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Analgesics during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Rofecoxib is a cyclooxygenase-2 (COX-2) selective analgesic. No studies of congenital anomalies in offspring exposed to rofecoxib during embryogenesis have been published. Premature closure of the ductus arteriosus is a theoretical risk of maternal therapy with rofecoxib because of the pharmacologic action of the drug. Rofecoxib (Vioxx) was withdrawn from the market in September 2004 because an increased risk of myocardial infarction or stroke was found. Among 109 infants exposed to rofecoxib during pregnancy the frequency of major congenital anomalies was not increased (Kallen, 2019).
Errors in Toxicology
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Clinical trials are the cornerstone of pharmaceutical development, with the intention of demonstrating the safety and efficacy of new medicines. Each successive stage of development is supported by prior trial in nonclinical test systems–in vitro, in silico, and in vivo–with the intention of revealing any toxicity that may be relevant to human volunteers and/or patients. These are especially important in the phase I studies (first in man), where dose choice is critical; however, although single doses may be given, successfully repeated dosing may be associated with severe adverse effects that have not been predicted by the nonclinical work. This lack of predictive success may be due to factors such as misinterpretation of the data or to species differences. Adverse effects may manifest themselves even after extensive nonclinical and clinical study, as shown by the case of Vioxx (rofecoxib), a nonsteroidal anti-inflammatory drug that was used to treat conditions such as osteoarthritis and acute pain. Despite widespread acceptance, rofecoxib was withdrawn from the market due to increased risk of heart attack and stroke, associated with long-term use at high doses, effects that were not predicted by the nonclinical or clinical studies. One factor to bear in mind here is that the number of animals and patients studied before marketing a new medicine is authorized is far lower than the number of patients to whom the drug is actually given following open sale, meaning that the ability to detect rare events is limited.
Cancer pain in older people
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
Rofecoxib is well absorbed after oral administration, with a plasma peak concentration at two to four hours. The plasma half-life is approximately 16–18 hours and elimination is almost entirely by metabolism by noncytochrome enzymes in the liver, resulting in inactive derivatives which are excreted in the urine. Studies of patients with osteoarthritis or rheumatoid arthritis have shown rofecoxib to have similar efficacy to diclofenac and naproxen, respectively.128, 129
The beneficial effect of salubrinal on neuroinflammation and neuronal loss in intranigral LPS-induced hemi-Parkinson disease model in rats
Published in Immunopharmacology and Immunotoxicology, 2022
Fatma Nihan Cankara, Meliha Sümeyye Kuş, Caner Günaydın, Sinan Şafak, Süleyman Sırrı Bilge, Ozlem Ozmen, Emine Tural, Arjan Kortholt
Our results also revealed that the increased COX-2 immunoreactivity after LPS injection was attenuated by salubrinal treatment, which contrasts with previously published results. Choi et al. [40] have shown that salubrinal increases COX-2 and iNOS expression in an intestinal inflammatory model. Although LPS is a strong inducer of COX-2 expression, ERS is a negative modulator of COX-2 expression [41]. LPS is a very potent inflammatory stimulus that both directly and indirectly increases COX-2 levels, which suppressed with salubrinal treatment in our study. Additionally, Soto et al. [42] showed that cotreatment of rofecoxib, a COX-2 selective nonsteroidal anti-inflammatory drug, improved the use and potency of salubrinal. However, they also concluded that these effects differ depending on the salubrinal treatment longevity. Therefore, as seen in our study, repetitive salubrinal treatment might have different effects on COX-2 activity, which needs further investigations.
Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
Ariana A. Entezari, Adam E. Snook, Scott A. Waldman
Multiple epidemiological studies have correlated the long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) with a lowered risk of colorectal cancer [73,74]. Thus, the NSAID sulindac reduces both tumor count and tumor burden in a carcinogen (azoxymethane) colon tumorigenesis model, through cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2)-dependent and independent mechanisms [75,76]. Furthermore, the COX-2 inhibitor celecoxib decreases rectal adenomas by 28% in familial adenomatous polyposis (FAP) patients and was approved for chemoprevention in that population. However, clinical trials of a similar COX-2 inhibitor, rofecoxib, produced unexpected cardiovascular toxicity, dampening enthusiasm for the use of NSAIDs to prevent and treat colon cancer [73]. Further studies of NSAIDs revealed the possibility of COX-1/-2-independent mechanisms of inhibition of tumor formation. For example, the COX-2 inhibitor NS-398 induces apoptosis in human cell lines regardless of change in COX-2 protein expression [77]. Furthermore, active metabolites of sulindac, which do not inhibit COX-1/-2, increase apoptosis in cancer cell lines [78]. Thus, NSAID metabolites or derivatives that do not inhibit COX-1 or COX-2 were explored further as a safe and effective therapeutic to treat and prevent colon cancer.
Evaluation of nanoscaled dual targeting drug-loaded liposomes on inhibiting vasculogenic mimicry channels of brain glioma
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2021
Hong-Jun Xie, NorBu Zhan-Dui, Jing Zhao, A. G. A. Er-Bu, Pu Zhen, DongZhi ZhuoMa, Tre Sang
Daunorubicin is widely used in treating a variety of cancers. The underlying mechanism that daunorubicin takes effects is mainly by interfering DNA and RNA synthesis in the cellular nuclei [21]. Rofecoxib is a cyclooxygenase 2 selective inhibitor, which is used for the treatment of inflammations. Increasing evidence has exhibited that rofecoxib could inhibit the formation of VM channels in the tumour tissues [22]. In this study, a type of dual targeting drug-loaded lipid vesicles was developed by modifying the liposomes with two functional materials, TPGS1000–GLU and DSPE–PEG2000–GGPFVYLI. The constructed nanoscaled liposomes could be transported across the BBB by via receptor-mediated endocytosis and adsorptive mediated endocytosis, thereby eliminating brain glioma by triggering their necrosis and apoptosis.