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Analgesics during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Sulindac is an NSAID used to treat rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute shoulder pain. Major congenital anomalies were not increased in frequency (4.3 percent) among 69 infants born to women who used sulindac during the first trimester, which is not different from the general population (Rosa, unpublished data, Briggs et al., 2005). Sulindac is another of several NSAIDs that has been used as a tocolytic. Sulindac was superior to indomethacin for tocolysis in two studies sulindac had equivalent efficacy but fewer side effects than indomethacin (Carlan et al., 1992; Rasenen and Jouppila, 1995).
Medicines in neonates
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Sulindac had a comparable efficacy, as compared to indomethacin, in a case control study in 16 closely matched infants. Severe unexpected gastrointestinal complications were encountered in the sulindac group [83]. In a case report, fatal haemorrhagic gastritis was described after oral administration [84].
Drugs Affecting the Musculoskeletal System
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: It is better to be avoided during the 1st and 3rd Trimesters because the pregnancy experience in humans suggests a risk of pulmonary hypertension of the newborn, SABs, and congenital malformations linked to the use of Sulindac.
Formyl peptide receptor-1 (FPR1) represses intestinal oncogenesis
Published in OncoImmunology, 2023
Julie Le Naour, Léa Montégut, Yuhong Pan, Sarah Adriana Scuderi, Pierre Cordier, Adrien Joseph, Allan Sauvat, Valerio Iebba, Juliette Paillet, Gladys Ferrere, Ludivine Brechard, Claire Mulot, Grégory Dubourg, Laurence Zitvogel, Jonathan G. Pol, Erika Vacchelli, Pierre-Laurent Puig, Guido Kroemer
Mice bearing the truncation mutation Min (multiple intestinal neoplasia) in codon 850 of the gene Apc (adenomatous polyposis coli), referred to as ApcMin/+ mice, show constitutive overactivation of the Wnt pathway leading to intestinal carcinogenesis.23,24 We treated such mice with the pharmacological Fpr1 antagonist cyclosporin H (CsH) once per week for 8 weeks (i.p. at 30 mg/kg/mouse), alone or in combination with two treatment periods of the non-steroidal anti-inflammatory drug sulindac (Figure 5a), which is known to attenuate intestinal oncogenesis.25 Of note, sulindac has a pleiotropic effect (on inflammation, proliferation, and Wnt/ß-catenin signaling).26–28 CsH treatment increased the number of lesions (atypical hyperplasias or intestinal adenomas across the intestine) developing in ApcMin/+ animals as compared to untreated ApcMin/+ mice. This pro-tumorigenic CsH effect was abrogated by simultaneous sulindac treatment (Figure 5b,c), suggesting that Fpr1 inhibition contributes to the manifestation of atypical hyperplasias or intestinal adenomas via pro-inflammatory effects.
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
Forskolin is an AC activator that inhibits the growth of chemoresistant colon cancer cells. Low levels of forskolin combined with an inhibitor of the cAMP-selective PDE isotype 4 (PDE4) arrested growth of chemoresistant colon cancer cells. This action was thought to be mediated by cAMP levels elevated by the synergistic effect of a low-dose AC activator and PDE4 inhibitor [39]. Cilastozol, an oral anti-platelet drug that inhibits cAMP-selective PDE3, inhibits the motility and invasion of colorectal cancer cells by increasing cAMP levels [40]. Sulindac, a non-steroidal anti-inflammatory drug, has been studied in precancerous adenomas with promising results, but is not recommended for long-term use due to toxicities resulting from COX inhibition. However, evidence has suggested that sulindac’s anticancer activity is not through COX. Indeed, sulindac derivatives that were unable to bind COX, inhibited cGMP-degrading PDE5 and/or PDE10, activated cGMP/PKG signaling, and suppressed β-catenin to inhibit the growth of colon cancer cells [41].
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
Sulindac, a nonsteroidal anti-inflammatory used for the treatment of familial adenomatous polyposis, is a prodrug. It is converted by gut bacteria from a sulfoxide to sulindac sulfide, the active form of the drug, which is then absorbed (Duggan et al., 1977; Etienne et al., 2003) and metabolized by FMO3 back to the inactive sulfoxide and, then, to sulindac sulfone (Hamman et al., 2000). In patients with familial adenomatous polyposis undergoing treatment with sulindac, the FMO3 variants c.472G>A[p.(Glu158Lys)] and c.923A>G[p.(Glu308Gly)] are associated with regression of existing polyps and protection against adenoma formation, particularly in those homozygous for the compound variant p.[(Glu158Lys);(Glu308Gly)] (Hisamuddin et al., 2004, 2005). Both variants decrease the ability of FMO3 to catalyze the oxygenation of sulindac in vitro (Hamman et al., 2000) and healthy individuals homozygous for p.[(Glu158Lys);(Glu308Gly)] metabolize the active drug more slowly than those homozygous for the ancestral allele (Tang et al., 2017). It is thought that reduction of FMO3 activity in vivo, as a consequence of these variants, would result in higher, more persistent concentrations of active drug, leading to increased drug efficacy and a positive effect on clinical outcome.