RESUMEN
Dermatophytosis is a very common public health problem with high prevalence. Dermatophytes are a highly specialized set of filamentous fungi, which are adapted to keratinized tissues of humans and animals. Dermatophytosis is the most common fungal infection worldwide, affecting approximately 20-25% of the world's population. The etiological agents of dermatophytosis, called dermatophytes, change with geography and socioeconomic status. Trichophyton rubrum (T. rubrum) is the prime species for skin and nail infections followed by T. mentagrophytes/ T. interdigital complex. There is a shift from T. rubrum to T. mentagrophytes in India for superficial fungal infections. In order to deal with fungal infections, treatment strategies involve the use of systemic antifungals and/or topical antifungal agents. Naftifine is a synthetic allylamine antifungal first reported in 1974 and in 1985 became the first commercially available allylamine. The highly lipophilic nature of allylamine allows efficient penetration and reasonably high concentrations in the stratum corneum (SC) and hair follicles. Naftifine is fungicidal as well as fungistatic. The higher efficacy rates of allylamines over imidazoles for the treatment of fungal infections, even for months after cessation of treatment, is thought to be due to their fungicidal effect, as well as to potentially greater keratin binding and slower release from the SC. The effectiveness of naftifine is also demonstrated against various bacteria belonging to both gram-negative and gram-positive classes. The antiinflammatory property of naftifine has been reported in various preclinical studies where it has been shown to target the prostaglandin pathway. Naftifine 1 and 2% gel and cream is approved by The United States Food and Drug Administration (USFDA), recently naftifine has been approved in India by the Indian regulatory authority Drug Controller General of India (DCGI) for the treatment of dermatophytosis. Naftifine 2% also appears to be a promising treatment, requiring fewer applications than the 1% formulation. Naftifine appears to be effective in a single dose and has a shorter treatment duration than azoles. Naftifine demonstrated its efficacy and safety in various clinical studies of tinea infections. Naftifine offers a very useful and promising option for treating dermatophytosis.
Asunto(s)
Alilamina , Dermatomicosis , Tiña , Humanos , Alilamina/uso terapéutico , Alilamina/metabolismo , Piel , Dermatomicosis/tratamiento farmacológico , Antifúngicos/uso terapéutico , Tiña/tratamiento farmacológico , Tiña/metabolismoRESUMEN
Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.
Asunto(s)
Albuminuria/tratamiento farmacológico , Alilamina/análogos & derivados , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Benzamidas/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Glomérulos Renales/patología , Túbulos Renales/patología , Insuficiencia Renal Crónica/tratamiento farmacológico , Alilamina/farmacología , Alilamina/uso terapéutico , Animales , Benzamidas/farmacología , Diabetes Mellitus Experimental , Nefropatías Diabéticas/patología , Inhibidores Enzimáticos/farmacología , Fibronectinas/metabolismo , Fibrosis , Glomérulos Renales/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Antígenos Comunes de Leucocito/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Renal Crónica/patología , Telmisartán/farmacología , Telmisartán/uso terapéuticoRESUMEN
BACKGROUND: Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) is a mass spectrometry-based technique, which can be applied for compound-specific imaging of pharmaceuticals in tissues samples. MALDI-MSI technology is widely used to visualise penetration and distribution profile through different tissues but has never been used with nail tissue. OBJECTIVES: This study used MALDI-MSI technology to visualise distribution profile and penetration into ex vivo human mycosis-infected toenails of three antifungal active ingredients amorolfine, ciclopirox and naftifine contained in topical onychomycosis nail treatment preparations, marketed as Loceryl® , Ciclopoli® and Exoderil® . METHODS: Three mycosis-infected toenails were used for each treatment condition. Six and twenty-four hours after one single topical application of antifungal drugs, excess of formulation was removed, nails were cryo-sectioned at a thickness of 20 µm, and MALDI matrix was deposited on each nail slice. Penetration and distribution profile of amorolfine, ciclopirox and naftifine in the nails were analysed by MALDI-MSI. RESULTS: All antifungal actives have been visualised in the nail by MALDI-MSI. Ciclopirox and naftifine molecules showed a highly localised distribution in the uppermost layer of the nail plate. In comparison, amorolfine diffuses through the nail plate to the deep layers already 6 hours after application and keeps diffusing towards the lowest nail layers within 24 hours. CONCLUSIONS: This study shows for the first-time distribution and penetration of certain antifungal actives into human nails using MALDI-MSI analysis. The results showed a more homogeneous distribution of amorolfine to nail and a better penetration through the infected nails than ciclopirox and naftifine.
Asunto(s)
Antifúngicos/farmacología , Onicomicosis/diagnóstico por imagen , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Administración Tópica , Alilamina/administración & dosificación , Alilamina/análogos & derivados , Alilamina/farmacología , Alilamina/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Ciclopirox/administración & dosificación , Ciclopirox/farmacología , Ciclopirox/uso terapéutico , Humanos , Laca , Morfolinas/administración & dosificación , Morfolinas/farmacología , Morfolinas/uso terapéutico , Uñas/microbiología , Uñas/patología , Onicomicosis/tratamiento farmacológicoRESUMEN
Inflammation, oxidative stress, and the formation of advanced glycated end-products (AGEs) are important components of atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation. Its enzymatic activity, semicarbazide-sensitive amine oxidase (SSAO), can catalyze oxidative deamination reactions to produce hydrogen peroxide and aldehydes, leading to the subsequent generation of AGEs. This study aimed to investigate the effect of VAP-1/SSAO inhibition on atherosclerosis. In our study, immunohistochemical staining showed that atherosclerotic plaques displayed higher VAP-1 expression than normal arterial walls in apolipoprotein E-deficient mice, cholesterol-fed New Zealand White rabbits and humans. In cholesterol-fed rabbits, VAP-1 was expressed on endothelial cells and smooth muscle cells in the thickened intima of the aorta. Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Aterosclerosis/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Conducta Alimentaria , Alilamina/análogos & derivados , Alilamina/farmacología , Alilamina/uso terapéutico , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Aorta/metabolismo , Apolipoproteínas E/deficiencia , Aterosclerosis/sangre , Aterosclerosis/patología , Benzamidas/farmacología , Benzamidas/uso terapéutico , Peso Corporal , Moléculas de Adhesión Celular/metabolismo , Colesterol , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Ayuno/sangre , Humanos , Peróxido de Hidrógeno/metabolismo , Mediadores de Inflamación/metabolismo , Activación de Macrófagos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , ConejosRESUMEN
Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/enzimología , Inhibidores Enzimáticos/uso terapéutico , Semicarbacidas/farmacología , Alilamina/análogos & derivados , Alilamina/farmacología , Alilamina/uso terapéutico , Animales , Aterosclerosis/sangre , Benzamidas/farmacología , Benzamidas/uso terapéutico , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colesterol , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/patologíaRESUMEN
OBJECTIVE: To evaluate efficacy of combined therapy with ozonated water and oil on patients with tinea pedis.â© Methods: A total of 60 patients with tinea pedis were divided into 2 groups in a randomized and blinded test. Patients in a control group were treated with naftinfine hydrochloride and ketoconazole cream once a day. Patients in an ozone group were treated with ozonated water bath and then ozonated oil topical application once a day. Patients in the 2 groups were treated for 4 weeks. Clinical and laboratory data were collected for both groups at the end of the 1st week, the 2nd week, and the 4th week. The Pearson chi-square was performed to compare scores of the clinical signs and symptoms (CSS) and the mycological result between the 2 groups. Independent samples T-test was performed to compare the curative effect between the 2 groups.â© Results: After 4 weeks' treatment, 6 patients were positive in the control group determined by mycological examination while 1 patient was positive in the ozone group, with no significant difference between the 2 groups (P>0.05). Changes in CSS at the end of the 1st week, 2nd week, and 4th week were obtained and showed no significant difference between the 2 groups at the 3 different time points (P>0.05). No side effects were observed.â© Conclusion: Combination of ozonated water with oil is effective on treatment of tinea pedis and it shows no side effects.
Asunto(s)
Alilamina/análogos & derivados , Antifúngicos/uso terapéutico , Hidroterapia/métodos , Cetoconazol/uso terapéutico , Aceites/uso terapéutico , Ozono/uso terapéutico , Tiña del Pie/terapia , Agua/química , Alilamina/uso terapéutico , Baños/métodos , Distribución de Chi-Cuadrado , Terapia Combinada/métodos , Método Doble Ciego , Humanos , Crema para la Piel/uso terapéutico , Resultado del TratamientoRESUMEN
Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.
Asunto(s)
Lesión Renal Aguda/prevención & control , Alilamina/análogos & derivados , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Antineoplásicos/efectos adversos , Benzamidas/uso terapéutico , Cisplatino/efectos adversos , Actinas/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Alilamina/farmacología , Alilamina/uso terapéutico , Animales , Benzamidas/farmacología , Quimiocina CCL2/metabolismo , Evaluación Preclínica de Medicamentos , Proteínas de Unión a Ácidos Grasos/genética , Fibrosis , Interleucina-6/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Naftifine hydrochloride (naftifine) is a topical antifungal of the allylamine class, displaying fungicidal and fungistatic activity. Naftifine is generally used to treat interdigital tinea pedis; however, systemic therapy is often prescribed by healthcare providers for moccasin tinea pedis. Well-controlled clinical data on topical antifungal therapy for moccasin tinea pedis is limited. OBJECTIVE: The objective of this analysis is to present data from two pooled randomized, vehicle-controlled studies that evaluated efficacy of once daily topical naftifine gel 2% and vehicle at end of treatment (week 2) and at 4 weeks post-treatment in subjects with moccasin tinea pedis. METHODS: At visit 1, subjects were randomized to naftifine gel 2% or vehicle groups and subjects underwent baseline mycology culture, KOH, and symptom (erythema, scaling, and pruritus) severity grading. Naftifine gel 2% and vehicle treatment were applied once daily for 2 weeks and the subjects returned at weeks 2 and 6 for efficacy evaluation (mycology culture and grading of symptom severity). A total of 1174 subjects were enrolled with interdigital tinea pedis with or without moccasin infection. Of these subjects, 674 subjects had interdigital presentation while 500 subjects had moccasin infection in addition to the interdigital presentation. All 1174 subjects with interdigital presentation satisfied the inclusion criteria of a minimum of moderate erythema and scaling, and mild pruritus. Of the 500 subjects who had moccasin presentation, 380 satisfied the same inclusion criteria as mentioned above. Since data was analyzed as observed cases, between 337 and 349 subjects had data available for analysis of efficacy. Mycologic cure is defined as a negative dermatophyte culture and KOH, treatment effectiveness is defined as mycologic cure and symptom severity scores of 0 or 1, and complete cure is defined as mycologic cure and symptoms severity scores of 0. RESULTS: At week 6, the cure rates in the naftifine arm vs. the vehicle were statistically higher (P < 0.0001) for mycological cure rate (65.8% vs. 7.8%), treatment effectiveness (51.4% vs 4.4%), and complete cure rate (19.2% vs 0.9%). CONCLUSION: Two weeks application of topical naftifine gel 2% is an effective monotherapy treatment for moccasin tinea pedis.
Asunto(s)
Alilamina/análogos & derivados , Antifúngicos/administración & dosificación , Tiña del Pie/tratamiento farmacológico , Administración Cutánea , Adolescente , Adulto , Anciano , Alilamina/administración & dosificación , Alilamina/uso terapéutico , Antifúngicos/uso terapéutico , Niño , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Femenino , Geles , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiña del Pie/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Tinea pedis is the most common superficial fungal infection. Naftifine hydrochloride is a topical antifungal of the allylamine class, displaying fungicidal activity and clinically significant anti-bacterial and anti-inflammatory effects. Clinical data on topical antifungal therapy using naftifine for tinea pedis in a pediatric population is limited. OBJECTIVE: To assess trends in efficacy, tolerability, safety, and to quantify the pharmacokinetics (PK) of topical naftifine hydrochloride gel 2% in pediatric subjects with tinea pedis. METHODS: Twenty-eight subjects (22 pediatric and 6 adult controls) were enrolled and treated in the study. Approximately 2 grams of naftifine hydrochloride gel 2% was applied to each foot (4 grams total) for subjects with tinea pedis. Pharmacokinetic blood and urine samples were collected at various time points throughout the study. Efficacy was assessed based on potassium hydroxide, dermatophyte culture, and signs and symptom results at days 7, 14, and 28. Adverse event information was collected routinely.
RESULTS: The rate and extent of systemic exposure among the pediatric and adult control subjects was low. Adverse events were minimal and were not related to treatment. Positive results were observed as early as day 7; however the proportion of subjects achieving success generally increased over time through day 28 in both treatment groups. CONCLUSIONS: Naftifine hydrochloride gel 2% was found to be well tolerated and safe. Trends in clinical benefit were observed throughout the treatment period; however, continued improvement in efficacy rates were observed during the post-treatment period.
Asunto(s)
Alilamina/análogos & derivados , Antifúngicos/uso terapéutico , Tiña del Pie/tratamiento farmacológico , Administración Cutánea , Adolescente , Adulto , Alilamina/administración & dosificación , Alilamina/efectos adversos , Alilamina/farmacocinética , Alilamina/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Niño , Esquema de Medicación , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
Although recognised as a cause of chronic diarrhoea for over forty years, diagnostic tests and treatments for bile acid malabsorption (BAM) remain controversial. Recent National Institute for Health and Care Excellence (NICE) guidelines highlighted the lack of evidence in the field, and called for further research. This retrospective study explores the BAM subtype and severity, the use and response to bile acid sequestrants (BAS) and the prevalence of abnormal colonic histology. 264 selenium-75-labelled homocholic acid conjugated taurine (SeHCAT)-tested patient records were reviewed and the severity and subtype of BAM, presence of colonic histopathology and response to BAS were recorded. 53% of patients tested had BAM, with type-2 BAM in 45% of patients with presumed irritable bowel syndrome. Colonic histological abnormalities were similar overall between patients with (29%) or without (23%) BAM (p = 0.46) and between BAM subtypes, with no significant presence of inflammatory changes. 63% of patients with BAM had a successful BAS response which showed a trend to decreased response with reduced severity. Colestyramine was unsuccessful in 44% (38/87) and 45% of these (17/38) were related to medication intolerance, despite a positive SeHCAT. 47% (7/15) of colestyramine failures had a successful colesevelam response. No patient reported colesevelam intolerance. Quantifying severity of BAM appears to be useful in predicting BAS response. Colesevelam was better tolerated than colestyramine and showed some efficacy in colestyramine failures. Colestyramine failure should not be used to exclude BAM. Colonic histology is of no relevance.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Ácidos y Sales Biliares/metabolismo , Diarrea/diagnóstico , Diarrea/terapia , Esteatorrea/diagnóstico , Esteatorrea/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alilamina/análogos & derivados , Alilamina/uso terapéutico , Resina de Colestiramina/uso terapéutico , Clorhidrato de Colesevelam , Colon/patología , Diarrea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esteatorrea/patología , Ácido Taurocólico/análogos & derivados , Adulto JovenRESUMEN
BACKGROUND: About one-third of patients with IBS-diarrhoea (irritable bowel syndrome-D) have evidence of increased bile acid synthesis or excretion. AIMS: To assess effects of the bile acid sequestrant, colesevelam, on faecal excretion of BAs, hepatic BA synthesis and diarrhoea in IBS-D; to appraise whether individual or random stool samples accurately reflect 48-h total faecal bile acid excretion and proportions of the main bile acids excreted and to study the faecal fat excretion in response to colesevelam. METHODS: A single-centre, unblinded, single-dose trial of effects of colesevelam, 1875 mg [3 tablets (625 mg tablets)] orally, twice daily, for 10 days on total 48-h faecal bile acid excretion and fasting serum C4 (7α-hydroxy-4-cholesten-3-one; surrogate of hepatic bile acid synthesis). Stool diaries documented bowel functions for 8 days prior and 8 days during colesevelam treatment. Stool 48-h samples and fasting serum were collected for faecal fat, faecal bile acid and serum C4. RESULTS: Colesevelam was associated with significantly increased faecal total bile acid excretion and deoxycholic acid excretion, increased serum C4 and more solid stool consistency. There was a significant inverse correlation between number of bowel movements per week and the total bile acid sequestered into stool during the last 48 h of treatment. Random stool samples did not accurately reflect 48-h total or individual faecal bile acid excretion. Sequestration of bile acids by colesevelam did not increase faecal fat. CONCLUSIONS: Colesevelam increases delivery of bile acids to stool while improving stool consistency, and increases hepatic bile acid synthesis, avoiding steatorrhoea in patients with IBS-D. Overall effects are consistent with luminal bile acid sequestration by colesevelam.
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Alilamina/análogos & derivados , Ácidos y Sales Biliares/metabolismo , Diarrea/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Adulto , Alilamina/uso terapéutico , Colestenonas/sangre , Clorhidrato de Colesevelam , Ácido Desoxicólico/metabolismo , Heces , Femenino , Humanos , Persona de Mediana EdadRESUMEN
PURPOSE: To explore the cross-sectional and longitudinal relationships between fractional liver fat content, liver volume, and total liver fat burden. METHODS: In 43 adults with non-alcoholic steatohepatitis participating in a clinical trial, liver volume was estimated by segmentation of magnitude-based low-flip-angle multiecho GRE images. The liver mean proton density fat fraction (PDFF) was calculated. The total liver fat index (TLFI) was estimated as the product of liver mean PDFF and liver volume. Linear regression analyses were performed. RESULTS: Cross-sectional analyses revealed statistically significant relationships between TLFI and liver mean PDFF (R 2 = 0.740 baseline/0.791 follow-up, P < 0.001 baseline/P < 0.001 follow-up), and between TLFI and liver volume (R 2 = 0.352/0.452, P < 0.001/< 0.001). Longitudinal analyses revealed statistically significant relationships between liver volume change and liver mean PDFF change (R 2 = 0.556, P < 0.001), between TLFI change and liver mean PDFF change (R 2 = 0.920, P < 0.001), and between TLFI change and liver volume change (R 2 = 0.735, P < 0.001). CONCLUSION: Liver segmentation in combination with MRI-based PDFF estimation may be used to monitor liver volume, liver mean PDFF, and TLFI in a clinical trial.
Asunto(s)
Imagen por Resonancia Magnética , Enfermedad del Hígado Graso no Alcohólico/patología , Tejido Adiposo/patología , Anciano , Alilamina/análogos & derivados , Alilamina/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Clorhidrato de Colesevelam , Estudios Transversales , Método Doble Ciego , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Hígado/patología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Tamaño de los ÓrganosRESUMEN
Aneurysmal subarachnoid hemorrhage (SAH) is a potentially devastating clinical problem. Despite advances in the diagnosis and treatment of SAH, outcome remains unfavorable. An increased inflammatory state, one that is characterized by enhanced leukocyte trafficking has been reported to contribute to neuronal injury in association with multiple brain insults, including hemorrhagic and ischemic stroke. This study was designed to investigate, in rats, the neuropathologic consequences of heightened leukocyte trafficking following SAH, induced via endovascular perforation of the anterior cerebral artery. Experiments focused on the initial 48 h post-SAH and sought to establish whether blockade of vascular adhesion protein-1 (VAP-1), with LJP-1586, was able to provide dose-dependent neuroprotection. Treatment with LJP-1586 was initiated at 6h post-SAH. An intravital microscopy and closed cranial window system, that permitted examination of temporal patterns of rhodamine-6G-labeled leukocyte adhesion/extravasation, was used. Effects of LJP-1586 on neurologic outcomes and leukocyte trafficking at 24 h and 48 h post-SAH were examined. In VAP-1-inhibited vs control rats, results revealed a significant attenuation in leukocyte trafficking at both 24 h and 48 h after SAH, along with an improvement in neurologic outcome. In conclusion, our findings support the involvement of an amplified inflammatory state, characterized by enhanced leukocyte trafficking, during the first 48 h after SAH. VAP-1 blockade yielded neuroprotection that was associated with an attenuation of leukocyte trafficking and improved neurologic outcome.
Asunto(s)
Alilamina/análogos & derivados , Amina Oxidasa (conteniendo Cobre)/metabolismo , Moléculas de Adhesión Celular/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/etiología , Hemorragia Subaracnoidea/complicaciones , Alilamina/farmacología , Alilamina/uso terapéutico , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Animales , Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/antagonistas & inhibidores , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Leucocitos/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Hemorragia Subaracnoidea/patología , Factores de TiempoRESUMEN
BACKGROUND: Tinea infections are fungal infections of the skin caused by dermatophytes. It is estimated that 10% to 20% of the world population is affected by fungal skin infections. Sites of infection vary according to geographical location, the organism involved, and environmental and cultural differences. Both tinea corporis, also referred to as 'ringworm' and tinea cruris or 'jock itch' are conditions frequently seen by primary care doctors and dermatologists. The diagnosis can be made on clinical appearance and can be confirmed by microscopy or culture. A wide range of topical antifungal drugs are used to treat these superficial dermatomycoses, but it is unclear which are the most effective. OBJECTIVES: To assess the effects of topical antifungal treatments in tinea cruris and tinea corporis. SEARCH METHODS: We searched the following databases up to 13th August 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2013, Issue 7), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched five trials registers, and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials. We handsearched the journal Mycoses from 1957 to 1990. SELECTION CRITERIA: Randomised controlled trials in people with proven dermatophyte infection of the body (tinea corporis) or groin (tinea cruris). DATA COLLECTION AND ANALYSIS: Two review authors independently carried out study selection, data extraction, assessment of risk of bias, and analyses. MAIN RESULTS: Of the 364 records identified, 129 studies with 18,086 participants met the inclusion criteria. Half of the studies were judged at high risk of bias with the remainder judged at unclear risk. A wide range of different comparisons were evaluated across the 129 studies, 92 in total, with azoles accounting for the majority of the interventions. Treatment duration varied from one week to two months, but in most studies this was two to four weeks. The length of follow-up varied from one week to six months. Sixty-three studies contained no usable or retrievable data mainly due to the lack of separate data for different tinea infections. Mycological and clinical cure were assessed in the majority of studies, along with adverse effects. Less than half of the studies assessed disease relapse, and hardly any of them assessed duration until clinical cure, or participant-judged cure. The quality of the body of evidence was rated as low to very low for the different outcomes.Data for several outcomes for two individual treatments were pooled. Across five studies, significantly higher clinical cure rates were seen in participants treated with terbinafine compared to placebo (risk ratio (RR) 4.51, 95% confidence interval (CI) 3.10 to 6.56, number needed to treat (NNT) 3, 95% CI 2 to 4). The quality of evidence for this outcome was rated as low. Data for mycological cure for terbinafine could not be pooled due to substantial heterogeneity.Mycological cure rates favoured naftifine 1% compared to placebo across three studies (RR 2.38, 95% CI 1.80 to 3.14, NNT 3, 95% CI 2 to 4) with the quality of evidence rated as low. In one study, naftifine 1% was more effective than placebo in achieving clinical cure (RR 2.42, 95% CI 1.41 to 4.16, NNT 3, 95% CI 2 to 5) with the quality of evidence rated as low.Across two studies, mycological cure rates favoured clotrimazole 1% compared to placebo (RR 2.87, 95% CI 2.28 to 3.62, NNT 2, 95% CI 2 to 3).Data for several outcomes were pooled for three comparisons between different classes of treatment. There was no difference in mycological cure between azoles and benzylamines (RR 1.01, 95% CI 0.94 to 1.07). The quality of the evidence was rated as low for this comparison. Substantial heterogeneity precluded the pooling of data for mycological and clinical cure when comparing azoles and allylamines. Azoles were slightly less effective in achieving clinical cure compared to azole and steroid combination creams immediately at the end of treatment (RR 0.67, 95% CI 0.53 to 0.84, NNT 6, 95% CI 5 to 13), but there was no difference in mycological cure rate (RR 0.99, 95% CI 0.93 to 1.05). The quality of evidence for these two outcomes was rated as low for mycological cure and very low for clinical cure.All of the treatments that were examined appeared to be effective, but most comparisons were evaluated in single studies. There was no evidence for a difference in cure rates between tinea cruris and tinea corporis. Adverse effects were minimal - mainly irritation and burning; results were generally imprecise between active interventions and placebo, and between different classes of treatment. AUTHORS' CONCLUSIONS: The pooled data suggest that the individual treatments terbinafine and naftifine are effective. Adverse effects were generally mild and reported infrequently. A substantial number of the studies were more than 20 years old and of unclear or high risk of bias; there is however, some evidence that other topical antifungal treatments also provide similar clinical and mycological cure rates, particularly azoles although most were evaluated in single studies.There is insufficient evidence to determine if Whitfield's ointment, a widely used agent is effective.Although combinations of topical steroids and antifungals are not currently recommended in any clinical guidelines, relevant studies included in this review reported higher clinical cure rates with similar mycological cure rates at the end of treatment, but the quality of evidence for these outcomes was rated very low due to imprecision, indirectness and risk of bias. There was insufficient evidence to confidently assess relapse rates in the individual or combination treatments.Although there was little difference between different classes of treatment in achieving cure, some interventions may be more appealing as they require fewer applications and a shorter duration of treatment. Further, high quality, adequately powered trials focusing on patient-centred outcomes, such as patient satisfaction with treatment should be considered.
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Antifúngicos/uso terapéutico , Prurito/tratamiento farmacológico , Tiña/tratamiento farmacológico , Administración Cutánea , Corticoesteroides/uso terapéutico , Alilamina/análogos & derivados , Alilamina/uso terapéutico , Antifúngicos/administración & dosificación , Azoles/uso terapéutico , Benzoatos/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Masculino , Naftalenos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Salicilatos/uso terapéutico , TerbinafinaRESUMEN
Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulin-based regimens. We evaluated colesevelam's effects in subjects on stable pioglitazone-based therapy. This 24-week multicenter, double-blind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control [HbA1c ≥ 58 mmol/mol (7.5%) and ≤ 80 mmol/mol (9.5%)] on pioglitazone (30 or 45 mg) with or without 1-2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c [least-squares mean treatment difference, - 3.5 mmol/mol (- 0.32%); p < 0.001] and fasting plasma glucose (- 14.7 mg/dl; p<0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7%) (40% vs. 25%; p<0.001) or HbA1c < 53 mmol/mol (7.0%) (21% vs. 13%; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, - 6.5%), LDL-cholesterol (- 16.4%), non-HDL-cholesterol (- 9.8%), apolipoprotein B (- 8.8%), and total LDL particle concentration, and increased apolipoprotein A1 (+3.4%) and triglycerides (median treatment difference, + 11.3%) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.
Asunto(s)
Alilamina/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/uso terapéutico , Alilamina/efectos adversos , Alilamina/uso terapéutico , Glucemia/metabolismo , Clorhidrato de Colesevelam , Demografía , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Ayuno/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Análisis de los Mínimos Cuadrados , Lípidos/sangre , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Pioglitazona , Placebos , Resultado del TratamientoRESUMEN
Tuning the material properties in order to control the cellular behavior is an important issue in tissue engineering. It is now well-established that the surface chemistry can affect cell adhesion, proliferation, and differentiation. In this study, plasma polymerization, which is an appealing method for surface modification, was employed to generate surfaces with different chemical compositions. Allylamine (AAm), acrylic acid (AAc), 1,7-octadiene (OD), and ethanol (ET) were used as precursors for plasma polymerization in order to generate thin films rich in amine (-NH2), carboxyl (-COOH), methyl (-CH3), and hydroxyl (-OH) functional groups, respectively. The surface chemistry was characterized by X-ray photoelectron spectroscopy (XPS), the wettability was determined by measuring the water contact angles (WCA) and the surface topography was imaged by atomic force microscopy (AFM). The effects of surface chemical compositions on the behavior of human adipose-derive stem cells (hASCs) were evaluated in vitro: Cell Count Kit-8 (CCK-8) analysis for cell proliferation, F-actin staining for cell morphology, alkaline phosphatase (ALP) activity analysis, and Alizarin Red S staining for osteogenic differentiation. The results show that AAm-based plasma-polymerized coatings can promote the attachment, spreading, and, in turn, proliferation of hASCs, as well as promote the osteogenic differentiation of hASCs, suggesting that plasma polymerization is an appealing method for the surface modification of scaffolds used in bone tissue engineering.
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Tejido Adiposo/química , Alilamina/química , Células Madre/citología , Ingeniería de Tejidos , Tejido Adiposo/citología , Alilamina/síntesis química , Alilamina/uso terapéutico , Regeneración Ósea , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Osteogénesis/efectos de los fármacos , Polimerizacion , Células Madre/químicaRESUMEN
INTRODUCTION: Colesevelam HCl (colesevelam) is a bile acid sequestrant initially approved by the US Food and Drug Administration (FDA) in 2000 as an adjunct to diet and exercise to lower elevated low-density lipoprotein cholesterol (LDL-C) levels in adults with primary lipidemia, as monotherapy, or in combination with a statin. More recently, the drug was approved for use in adults with type 2 diabetes mellitus (T2DM) to improve glycemic control. Thus, colesevelam is currently the only single-agent monotherapy approved by the FDA to lower both LDL-C and glycated hemoglobin (A1c) levels in adults with T2DM and elevated LDL-C. Moreover, the formulation options for colesevelam have also expanded since its original approval. MATERIALS AND METHODS: A Medline search was conducted to provide evidence to support the efficacy and safety for the use of colesevelam tablets or oral suspension preparations when treating patients with lipidemia, T2DM, or both. No limitations were placed on publication date or any other parameter. RESULTS: Clinical studies have shown that colesevelam is efficacious in lowering LDL-C levels, improving the lipid profile, and improving glycemic control by reducing both A1c and fasting plasma glucose levels in T2DM. Equilibrium and kinetics data show that colesevelam is equivalent in its tablet and oral suspension formulation. CONCLUSION: Having 2 effective oral routes enhances convenience and improves compliance, both of which contribute to maximal therapeutic outcomes. These compliance benefits are due to the ease and flexibility of preparing the powder in various beverages and the pleasant taste from the inclusion of a low-calorie citrus flavoring.
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Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipercolesterolemia/tratamiento farmacológico , Alilamina/administración & dosificación , Alilamina/efectos adversos , Alilamina/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Glucemia , LDL-Colesterol/efectos de los fármacos , Clorhidrato de Colesevelam , Diabetes Mellitus Tipo 2/epidemiología , Hemoglobina Glucada , Humanos , Hipercolesterolemia/epidemiología , Lípidos/sangre , Suspensiones , ComprimidosRESUMEN
BACKGROUND AND AIMS: Bile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohn's disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM-associated diarrhea in CD patients in a randomized, double-blind, placebo-controlled study. METHODS: The primary endpoint was the proportion of patients with >30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life. RESULTS: 26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD=.394, 95%CI:[-0.012; 0.706]; P=.0566). In the per-protocol analysis (n=22), the risk difference was statistically significant (RD=.470, 95%CI:[0.018; 0.788], P(H0: RD=0)=0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam-treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P=0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P=0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P=0.003). CONCLUSIONS: We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency. ClinicalTrials.gov number: NCT01203254.
Asunto(s)
Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapéutico , Ácidos y Sales Biliares/metabolismo , Enfermedad de Crohn/complicaciones , Diarrea/tratamiento farmacológico , Síndromes de Malabsorción/tratamiento farmacológico , Adulto , Anciano , Alilamina/efectos adversos , Alilamina/uso terapéutico , Anticolesterolemiantes/efectos adversos , Colestenonas/sangre , Clorhidrato de Colesevelam , Enfermedad de Crohn/cirugía , Diarrea/sangre , Diarrea/etiología , Método Doble Ciego , Heces , Femenino , Humanos , Análisis de Intención de Tratar , Síndromes de Malabsorción/sangre , Síndromes de Malabsorción/etiología , Masculino , Persona de Mediana Edad , Calidad de Vida , Resultado del TratamientoRESUMEN
Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA1c. This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.