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

Despite the fact that the prevalence of autism spectrum disorder (ASD) continues to rise, no effective medical treatments have become standard of care. In this paper we review some of the pathophysiological abnormalities associated with ASD and their potential associated treatments. Overall, there is evidence for some children with ASD being affected by seizure and epilepsy, neurotransmitter dysfunction, sleep disorders, metabolic abnormalities, including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and gastrointestinal disorders. Although evidence for an association between these pathophysiological abnormalities and ASD exists, the exact relationship to the etiology of ASD and its associated symptoms remains to be further defined in many cases. Despite these limitations, treatments targeting some of these pathophysiological abnormalities have been studied in some cases with high-quality studies, whereas treatments for other pathophysiological abnormalities have not been well studied in many cases. There are some areas of more promising treatments specific for ASD including neurotransmitter abnormalities, particularly imbalances in glutamate and acetylcholine, sleep onset disorder (with behavioral therapy and melatonin), and metabolic abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, and redox pathways. There is some evidence for treatments of epilepsy and seizures, mitochondrial and immune disorders, and gastrointestinal abnormalities, particularly imbalances in the enteric microbiome, but further clinical studies are needed in these areas to better define treatments specific to children with ASD. Clearly, there are some promising areas of ASD research that could lead to novel treatments that could become standard of care in the future, but more research is needed to better define subgroups of children with ASD who are affected by specific pathophysiological abnormalities and the optimal treatments for these abnormalities.

https://journals.sagepub.com/doi/pdf/10.4137/CMPed.S38337

Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes

Autism spectrum disorders (ASD) are characterized by impairments in language and communication development, social behavior, and the occurrence of stereotypic patterns of behavior and interests. Despite substantial speculation about causes of ASD, its exact etiology remains unknown. Recent studies highlight a link between immune dysfunction and behavioral traits. Various immune anomalies, including humoral and cellular immunity along with abnormalities at the molecular level, have been reported. There is evidence of altered immune function both in cerebrospinal fluid and peripheral blood. Several studies hypothesize a role for neuroinflammation in ASD and are supported by brain tissue and cerebrospinal fluid analysis, as well as evidence of microglial activation. It has been shown that immune abnormalities occur in a substantial number of individuals with ASD. Identifying subgroups with immune system dysregulation and linking specific cellular immunophenotypes to different symptoms would be key to defining a group of patients with immune abnormalities as a major etiology underlying behavioral symptoms. These determinations would provide the opportunity to investigate causative treatments for a defined patient group that may specifically benefit from such an approach. This review summarizes recent insights into immune system dysfunction in individuals with ASD and discusses the potential implications for future therapies.

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Immune Abnormalities in Autism Spectrum Disorder-Could They Hold Promise for Causative Treatment?

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.

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.

Autistic disorder is a severe neurodevelopment disorder characterized by a triad of impairments in reciprocal social interaction, verbal and nonverbal communication, and a pattern of repetitive stereotyped activities, behaviours and interests. There are strong lines of evidence to suggest that the immune system plays an important role in the pathogenesis of autistic disorder. The aim of this study was to analyze quantitative plasma concentration of immunoglobulin classes, and subclasses in autistic patients and their families. The investigation was performed retrospectively in 50 persons with autistic disorder in the Republic of Macedonia. Infantile autistic disorder was diagnosed by DSM-IV and ICD-10 criteria. Plasma immunoglobulin classes (IgM, IgA, and IgG) and subclasses (IgG1, IgG2, IgG3, and IgG4) were determined using Nephelometer Analyzer BN-100. Multiple comparisons for the IgA variable have shown statistically significant differences between three pairs: male autistic from the fathers (p = 0,001), female autistic from the mothers (p = 0,008), as well as healthy sisters from the fathers (p = 0,011). Statistically significant differences found between three groups regarding autistic disorder (person with autistic disorder, father/mother of a person with autistic disorder, and brother/sister) independent of sex belongs to IgA, IgG2, and IgG3 variables. Multiple comparisons for the IgA variable have shown statistically significant differences between children with autistic disorder from the fathers and mothers (p < 0,001), and healthy brothers and sisters from the fathers and mothers (p < 0,001). Comparison between healthy children and children with autistic disorder from the same family should be tested for immunoglobulin classes and subclasses in order to avoid differences between generations.

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Prevalence of resistence to activated protein C (APC-resistance) in blood donors in Kosovo.

Context: Several studies have reported that thrombophilia is responsible for recurrent pregnancy loss (RPL). AIMS: The aim of this study was to evaluate the prevalence and role of inherited thrombophilia in early pregnancy loss, specifically in the first trimester. Materials and Methods: A total of 104 women (patients) with a history of two or more miscarriages during the first trimester of pregnancy and 110 women (controls) who had experienced two or more births without a miscarriage were included in this study. In both groups, we determined the biological activities of antithrombin III (ATIII) and protein C (PC) using the chromogenic method and the biological activity of protein S (PS) and the activated protein C resistance (APCR) were examined using a clotting method. Results: In the patient group, deficiencies of ATIII, PC, and PS were detected in 3 (2.88%), 4 (3.85%), and 6 (5.77%) cases, respectively. In the control group, ATIII (0%) deficiencies were not detected, and deficiencies for PC (0.9%) and PS (0.9%) were each detected in 1 patient. APCR was detected in 9 patients (8.65%) and 4 control subjects (3.63%). Conclusion: Based on our results, we can conclude that thrombophilia is a causal factor for miscarriages in the first trimester of pregnancy, although there are the conflicting data in the literature.

Prevalence and role of antithrombin III, protein C and protein S deficiencies and activated protein C resistance in Kosovo women with recurrent pregnancy loss during the first trimester of pregnancy

Ermira I Miftari

Papers

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

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

Prevalence of resistence to activated protein C (APC-resistance) in blood donors in Kosovo.

Prevalence and role of antithrombin III, protein C and protein S deficiencies and activated protein C resistance in Kosovo women with recurrent pregnancy loss during the first trimester of pregnancy