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Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
More than 10 years earlier, Baeckvall and his group (Pàmies and Baeckvall, 2001) developed an efficient kinetic resolution of racemic β-hydroxy nitriles via Candida antarctica lipase (Novozyme-435)-catalyzed transesterification in toluene at 80°C with 4-chlorophenyl acetate as acylating agent. A variety of racemic alkyl, aryl, and aryloxymethyl substituted β-hydroxy nitriles was efficiently transformed to the corresponding enantiomerically pure acetates. The combination with a Ru-complex-catalyzed alcohol racemization led to a DKR enabling the synthesis of enantiomerically pure acetates with ee’s up to 99%, and yields up to 85%. Examples are the synthesis of Denopamine and Propanolol precursors (see the below scheme). Denopamine is an orally administered drug acting as a β1 adrenergic receptor (ADRB1) agonist and used to treat angina as well as congestive heart failure and for clearing pulmonary edema. Propranolol, already detected 1964, belongs to the drug class of non-selective beta blockers. It is used to treat among others high blood pressure, cardiovascular hypertension, angina pectoris, tachyarrhythmia, myocardial infarction, or tachycardia and is administered intravenously or orally. The drug is on the World Health Organization’s List of Essential Medicines (WHO Model List of Essential Medicines (19th List)”; World Health Organization. April 2015).
Pain and controlled pain-relieving substances
Published in Jennifer Corns, The Routledge Handbook of Philosophy of Pain, 2017
Sunil Kumar Aggarwal, Katherine Pettus
Let us identify the pain-relieving substances in question. International law, beginning with the Single Convention on Narcotic Drugs (United Nations 1972/1961) organizes opioid analgesics used for the relief of moderate to severe pain (“drugs”) into “schedules,” which detail how and by whom these substances should be made available (which relationships are legitimate for medical consumption, if indeed they should be available at all). (See Chapter 34, this volume.) The drug control treaties assign the WHO, through its Expert Committee on Drug Dependence, to this scheduling task. The principle opioid analgesics are: morphine, diacetylmorphine (heroin), hydromorphone, oxycodone, fentanyl, and methadone. All except heroin are included in the WHO Model List of Essential Medicines. Unprocessed opium is still actively used in medicine in preparations known as paregoric and deodorized tincture of opium. Regarding non-opioids, one essential medication for both anesthesia and pain relief is ketamine, which some countries have chosen to control under domestic law, and which China has repeatedly, and unsuccessfully, petitioned to bring under international control, because of reported non-medical use in the region. Additionally, benzodiazepines such as lorazepam and diazepam, anxiolytics that help treat anxiety in burn patients and related types of patients in pain, synergistically improve the efficacy of opioid analgesics.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
In a recent development that has global implications, the WHO included a list of essential medicines in pain and palliative care in the WHO Model List of Essential Medicines. The 18th edition of the model list includes morphine in all its available formulations for the management of pain, with oxycodone and hydromorphone as substitutes [17].
Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children
Published in Expert Review of Clinical Pharmacology, 2018
H. Simon Schaaf, Anthony J. Garcia-Prats, Lindsay McKenna, James A. Seddon
The nitroimidazo-oxazole, delamanid (Deltyba, Otsuka Novel Products GmbH, Munich, Germany), previously known as OPC-67683 is another new drug shown to be effective when added to an MDR-TB regimen in a randomized, placebo-controlled phase 2b trial [67]. Delamanid is the first compound from a new drug class (nitro-dihydro-imidazooxazoles) that is bactericidal and specific to M. tuberculosis, including MDR strains. Following bioreduction within M. tuberculosis by the mycobacterial F420 system (as it is thought to be a prodrug), it inhibits mycolic acid biosynthesis. It has activity against both growing and dormant mycobacteria. A phase 3 randomized controlled trial of delamanid vs. placebo with an OBR for MDR-TB has recently been completed (NCT01424670) [41]; provisional results presented at the 48th Union World Conference on Lung Health in Guadalajara, Mexico, showed similar outcomes with or without delamanid under strict trial conditions, though shorter times to culture conversion were observed among those treated with delamanid. In April 2014, delamanid received conditional approval by the EMA based on phase 2b data – since then it has also been approved in Hong Kong, Japan, South Korea, Turkey, The Philippines, China, Indonesia, and India and filed in Peru and South Africa; dossiers are also reportedly being prepared for registration in Vietnam and Russia. It is also included in the complimentary list (with age restriction >6 years) of the WHO Model List of Essential Medicines (March 2017), the most effective and safe medicines needed in a health system.
Local anesthetics systemic toxicity association with exparel (bupivacaine liposome)- a pharmacovigilance evaluation
Published in Expert Opinion on Drug Safety, 2018
Local anesthetics have been an integral part of medical care for over 120 years. One of the local anesthetics, bupivacaine HCl, synthesized in 1957, has been in the clinical market since 1963. It is also on the list of WHO Model list of Essential medicines. A new liposomal formulation of bupivacaine – Exparel® (bupivacaine liposome) injectable suspension – was approved by FDA on 28 October 2011 [1] and has been in the clinical market since 2012. Exparel is indicated for administration into the surgical site to produce postsurgical analgesia.
Temporal trends in admissions for atrial fibrillation and severe bleeding in England: an 18-year longitudinal analysis
Published in Scandinavian Cardiovascular Journal, 2023
Samuel Seidu, Clare Gillies, Francesco Zaccardi, Katharine Reeves, Suzy Gallier, Kamlesh Khunti
Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice globally. It is associated with increased morbidity (measured by disability adjusted life years (DALYs)), mortality and healthcare resource utilisation [1]. With increasing population ageing and survival with chronic diseases, there has been a proportionate increase in the prevalence and incidence of AF, which justifies the use of the term “global epidemic” [2]. Among other clinical outcomes such as systemic embolism, AF is associated with about a five-fold increased risk of ischaemic stroke [3]. Primary prevention of AF has always been the ultimate goal, but this approach has been met with challenges because of huge knowledge gaps with respect to the pathophysiology of AF [1]. The role of anticoagulants for the prevention of stroke and systemic embolism in patients with AF is well established. The main challenges associated with anticoagulant therapy is achieving a balance between the threat of bleeding and the prevention of a disabling stroke. Vitamin K antagonists (VKAs) have been the first-choice treatment for stroke prevention in AF; warfarin remains the most commonly used anticoagulant and was the only one on the World Health Organization’s (WHO) Essential Medicines list (EML) [4] till recently [5]. Though VKAs are effective and cause substantial reductions in stroke, systemic embolism and all-cause mortality [6], they are associated with limitations which include the need for frequent monitoring and dose-adjustment and an increased risk of major bleeding events [7,8]. Since 2009, several new oral anticoagulants – direct oral anticoagulants (DOACs) – have been developed and approved for use by regulatory authorities [9–12]. The DOACs (comprising dabigatran, rivaroxaban, apixaban and edoxaban) have comparable efficacy and safety profiles with warfarin, but have several advantages such as rapid onset, fewer drug interactions, lower rates of bleeding and simplified treatment without the need for regular international normalised ratio (INR) monitoring [13]. Their use has increased substantially because of their efficacy in stroke or systemic embolism prevention in AF among the general population [14–16]. They have recently been successfully included in the 21st WHO Model List of Essential Medicines [5]. In 2014, the UK National Institute for Health and Care Excellence (NICE) guidelines recommended the use of DOACs for stroke prevention in patients with non-valvular AF in the UK. Though the DOACs are generally associated with decreased risk of bleeding complications [17], there have been recent concerns about bleeding risks attributed to them, especially with rivaroxaban [18]. With the widespread uptake of DOACs into clinical practice, trends in admissions for severe bleeding in AF have varied worldwide. Some studies have reported an increase in hospital admissions for bleeding attributable to DOACs [19,20], others have reported no significant increases in admissions for bleeding complications [21], whereas others have reported less admissions for bleeding complications [22]. Given the uncertainty in the evidence, we aimed to explore temporal trends in admissions for AF and severe bleeding associated with AF in England and their relation to the introduction of DOACs in 2014 in the UK.