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Diarrhea is a common comorbidity present in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) who are treated with highly active antiretroviral therapy. With a multifactorial etiology, this diarrhea often becomes difficult to manage. In addition, some antiretrovirals are associated with chronic diarrhea, whic...
Contexts in source publication
Context 1
... Treatment of noninfectious or secretory diarrhea currently includes both pharmacological and nonpharmacological approaches. Pharmacological treatments comprise those listed in Table 1. 2,[11][12][13] Most of these antidiarrheals are antimotility agents that cause unwanted side effects, such as constipation, bloating, and flatulence. ...
Context 2
... no clinical trials have compared the efficacy of crofelemer with other commonly used antidiarrheal agents (Table 1) for the symptomatic relief of diarrhea in HIV- infected patients, it is important to highlight the advantages of crofelemer. 2,[11][12][13] These include minimal systemic absorp- tion, low incidence of adverse events, and few drug-drug interactions. ...
Citations
... Preliminary evidence suggests crofelemer may prevent CRD in breast cancer due to neratinib and combination trastuzumab, pertuzumab, and a taxane [22,23]. Crofelemer is the subject of an ongoing large phase III study to prevent CRD (NCT04538625) [24]. ...
Purpose
The impact of cancer-related diarrhea (CRD) on changes in cancer therapy remains poorly characterized despite its prevalence.
Methods
We performed a longitudinal observational study using IQVIA PharMetrics Plus claims data. Patients included adults with CRD identified by diagnosis codes or pharmacy claims and compared their outcomes to matched (1:1) patients without CRD. Treatment parameters (discontinuation, persistence, augmentation, dose titration, adherence) were evaluated and stratified for the first cancer therapy (chemotherapy vs. targeted therapy vs. both). A multivariate Cox proportional hazards model was used to estimate the difference in risk of each treatment parameter between cohorts, adjusting for cancer type, therapy, and comorbidities.
Results
We identified 104,135 matched pairs of patients with solid (n = 94,411) or hematologic cancers (n = 9,724) receiving chemotherapy (n = 47,220), targeted therapy (n = 2,427), or both (n = 5,313). Patients with CRD discontinued therapy more frequently than those without CRD (chemotherapy [81.5% vs. 62.3%], targeted therapy [69.2% vs. 64.3%], both [96.0% vs. 85.5%], p < 0.0001). The overall proportion of discontinuation was higher (82.4% vs. 64.6%, p < 0.0001), including a higher risk of discontinuation (HR = 1.40, p < 0.001) for patients with CRD. The mean time to discontinuation (59.6 ± 54.1 vs. 68.3 ± 76.6 days), switch (72.0 ± 48.6 vs. 96.9 ± 84.0 days), persistence (95.1 ± 98.1 vs. 154.3 ± 142.7 days), and adherence (25.5%±37.2 vs. 47.9 ± 41%) were all lower (p < 0.0001) among patients with CRD.
Conclusion
Patients who develop CRD undergo significant and clinically impactful index treatment discontinuation, treatment switching, and have lower adherence and persistence of anticancer therapy compared to patients without CRD. Strategies to control CRD to optimize cancer therapy are urgently needed.
... Crofelemer has also been studied in patients with diarrhea-predominant irritable bowel syndrome (d-IBS) [10,11] and Traveler's diarrhea [12] as well as acute infectious diarrhea with pathogens like Escherichia coli [13] and Vibrio cholerae [14]. When compared with placebo, crofelemer significantly reduced the frequency of loose/watery stools as well as improved in stool consistency in these patient populations [15][16][17][18]. ...
Targeted therapies have increased cancer therapy-related diarrhea (CTD) burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib is a pan-HER tyrosine kinase inhibitor approved for breast cancer treatment and causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal drug for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence /severity of neratinib-induced diarrhea without concomitant administration of loperamide in female beagle dogs. A pilot study using 3 dogs determined a maximum daily tolerated dose of neratinib was between 40 and 80 mg; this dose would induce a consistent incidence/severity of diarrhea without risking severe dehydration. In the definitive study, 24 female beagle dogs (8/group) received neratinib once daily and placebo capsules (CTR) four times/day, or neratinib once daily and crofelemer 125 mg delayed-release tablets given two times (BID), or neratinib once daily and crofelemer 125 mg delayed-release tablets given four times per day (QID). Fecal scores were collected twice daily using an established canine stool scoring scale called the Purina Fecal Scoring (PFS) System. After 28 days, using analysis of covariance (ANCOVA), dogs in the CTR group had a significantly higher average number of weekly loose/watery stools (PFS of 6 or 7) when compared to either crofelemer BID (8.71±2.2 vs. 5.96±2.2, p = 0.028) or crofelemer QID (8.70±2.2 vs. 5.74±2.2, p = 0.022) treatment groups. The average number of weekly loose/watery stools were not different between the crofelemer BID and QID treatment groups (p = 0.84). This study showed that crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the need for any loperamide administration.
... Crofelemers are approved by the US FDA for the symptomatic relief of noninfectious diarrhea in adult HIV/AIDS patients on antiretroviral therapy. Crofelemers have demonstrated safety and efficacy in people living with HIV/AIDS in numerous clinical studies when compared with placebo in reducing the frequency of loose/watery bowel movements as well as improvement in stool consistency (6,7,8,9). ...
Management guidelines for cancer therapy-related diarrhea (CTD) should be revised because newer targeted therapies have increased CTD burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib, a pan-HER tyrosine kinase inhibitor, approved for breast cancer treatment, causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal for patients with HIV receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence and severity of neratinib-induced diarrhea without loperamide in dogs. Female dogs received neratinib orally daily concomitantly with either matching placebo tablets (CTR) or crofelemer 125 mg delayed-release tablet two or four times/day (BID or QID) for 28 consecutive days. At the end of treatment, 37.5%, 75%, and 87.5% of the CTR, BID, and QID dogs were ‘responders’ defined as ≤7 loose/watery stools/week for at least 2 of 4 weeks (p<0.05). The average number of watery stools per week was 9, 6, and 6 in the CTR, BID, and QID groups, respectively (p<0.05). The average number of weeks with no loose/watery stools was 1.3, 2.1, and 2.3 for the CTR, BID, and QID groups, respectively (p<0.05). The weekly mean fecal scores and stool consistency were 5.1, 3.9, and 4.1 for the CTR, BID, and QID groups (p<0.05). In this 28-day preclinical study, crofelemer prophylaxis without loperamide reduced the incidence and severity of neratinib-associated diarrhea in female dogs by 30%.
Ethical Compliance
All procedures performed in studies involving canine participants were in accordance with the ethical standards of the institutional and/or national research committee and applicable Institutional Animal Care and Use Committee (IACUC).
... The structural diversity of flavonoids stems from variable substituent positions of the phenyl, variable numbers and positions of phenol groups on the aromatic rings, number and degree of glycosylation, and formation of flavonoid dimers and oligomers. Flavonoids are known to promote human health not only by reducing the risk factors of non-communicable diseases, including chronic inflammation 3 , hypertension 4 , diabetes 5 , cognitive impairment 6 , and diarrhea (Crofelemer) 7 , but also combating infectious diseases such as anti-urinary tract infection by A-type proanthocyanidins in cranberry 8 and potential antivirus (SARS-CoV-2) activity of amentoflavone (3′-8-biapigenin) and its derivatives 9 , which are active compounds in Ginkgo biloba (the oldest tree on the Earth). While flavone monomers are relatively abundant in fruits and vegetables and can be extracted on an industrial scale from agri-food by-products, flavonoid dimers and oligomers are minor components in plant biomass, and it is not economical to obtain them in a large scale from natural sources. ...
... Equations (7)(8) were applied to determine the mole fraction of conjugate pair from chemical shift of a specific carbon. The assignment of 13 C NMR of luteolin was further confirmed by HSQC and HMBC methods with 2D correlation with 1 H NMR ( Supplementary Figs. ...
Catalyzed oxidative C-C bond coupling reactions play an important role in the chemical synthesis of complex natural products of medicinal importance. However, the poor functional group tolerance renders them unfit for the synthesis of naturally occurring polyphenolic flavones. We find that molecular oxygen in alkaline water acts as a hydrogen atom acceptor and oxidant in catalyst-free (without added catalyst) oxidative coupling of luteolin and other flavones. By this facile method, we achieve the synthesis of a small collection of flavone dimers and trimers including naturally occurring dicranolomin, philonotisflavone, dehydrohegoflavone, distichumtriluteolin, and cyclodistichumtriluteolin. Mechanistic studies using both experimental and computational chemistry uncover the underlying reasons for optimal pH, oxygen availability, and counter-cations that define the success of the reaction. We expect our reaction opens up a green and sustainable way to synthesize flavonoid dimers and oligomers using the readily available monomeric flavonoids isolated from biomass and exploiting their use for health care products and treatment of diseases. Catalysed oxidative C-C bond formation reactions are important in the synthesis of natural products, but poorly tolerated by polyphenolic flavones. Here the authors report the reactivity of molecular oxygen in alkaline water without added catalyst for the synthesis of a collection of flavone dimers and trimers.
... Crofelemer regulates luminal chloride efflux and fluid secretion through the use-dependent inhibition of CFTR and CaCC chloride ion channels in the apical membrane of the intestinal mucosa [17] and is FDA-approved for adult patients with HIV with non-infectious diarrhea receiving antiretroviral therapy [18]. Due to its large molecular size and polarity, crofelemer acts mainly in the lumen and, thus, is typically well tolerated [17,[19][20][21]. Only a negligible amount is systemically absorbed following oral dosing in humans in the fasted or fed state [22]. ...
Purpose
To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel).
Methods
Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score).
Results
Fifty-one patients were randomized to crofelemer ( n = 26) or control ( n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea.
Conclusion
Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID.
Trial registration
Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.
... 14 In LMICs, parity can be high, so pregnancy is an additional risk factor. In addition, HIV-related chronic diarrhea can lead to HD. 15 Conservative management with fiber supplementation and mitigation of risk factors is the standard treatment for all causes of HD in these settings. Since rubber band ligation can be done in the outpatient setting, this is a popular HD treatment although sourcing rubber bands can be challenging. ...
Colorectal surgery (CRS) practice, training, and research differ between low- and middle-income countries (LMICs) and high-income countries due to disparity in resources. LMIC CRS is primarily done by general surgeons due to the paucity of fully trained colorectal surgeons. The majority of colon and rectal resections are done using open techniques, and laparoscopy and robotic platforms are only available in select private or academic centers. Multi-disciplinary teams are not available in most hospitals, so surgeons must have a broad knowledge base, and learn to adapt their practice. Formal CRS training opportunities through accredited post-residency fellowships and professional colorectal surgical associations are limited in LMICs. CRS is less established as an academic field, and less data are generated in LMICs. There are fewer staff and less dedicated funding for CRS research. However, LMIC colorectal surgeons and researchers can contribute valuable clinical findings especially on conditions of higher prevalence in their settings such as anal squamous cell carcinoma and obstetric fistulas. Effective surgical care for colorectal conditions requires significant investment in infrastructure, training, and governance in LMICs. This is critical to improve access to safe surgical care for all.
... In addition, AIDS can involve different systems of the body including skin, nervous system, lymph glands, lungs, mucous membrane, and gastrointestinal (GI) tract (1)(2)(3)(4). One of the common GI symptoms is diarrhea, particularly secretory diarrhea that can occur in all stages of HIV infection (5). This type of diarrhea can cause several complications and lead to death if left untreated (5-7). ...
... Crofelemer is a Food and Drug Administration (FDA)-approved drug for symptomatic relief of noninfectious diarrhea in adult patients living with HIV/AIDS receiving antiretroviral therapy [15]. Unlike other medications used for diarrhea, crofelemer exerts its antisecretory September 2016 displayed reduced hypermetabolism and the metastatic mass measuring 56.8 mm effects by negatively modulating the CFTR chloride channel and calcium-activated chloride channel at the luminal membrane of enterocytes [16] (Fig. 3). ...
... This novel mechanism of action helps restore the fluid and electrolyte balance in the GI tract, leading to symptomatic relief of noninfectious chronic diarrhea in adult HIV/AIDS patients and avoids the development of constipation often observed with opioids. Crofelemer also has negligible oral bioavailability, thus keeping the drug localized to the GI tract and minimizing any significant drug-drug interactions [15]. ...
Despite the efficacy of tyrosine kinase inhibitors (TKIs) across multiple cancers, side effects including treatment-related diarrhea can impede a patient’s ability to reach therapeutic doses or stay on therapy. Below, we present the case of a 72-year-old patient with metastatic papillary renal cell carcinoma recurrent despite nephrectomy. Over the course of treatment, the patient received multiple different tyrosine kinase inhibitors with varying efficacy. Treatment with the TKI cabozantinib after failure of two prior TKIs resulted in a clinical response with shrinkage of his nodal metastatic disease. However, the severe treatment-related diarrhea refractory to conventional management required both dose holds and dose reductions of cabozantinib. Off-label administration of crofelemer, a novel FDA-approved antidiarrheal agent, successfully controlled the treatment-related diarrhea and allowed resumption and partial dose increase of cabozantinib. This case suggests that crofelemer could be a viable therapeutic strategy to address TKI-induced diarrhea.
... The use of these approaches is limited by numerous adverse effect and financial constraints. As such, there has been an increase in adoption of alternative medicine approaches in the management of diarrheal diseases (Patel et al., 2013). Some of the antidiarrheal herbal drugs in use include but not limited to Idigofera spicata Forssk(Fabaceae) (Awe et al., 2011), Pyrenacantha staudtii (Engl.) ...
... (Zingiberaceae) (Wang et al., 2015). The increase in the adoption of herbal medicine is attributed to their availability, affordability, efficacy, and reduced side effects (Patel et al., 2013). The tubers of Tylosema fassoglense (Kotschy ex Schweinf.) ...
Tylosema fassoglense (TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts in-vivo and the putative mechanism (s) of action ex-vivo using Sprague-Dawley rats and New Zealand white rabbits respectively. The in-vivo antidiarrheal effects of the extract were evaluated in castor oil-induced diarrhea, the castor oil-induced enteropooling, and phenol red gastric motility tests. On the other hand, isolated rabbit’s jejunal segments were used to evaluate the spasmolytic effect of TFG on spontaneous contraction, in acetylcholine-induced contraction, in presence of 80mMK⁺, calcium chloride-induced contraction as well as in presence of the following antagonists: naloxone, methylene blue, L-NAME, prazosin, and propranolol in the ex-vivo studies. The data were express as Mean ± S.E.M and analyzed by one-way ANOVA and Tukey’s post hoc test in cases of significance which was set at p < 0.05. The extract was phytochemically characterized using Liquid chromatography Mass spectroscopy (LC-MS).The extract possessed significant inhibitory effect in the in-vivo experiments. The extract exhibited significant spasmolytic effect on both spontaneous contraction and in jejunal segment pre-contracted acetylcholine as well as in presence of 80mMK⁺ solution. It also attenuated the spasmogenic effect of various concentration of calcium chloride. The extract’s spasmolytic effect was, however, significantly attenuated in presence of several antagonists (methylene blue and L-NAME) but the adrenergic blockers (prazosin and propranolol) had no significant effect in the ex-vivo studies. LC-MS identified thirty compounds where Proathocyanidin (11.54%), Syringic acid (7.30%), and 4-Hydroxybenzoic acid (6.19%) had the highest percentage abundance. In conclusion, the results obtained in this study partially validate the traditional uses of the tubers of this plant species as an antidiarrheal. These antidiarrheal effects are probably mediated via modulation of nitrous oxide pathway, voltage gated calcium channels, and muscarinic receptors.
... FDA authorized Complera (FDC of emtricitabine/rilpivirine/tenofovir DF) in 2011 and Stribild (FDC of elvitegravir, cobicistat, emtricitabine, and tenofovirdisoproxilfumarate) in 2012 for the treatment of infected patients [93,94]. The end of 2012 presented an approval of crofelemer (Fulyzaq) to alleviate the diarrhea in HIV/AIDS patients on ART by FDA [95]. Successively many drugs were approved such as dolutegravir (Tivicay) a newer INSTI class of HIV drug in 2013 [96], INSTI elvitegravir (Vitekta) [97], pharmacokinetic enhancer (PE) cobicistat (Tybost) and FDC of abacavir sulfate, do-lutegravir, lamivudine (Triumeq) in 2014, FDC of atazanavir and cobicistat (Evotaz), lamivudine and raltegravir (Dutrebis), darunavir and cobicistat (Prezcobix), concluded with the combination of elvitegravir, cobicistat, emtricitabine, and tenofoviralafenamide (Genvoya) in 2015, FDC of emtricitabine and tenofoviralafenamide (Descovy) with FDC containing emtricitabine, rilpivirine, and tenofoviralafenamide (Odefsey) in 2016, and following to these, few of drugs like FDC of dolutegravir and rilpivirine (Juluca) and new FDC such as Biktarvy, Cimduo, Delstrigo, Symfi, Symfi Lo, Symtuza, and Temixys got an approval in 2017 and 2018, respectively [49,[98][99][100][101][102][103][104][105][106]. ...
Background
Today, HIV-1 infection has become an extensive problem to public health and a greater challenge to all working researchers throughout the world. Since the beginning of HIV-1 virus, several antiviral therapeutic agents have been developed at various stages to combat HIV-1 infection. But, the many of antiviral drugs are on the platform of drug resistance and toxicology issues, needs an urgent constructive investigation for the development of productive and protective therapeutics to make an improvement of individual life suffering with viral infection. As developing a novel agent is very costly, challenging and time taking route in the recent times.
Methods
The review summarized about the modern approaches of computational aided drug discovery to developing a novel inhibitor within a short period of time and less cost.
Results
The outcome suggests on the premise of reported information that the computational drug discovery is a powerful technology to design a defensive and fruitful therapeutic agents to combat HIV-1 infection and recover the lifespan of suffering one.
Conclusion
Based on survey of the reported information, we concluded that the current computational approaches is highly supportive in the progress of drug discovery and controlling the viral infection.
