ear trouble.Wax is part of the ear's self-cleaning mechanism and is usually naturally expelled from the ear canal without causing problems. When this mechanism fails, wax is retained in the canal and may become impacted; interventions to encourage its removal may then be needed. Application of ear drops is one of these methods. Liquids used to remove and soften wax are of several kinds: oil-based compounds (e.g. olive or almond oil); water-based compounds (e.g. sodium bicarbonate or water itself); a combination of the above or non-water, non-oil-based solutions, such as carbamide peroxide (a hydrogen peroxide-urea compound) and glycerol. OBJECTIVES: To assess the effects of ear drops (or sprays) to remove or aid the removal of ear wax in adults and children. SEARCH METHODS: We searched the Cochrane ENT Trials Register; Cochrane Register of Studies; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 March 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which a 'cerumenolytic' was compared with no treatment, water or saline, an alternative liquid treatment (oil or almond oil) or another 'cerumenolytic' in adults or children with obstructing or impacted ear wax. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were 1) the proportion of patients (or ears) with complete clearance of ear wax and 2) adverse effects (discomfort, irritation or pain). Secondary outcomes were: extent of wax clearance; proportion of people (or ears) with relief of symptoms due to wax; proportion of people (or ears) requiring further intervention to remove wax; success of mechanical removal of residual wax following treatment; any other adverse effects recorded and cost. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 10 studies, with 623 participants (900 ears). Interventions included: oil-based treatments (triethanolamine polypeptide, almond oil, benzocaine, chlorobutanol), water-based treatments (docusate sodium, carbamide peroxide, phenazone, choline salicylate, urea peroxide, potassium carbonate), other active comparators (e.g. saline or water alone) and no treatment. Nine of the studies were more than 15 years old.The overall risk of bias across the 10 included studies was low or unclear. PRIMARY OUTCOME: proportion of patients (or ears) with complete clearance of ear waxSix studies (360 participants; 491 ears) contributed quantitative data and were included in our meta-analyses.Active treatment versus no treatmentOnly one study addressed this comparison. The proportion of ears with complete clearance of ear wax was higher in the active treatment group (22%) compared with the no treatment group (5%) after five days of treatment (risk ratio (RR) 4.09, 95% confidence interval (CI) 1.00 to 16.80); one study; 117 ears; NNTB = 8) (low-quality evidence).Active treatment versus water or salineWe found no evidence of a difference in the proportion of patients (or ears) with complete clearance of ear wax when the active treatment group was compared to the water or saline group (RR 1.47, 95% CI 0.79 to 2.75; three studies; 213 participants; 257 ears) (low-quality evidence). Two studies applied drops for five days, but one study only applied the drops for 15 minutes. When we excluded this study in a sensitivity analysis it did not change the result.Water or saline versus no treatmentThis comparison was only addressed in the single study cited above (active versus no treatment) and there was no evidence of a difference in the proportion of ears with complete wax clearance when comparing water or saline with no treatment after five days of treatment (RR 4.00, 95% CI 0.91 to 17.62; one study; 76 ears) (low-quality evidence).Active treatment A versus active treatment BSeveral single studies evaluated 'head-to-head' comparisons between two active treatments. We found no evidence to show that one was superior to any other.Subgroup analysis of oil-based active treatments versus non-oil based active treatmentsWe found no evidence of a difference in this outcome when oil-based treatments were compared with non-oil-based active treatments. PRIMARY OUTCOME: adverse effects: discomfort, irritation or painOnly seven studies planned to measure and did report this outcome. Only two (141 participants;176 ears) provided useable data. There was no evidence of a significant difference in the number of adverse effects between the types of ear drops in these two studies. We summarised the remaining five studies narratively. All events were mild and reported in fewer than 30 participants across the seven studies (low-quality evidence).Secondary outcomesThree studies reported 'other' adverse effects (how many studies planned to report these is unclear). The available information was limited and included occasional reports of dizziness, unpleasant smell, tinnitus and hearing loss. No significant differences between groups were reported. There were no emergencies or serious adverse effects reported in any of the 10 studies.There was very limited or no information available on our remaining secondary outcomes. AUTHORS' CONCLUSIONS: Although a number of studies aimed to evaluate whether or not one type of cerumenolytic is more effective than another, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain.A single study suggests that applying ear drops for five days may result in a greater likelihood of complete wax clearance than no treatment at all. However, we cannot conclude whether one type of active treatment is more effective than another and there was no evidence of a difference in efficacy between oil-based and water-based active treatments.There is no evidence to show that using saline or water alone is better or worse than commercially produced cerumenolytics. Equally, there is also no evidence to show that using saline or water alone is better than no treatment.

Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula.

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

Mild water restriction with or without urea for the longterm treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH): Can urine osmolality help the choice?

BACKGROUND: Treatment options for chronic SIADH include water restriction (WR) and urea. The usefulness of urine osmolality to guide the choice of the treatment option is not clearly defined. We hypothesized that urine osmolality can indicate whether treatment with mild water restriction alone could be successful. METHODS: Retrospective Review of clinical and biochemical (blood and urine) data of patients with chronic SIADH treated for at least one year with mild WR (1.5-2l/day) either with or without urea. RESULTS: Twenty nine patients were included. Nine patients were treated by mild WR. Mean serum sodium (SNa) and mean Uosm were 129±2mEq/l and 274±78mOsm/kgH2O respectively before WR, and increased to 138.5±3mEq/l and 505±87mOsm/kgH2O (P<0.001). Eight patients were treated with mild WR and 15g urea daily, the SNa and Uosm before treatment were 127.5±3mEq/l and 340±100mOsm/kgH2O respectively and increased to 136.5±1mEq/l and 490±151mOsm/kgH2O (P<0.001). Four of the eight patients had a permanent low solute intake which contributed to hyponatremia. Twelve patients needed 30g urea daily combined with mild WR. The SNa and Uosm were respectively 126±2mEq/l and 595±176mOsm/kgH2O and increased to 136.5±2mEq/l and 698±157mOsm/kgH2O (P<0.05). Uosm increased in most of the treated patients. CONCLUSIONS: About 30% of patients could be treated by moderate WR alone. All these patients presented an initial urine osmolality lower than 400mOsm/kgH2O.

Itch Management: Topical Agents.

Chronic pruritus is a common problem in patients with inflammatory skin diseases as well as in subjects with dry or sensitive skin. Regardless of the underlying cause of the pruritus, a topical therapy is not only useful but most often necessary to achieve symptom control. A good topical therapy should fulfill different functions. An optimal basic therapy based on the condition of the skin is important to repair epithelial barrier defects and to rehydrate the skin. An adequate disease-specific topical therapy is crucial for inflamed skin, e.g. anti-inflammatory topical therapy is an important part in the treatment of atopic dermatitis. Finally, the use of specific antipruritic substances can help to improve pruritus in patients irrespective of the underlying disease. Here, we summarize topical agents used in the treatment of chronic pruritus.