In the present work, we report compilation and analysis of 245 drugs, including small and macromolecules approved by the U.S. FDA from 2015 until June 2020. Nearly 29% of the drugs were approved for the treatment of various types of cancers. Other major therapeutic areas of focus were infectious diseases (14%); neurological conditions (12%); and genetic, metabolic, and cardiovascular disorders (7-8% each). Itemization of the approved drugs according to the year of approval, sponsor, target, chemical class, major drug-metabolizing enzyme(s), route of administration/elimination, and drug-drug interaction liability (perpetrator or/and victim) is presented and discussed. An effort has been made to analyze the pharmacophores to identify the structural (e.g., aromatic, heterocycle, and aliphatic), elemental (e.g., boron, sulfur, fluorine, phosphorus, and deuterium), and functional group (e.g., nitro drugs) diversity among the approved drugs. Further, descriptor-based chemical space analysis of FDA approved drugs and several strategies utilized for optimizing metabolism leading to their discoveries have been emphasized. Finally, an analysis of drug-likeness for the approved drugs is presented.

U.S. FDA Approved Drugs from 2015-June 2020: A Perspective

Peripheral nerve injuries (PNI) resulting from trauma can be severe and permanently debilitating. Despite the armamentarium of meticulous microsurgical repair techniques that includes direct repair, grafting of defects with autograft nerve, and grafting with cadaveric allografts, approximately one-third of all PNI demonstrate incomplete recovery with poor restoration of function. This may include total loss or incomplete recovery of motor and/or sensory function, chronic pain, muscle atrophy, and profound weakness, which can result in lifelong morbidity. Much of this impaired nerve healing can be attributed to perineural scarring and fibrosis at the site of injury and repair. To date, this challenging clinical problem has not been adequately addressed. In this review, we summarize the existing literature surrounding biological aspects of perineural fibrosis following PNI, detail current strategies to limit nerve scarring, present our own work developing reliable nerve injury models in animal studies, and discuss potential future studies which may ultimately lead to new therapeutic strategies.

Peripheral nerve injury, scarring, and recovery.

Electrospun polymeric micro/nanofibrous scaffolds for long-term drug release and their biomedical applications.

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants

Introduction Medications cannot exert their effect if not taken as prescribed by patients. Our objective was to summarise the observational evidence on adherence to oral anticoagulants (OACs) among patients with atrial fibrillation (AF). Methods In March 2019, we systematically searched PubMed/Medline, Embase, CINAHL and PsycINFO (from inception) for observational studies measuring adherence, its determinants and impacts in patients with AF. Mean adherence measures and corresponding proportions of adherent patients were pooled using random effects models. Factors shown to be independently associated with adherence were extracted as well as the clinical and economic outcomes of adherence. Results We included 30 studies. Pooled mean adherence scores of over half a million patients with AF 6 months and 1 year after therapy initiation were 77 (95% CI: 74–79) and 74 (68–79) out of 100, respectively. Drug-specific pooled mean adherence score at 6 months and 1 year were as follows: rivaroxaban: 78 (73–84) and 77 (69–86); apixaban: 77 (75–79) and 82 (74–89); dabigatran: 74 (69–79) and 75 (68–82), respectively. There was inadequate information on warfarin for inclusion in meta-analysis. Factors associated with increased adherence included: older age, higher stroke risk, once-daily regimen, history of hypertension, diabetes or stroke, concomitant cardiovascular medications, living in rural areas and being an experienced OAC user. Non-adherent patients were more likely to experience stroke and death, and incurred higher medical costs compared with patients with poor adherence. Conclusions Our findings show that up to 30% of patients with AF are non-adherent, suggesting an important therapeutic challenge in this patient population.

https://bmjopen.bmj.com/content/bmjopen/10/4/e034778.full.pdf

Adherence to oral anticoagulants among patients with atrial fibrillation: a systematic review and meta-analysis of observational studies.

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs.

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New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.

Traumatic injuries of the peripheral nerves are very common. Surgical repair of the damaged nerve is often complicated by scar tissue formation around the damaged nerve itself. The main objective of this study is to present the recent data from animal experimental studies where pharmacological topical agents are used at the site of peripheral nerve repair. Some of the most commonly topical agents used are tacrolimus (FK506), hyaluronic acid and its derivatives, and melatonin, whereas methylprednisolone and vitamin B12 have been used less. These studies have shown that the abovementioned substances have neuroprotective and neuroregenerative properties though different mechanisms. The successes of the regenerative process of the nerve repair in experimental research, using topical agents, can be evaluated using variety of methods such as morphological, electrophysiologic, and functional evaluation. However, most authors agree that despite good microsurgical repair and topical application of these substances, full regeneration and functional recovery of the nerve injured are almost never achieved.

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Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process

Scar formation after injured peripheral nerve repair is a significant clinical problem because it prevents nerve regeneration. The aim of this study was to investigate and compare the effects of hyaluronic acid (HA) and tacrolimus (FK506) on peripheral nerve regeneration in rabbits after the drugs were topically applied at the site of nerve repair. Thirty adult male European rabbits (Oryctolagus cuniculus), ranging in weight from 2.5 to 3 kg, were randomly assigned to three groups: the HA and FK506 groups comprised the experimental groups, while the saline group served as the control. At week 12, macroscopic and microscopic evaluations were performed and analyzed. In general, the macroscopic evaluations (skin and muscle fascia closure and nerve adherence), microscopic evaluations (cellular components, scar tissue formation index, and histomorphological organization), and measurements of nerve diameter and gastrocnemius muscle wet weight demonstrated the positive effects of topical application of these pharmacological agents (HA and FK506); HA and FK506 prevented scar formation and enhanced nerve regeneration. No significant differences in the parameters described above were observed between the HA and FK506 groups (P > 0.05). However, significant differences were observed between both the HA and FK506 groups and the saline group (P < 0.05). Based on our findings, topical application of HA and FK506 exhibits equally positive effects, preventing perineural scar formation and enhancing nerve regeneration after peripheral nerve repair.

Effects of hyaluronic acid and tacrolimus on the prevention of perineural scar formation and on nerve regeneration after sciatic nerve repair in a rabbit model

Background: Chronic subdural hematoma (CSDH) is frequent pathology in neurosurgical practice. The aim of this study is to present the first series of patients with CSDH, who got surgically treated in Clinic of Neurosurgery, University Clinical Center of Kosovo. Materials and Methods: This is a retrospective study that included 137 patients with CSDH who had been treated during the period 2008-2012. The data were collected and analyzed from the archives and protocols of the University Clinical Center of Kosovo. Patients were analyzed in many aspects such as age, gender, etiological factors, clinical features, localization, diagnoses, methods of surgical interventions, recurrences and mortality of patients. Results: From 137 patients with CSDH, 106 (77.3%) were males and 31 (22.7%) females. Average age of patients was 62.85 years. Analyzed according to the decades, the highest number of causes with CSDH was between 70 and 79 years (46%). The head trauma has been responsible for CSDH in 88 patients (64.3%), while the main symptom was headache (92 patients or 67.1%). One burr-hole trepanation with closed drainage system has been used in majority of cases (in 101 patients or 73.7%). The recurrence of CSDH was 6.5%, whereas mortality 2.9%. Conclusion: CSDH is more common in elderly patients. The male-female ratio is 3.4:1. Like other authors we also think that treatment with one burr-hole and drainage is a method of choice, because of its simplicity and safety.

Surgical treatment of 137 cases with chronic subdural hematoma at the university clinical center of Kosovo during the period 2008-2012.

UNLABELLED Recovery following nerve repair can be evaluated based on electrophysiological and morphological assessments of biomechanical properties. This study compared the effects of topical hyaluronic acid (HA), tacrolimus (FK-506) or saline administration on the biomechanical properties of the sciatic nerve at 12 weeks after nerve repair. MATERIALS AND METHODS Eighteen male European rabbits (Oryctolagus cuniculus) (weight from 2.5 to 3 kg) were randomly assigned to one of the following experimental groups (six animals per group): Saline, HA, or FK-506. The non-transected left leg was used as a control group (eighteen sciatic nerves). Biomechanical assays were performed and statistically analyzed. RESULTS The average maximal load, elastic limit load, maximal stress, and elastic limit strain of the control group were significantly different (P 0.05). At 12 weeks after nerve repair, Saline, HA, and FK-506 groups displayed average maximal stress values that were 72.6%, 77.38%, and 73.8% of those in the control group (100%), respectively. CONCLUSION The biomechanical properties of the HA and FK-506 groups were similar to those of the saline group at 12 weeks after nerve repair.

Shkelzen B Duci

Papers

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.

Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process

Effects of hyaluronic acid and tacrolimus on the prevention of perineural scar formation and on nerve regeneration after sciatic nerve repair in a rabbit model

Surgical treatment of 137 cases with chronic subdural hematoma at the university clinical center of Kosovo during the period 2008-2012.

Biomechanical properties of the sciatic nerve following repair: effects of topical application of hyaluronic acid or tacrolimus.