Crofelemer for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy

Castro, José G.; Chin‐Beckford, Nafeesa

doi:10.1586/17512433.2015.1082424

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…A product, Fulyzaq TM (crofelemer), was recently approved by FDA for the treatment of diarrhea caused by antiretroviral therapy. [14][15][16] The involvement of CFTR and the intestinal Ca 2þactivated Cl À channel (CaCC) in SED is supported by numerous studies. 8,9,17,18 There is evidence that the CFTR is the main pathway involved in SED.…”

Section: Impact Statementmentioning

confidence: 99%

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Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

Thompson

Ray

Alli

et al. 2018

Exp Biol Med (Maywood)

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Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed Rx100, which is a metabolically stable analog of lysophosphatidic acid. We tested the hypothesis that Rx100, similarly to lysophosphatidic acid, inhibits the activation of the cystic fibrosis transmembrane regulator Cl− channel and also reduces barrier permeability resulting in the decrease of fluid loss in multiple etiologies of secretory diarrhea. Here we have established the bioavailability and efficacy of Rx100 in cholera toxin-induced secretory diarrhea models. We have demonstrated the feasibility of Rx100 as an effective treatment for Citrobacter rodentium infection-induced secretory diarrhea. Using both the open- and closed-loop mouse models, we have optimized the dosing regimen and time line of delivery for Rx100 via oral and parenteral delivery. Impact statement A critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.

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Section: Impact Statementmentioning

confidence: 99%

“…A product, Fulyzaq™ (crofelemer), was recently approved by FDA for the treatment of diarrhea caused by antiretroviral therapy. 14–16…”

Section: Introductionmentioning

confidence: 99%

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

Thompson

Ray

Alli

et al. 2018

Exp Biol Med (Maywood)

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“…Crofelemer, a chloride channel antagonist, is approved for the treatment of HIV-associated diarrhea but may be of use in a variety of diarrheal diseases in which the cystic fibrosis transmembrane receptor chloride channel is active. 87 However, this has not been tested.…”

Section: How Can Cliniciansmentioning

confidence: 99%

Chronic Diarrhea: Diagnosis and Management

Schiller

Pardi

Sellin

2017

Clinical Gastroenterology and Hepatology

186

129

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Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self-limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available.

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“…Sin embargo, existen estudios de toxicidad subcrónica, como el realizado por Itokawa et al (28) que ha mostrado citotoxicidad in vitro con taspina extraída de Croton palanostigma, con una IC 50 de 0,39 mg/mL, contra células KB y 0,17 mg/mL contra células V-79. Asimismo, Ayala et al (29) en un estudio realizado del látex de Croton palanostigma, en 30 días, encontraron riesgo de esteatosis hepática a dosis de 1,2 mL/kg.…”

Section: Resultsunclassified

Efecto de la administración crónica del látex liofilizado de Croton lechleri Muell. Arg. "sangre de drago" en Rattus norvegicus var. Albinus

Betancur-Badel¹,

Rios-Isern²,

Villacrés-Vallejo³

et al. 2017

Rev. per. med. integr.

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Objetivo: Determinar si la administración crónica (90 días) del látex liofilizado de Croton lechleri Muell. Arg. “Sangre de drago” modifica los parámetros hematológicos y bioquimicos en Rattus norvegicus var albinus. Materiales y métodos: Se utilizó ratas con un peso corporal (p.c.) entre 150 g a 170 g, distribuidos en Grupo A (control) y Grupos B y C (experimentales), de 20 especímenes cada uno (10 hembras y 10 machos) a las que se administró por vía oral NaCl 0.9% y una dosis diaria de 100 y 200 mg de látex liofilizado/Kg p.c. respectivamente, durante 90 días. Se tomaron muestras de sangre cada 15 días para determinar parámetros hematológicos (hematocrito, linfocitos, leucocitos y segmentados) y bioquímicos (glucosa, urea, creatinina, colesterol total y perfil hepático). Resultados: Todos los valores se encontraron dentro del rango normal. Se encontraron diferencias significativas al comparar los grupos de estudio en los resultados de glucosa (Control vs Grupo I: p<0.001 y Grupo II: p=0.003) y creatinina (Grupo II vs Grupo I: p=0.008 y control: p<0.001). Los valores de bilirrubina total y proteínas totales variaron significativamente durante el tiempo de estudio (p=0.001 y p<0.001, respectivamente). El resto de parámetros no presentaron variaciones significativas por grupos (p>0.05). Conclusión: El látex liofilizado de Croton lechleri Muell. Arg. no generó toxicidad en los parámetros hematológicos y bioquímicos estudiados en Rattus norvegicus var Albinus.

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Crofelemer for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy

Cited by 11 publications

References 27 publications

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100

Chronic Diarrhea: Diagnosis and Management

Efecto de la administración crónica del látex liofilizado de Croton lechleri Muell. Arg. "sangre de drago" en Rattus norvegicus var. Albinus

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