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Mechanisms of triazole resistance in Aspergillus fumigatus.
Nywening, AV, Rybak, JM, Rogers, PD, Fortwendel, JR
Environmental microbiology. 2020;(12):4934-4952
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Abstract
The ubiquitous fungal pathogen Aspergillus fumigatus is the primary cause of opportunistic mould infections in humans. Aspergilli disseminate via asexual conidia passively travelling through air currents to germinate within a broad range of environs, wherever suitable nutrients are found. Though the average human inhales hundreds of conidia daily, A. fumigatus invasive infections primarily affect the immunocompromised. At-risk individuals can develop often fatal invasive disease for which therapeutic options are limited. Regrettably, the global insurgence of isolates resistant to the triazoles, the frontline antifungal class used in medicine and agriculture to control A. fumigatus, is complicating the treatment of patients. Triazole antifungal resistance in A. fumigatus has become recognized as a global, yet poorly comprehended, problem. Due to a multitude of factors, the magnitude of resistant infections and their contribution to treatment outcomes are likely underestimated. Current studies suggest that human drug-resistant infections can be either environmentally acquired or de novo host selected during patient therapy. While much concerning development of resistance is yet unknown, recent investigations have revealed assorted underlying mechanisms enabling triazole resistance within individual clinical and environmental isolates. This review will provide an overview of triazole resistance as it is currently understood, as well as highlight some of the prominent biological mechanisms associated with clinical and environmental resistance to triazoles in A. fumigatus.
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2.
Clinical Pharmacokinetics and Drug Interactions of Doravirine.
Wilby, KJ, Eissa, NA
European journal of drug metabolism and pharmacokinetics. 2018;(6):637-644
Abstract
Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor that has demonstrated a good efficacy and safety profile in clinical trials. It has a therapeutic profile that makes it an attractive option for treatment of HIV-1 infection. As such, there has been an increase in the published literature regarding the pharmacokinetics of doravirine and potential for drug-drug interactions. This review aimed to identify pharmacokinetic literature pertaining to doravirine, used findings from the literature to summarize its pharmacokinetic profile, and finally evaluated literature describing actual and potential drug interactions. Review findings show doravirine is well-absorbed, exhibits moderate protein binding activity, and is extensively metabolized by cytochrome P450 enzymes (specifically CYP3A). It has an elimination half-life of 12-21 h. Gender, age, moderate hepatic impairment, and co-administration with food did not greatly alter doravirine's pharmacokinetic profile. Drug interaction studies have shown doravirine does not affect the pharmacokinetics of dolutegravir or atorvastatin but may have its pharmacokinetics altered by rifampicin (rifampin) and other rifamycins (CYP3A inducers) and ritonavir (CYP3A inhibitor). No clinically significant interactions were noted between doravirine and an antacid (aluminum-magnesium), pantoprazole, ledipasvir/sofosbuvir, or elbasvir/grazoprevir. Further study is needed to better understand doravirine's efficacy and safety profile when co-administered with other agents known to be CYP inducers or inhibitors.
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Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy.
Donald, BJ, Surani, S, Deol, HS, Mbadugha, UJ, Udeani, G
Drug design, development and therapy. 2017;:3559-3566
Abstract
Community-acquired bacterial pneumonia (CABP) is a leading cause of death worldwide. However, antibacterial agents used to treat common pathogens in CABP are marked by adverse drug events and increasing antimicrobial resistance. Solithromycin is a new ketolide antibiotic, based on the macrolide antibiotic structure, being studied for use in CABP. It has efficacy in vitro against the common causative pathogens in CABP including Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens. In Phase II and Phase III clinical trials, it has been demonstrated efficacious as a single agent for treatment of CABP with an apparently milder adverse event profile than alternative agents.
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The use of aromatase inhibitors in boys with short stature: what to know before prescribing?
Linardi, A, Damiani, D, Longui, CA
Archives of endocrinology and metabolism. 2017;(4):391-397
Abstract
Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.
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5.
Azole-Resistant Aspergillosis: Epidemiology, Molecular Mechanisms, and Treatment.
Chowdhary, A, Sharma, C, Meis, JF
The Journal of infectious diseases. 2017;(suppl_3):S436-S444
Abstract
Aspergillus fumigatus remains the most common species in all pulmonary syndromes, followed by Aspergillus flavus which is a common cause of allergic rhinosinusitis, postoperative aspergillosis and fungal keratitis. The manifestations of Aspergillus infections include invasive aspergillosis, chronic pulmonary aspergillosis and bronchitis. Allergic manifestations of inhaled Aspergillus include allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Triazoles are the mainstay of therapy against Aspergillus infections for treatment and prophylaxis. Lately, increased azole resistance in A. fumigatus has become a significant challenge in effective management of aspergillosis. Earlier studies have brought to light the contribution of non-cyp51 mutations along with alterations in cyp51A gene resulting in azole-resistant phenotypes of A. fumigatus. This review highlights the magnitude of azole-resistant aspergillosis and resistance mechanisms implicated in the development of azole-resistant A. fumigatus and address the therapeutic options available.
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Review of empagliflozin monotherapy for previously untreated patients with type 2 diabetes mellitus: Comparison with sitagliptin.
Cornell, S
Postgraduate medicine. 2015;(3):277-81
Abstract
This Practice Pearl provides a review and brief commentary of the 24-week, double-blind, parallel-group, randomized, Phase III study by Roden et al., which assessed the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin, 10 mg or 25 mg as monotherapy, versus placebo and the dipeptidyl peptidase-4 inhibitor sitagliptin, in previously untreated patients with type 2 diabetes mellitus (T2DM). Compared to placebo, empagliflozin improved glycemic control, with additional benefits on bodyweight and systolic blood pressure, versus placebo and sitagliptin. Treatment was well tolerated. The authors concluded that empagliflozin is a potential new approach to treat patients with T2DM who are inadequately controlled with diet and exercise alone. This paper advances our understanding of empagliflozin, which so far, appears to be a promising therapeutic option for the management of patients with T2DM.
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7.
Aceruloplasminaemia: a rare but important cause of iron overload.
Doyle, A, Rusli, F, Bhathal, P
BMJ case reports. 2015
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Abstract
We present a case of a 20-year-old man referred to our service with iron overload and mildly deranged liver biochemistry. Although liver histopathology was consistent with haemochromatosis, iron studies were not consistent with this diagnosis. Serum ceruloplasmin levels were undetectable, leading to a diagnosis of aceruloplasminaemia. Unlike other iron overload disorders, neurological complications are a unique feature of this illness, and often irreversible, once established. The patient was treated with iron chelation prior to the onset of neurological injury, and experienced progressive normalisation of his ferritin and liver biochemistry. This is one of the youngest diagnosed cases in the published literature and, crucially, was a rare case of diagnosis and treatment prior to the onset of neurological sequelae. This is presented alongside a review of previously published cases of aceruloplasminaemia, including responses to iron chelation therapy.
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Deferasirox nephrotoxicity-the knowns and unknowns.
Díaz-García, JD, Gallegos-Villalobos, A, Gonzalez-Espinoza, L, Sanchez-Niño, MD, Villarrubia, J, Ortiz, A
Nature reviews. Nephrology. 2014;(10):574-86
Abstract
In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.
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Enantiopure 1,2,3-triazolyl-β-amino acids via click cycloaddition reaction on racemic alkynyl precursors followed by separation of stereoisomers.
Escudero-Casao, M, Vega-Penaloza, A, Juaristi, E
Current topics in medicinal chemistry. 2014;(10):1257-70
Abstract
In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, β-peptides incorporating β2- and β3-amino acids (the higher homologs of natural α-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to β-amino acids were prepared selectively from the corresponding alkynyl-β2-amino acids according to Huisgen's copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating α-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation.
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10.
A case report of deferasirox-induced kidney injury and Fanconi syndrome.
Murphy, N, Elramah, M, Vats, H, Zhong, W, Chan, MR
WMJ : official publication of the State Medical Society of Wisconsin. 2013;(4):177-80
Abstract
Cases of kidney injury associated with the use of deferasirox chelation therapy during the course of treatment for iron overload have been reported infrequently. We present the case of a patient treated with deferasirox who had biopsy-proven tubular injury in the setting of clinical Fanconi syndrome. The patient required hospitalization for metabolic acidosis, electrolyte abnormalities, and associated symptoms. With supportive care and cessation of chelation therapy he improved, but has yet to fully recover. This is the first known case reporting biopsy-proven tubular damage in the setting of deferasirox use.