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Effects of Antithrombotic and Results of Drug Screening
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
The group of agents (2.a in the listing above) is based on the favorable effect of PGI2 (epoprostenol, prostacyclin) against platelet aggregation by stimulating adenylate cyclase. This results in an increase of the powerful endogenous antiaggregant cAMP. Unfortunately, prostacyclin alone is chemically unstable, possesses a very short biological half-life, and has to be administered in infusions. In addition, tachyphylaxis develops rapidly and the drug may exert serious side effects. Therefore, a search was started for more stable analogues with a prolonged effect and devoid of side effects. Numerous drugs were tested, including a carbacyclin derivative, iloprost (ZK 36,374, Euprostil®), TRK-100, CG 4203, and GG 4305. The effort has only been partially successful since the agents are still unsuitable for prolonged thrombosis prevention and could be used as short-term antithrombotics only, e.g., in hemodialysis and cardiopulmonary bypass, often in place of heparin. Meanwhile, their main application is in indications other than antithrombotic.
Control of Uterine Contractility: Human Tissue
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
It is unlikely that tissue from preterm gestations will be routinely available without prior pharmacologic intervention during the pregnancy. Preterm labor in the United States is often treated with beta-adrenergic agonists. This therapy is clinically seen to exhibit tachyphylaxis. Tachyphylaxis to isoproterenol was seen to occur on the time-scale of minutes with strips of pregnant human uterine tissue.4 Chronic treatment of preterm pregnancies leads to a significant increase in phosphodiesterase,5 which may contribute to the clinically observed decrease in effectiveness of beta-adrenergic agonists on the time scale of days to weeks. Studies concerned with adrenergic receptors or intracellular cAMP must control for prior adrenergic treatment.
Non-Surgical Management of Thyroid Cancer
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
If a patient responds favourably to a twice or three times daily subcutaneous administration of octreotide, a synthetic somatostatin analogue, with a reduction in diarrhoea frequency or severity, then they can be commenced on a monthly depot preparation. With prolonged use, there is a risk of tachyphylaxis developing with loss of symptomatic benefit. However, if symptom control deteriorates, it is important to consider if disease progression is the cause before attributing the change to tachyphylaxis. Octreotide and lanreotide have a different spectrum of somatostatin receptor blockade. Side effects of the somatostatin analogues include gastrointestinal disturbances, such as anorexia, nausea, vomiting, abdominal pain, flatulence, diarrhoea and steatorrhoea, and rarely with long-term use gallstones may occur. Abnormalities of glucose metabolism may also occur. Local reactions at the site of administration may be seen and rotation of the injection site is recommended.
The efficacy and safety of adjunctive intranasal esketamine treatment in major depressive disorder: a systematic review and meta-analysis
Published in Expert Opinion on Drug Safety, 2022
Muhammad Youshay Jawad, Joshua D. Di Vincenzo, Felicia Ceban, Saja Jaberi, Leanna M.W. Lui, Emily S. Gillissie, Yazen Alnafeesi, Joshua D. Rosenblat, Roger S. McIntyre
Adjunctive IN Esketamine is provided in specialized clinics and cannot be used at home across the United States and Canada. The dissociation, sedation, and overall change in adverse effect parameters make it a time-consuming intervention with proper phases of induction, preparation, and discharge [38]. A concern has been raised that long-term treatment with adjunctive IN Esketamine might lead to tachyphylaxis (i.e. progressive decrease in efficacy with repeated use) [28]. Long-term SUSTAIN-II trial has reported either continued decrease in MADRS scores or maintenance of decreased MADRS scores achieved at the end of induction phase showing little tachyphylaxis with maintenance adjunctive IN Esketamine treatment for one year. The SUSTAIN-3 trial is an open-label long-term extension study ascertaining the efficacy and safety of adjunctive IN Esketamine treatment over the course of 5 years. This trial can answer concerns related to tachyphylaxis in a more comprehensive and definitive way; the study is currently underway (NCT02782104).
Osilodrostat for the treatment of Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
Osilodrostat will prove a valuable addition as adjunctive therapy for patients who experience remission after surgery. Its role as a potential first-line agent for those unable to tolerate surgery is intriguing, yet this patient population was underrepresented in clinical trials as a combined six patients did not undergo surgery prior to intervention (0 [0%], 2 (10.5%), and 4 (12%) respectively in LINC1, LINC2, and LINC3) [8–10]. The safety profile of osilodrostat appears improved or similar to that of other adrenal steroidogenesis inhibitors, and appears to be more effective than current pituitary-directed agents and glucocorticoid receptor antagonists. The safety and efficacy of combination medication treatment with osilodrostat should be a point for further study exploration. Interestingly, Asian patients had a 20% higher bioavailability than the average Caucasian patient; although specific dosing recommendations are not suggested for specific demographics, clinicians should anticipate and monitor accordingly [56]. Although TSS remains the standard initial treatment for CD, medical treatment with osilodrostat provides a noninvasive means that deserves greater exploration and representation in future clinical trials with adequate power. Lastly, more information is needed to identify whether tachyphylaxis development is a concern that could lead to treatment failure.
Selexipag for the treatment of pulmonary arterial hypertension
Published in Expert Review of Respiratory Medicine, 2021
Léon Genecand, Julie Wacker, Maurice Beghetti, Frédéric Lador
IV epoprostenol is a synthetic PGI2. It was the first treatment that demonstrated 6-min walk distance (6MWD) and hemodynamic improvement in PAH patients [3,10] and it is the only treatment that showed direct reduction of mortality in a single randomized trial [10]. Its effect was confirmed in specific PAH populations including CTD-PAH [11]. However IV epoprostenol has a short half-life (3–5 minutes) and was initially stable at room temperature for only 8 hours [1]. Thermostable formulations now exist, avoiding the necessity of cooling, but still require a continuous administration with a pump device in a tunneled catheter [1]. Tachyphylaxis necessitating increasing dose is frequently observed [3]. While thermostable formulations are less cumbersome, IV epoprostenol treatment is still inconvenient, painful, and has potential severe complications and implications including infection, catheter obstruction, thrombotic events, and the need for an anticoagulant therapy [1,10]. In addition, a rebound effect can be observed when IV epoprostenol is abruptly stopped, leading to clinical worsening and even death [1,10]. This can be observed in case of dysfunction of the drug delivery system [10].