New Class Of Medications Research Articles

Physician experiences with sodium-glucose cotransporter (SGLT2) inhibitors, a new class of medications in type 2 diabetes, and adverse effects.

The primary aim of our study is to identify physicians who have witnessed a complication attributed to sodium-glucose cotransporter (SGLT2) inhibitors. The secondary aim is to determine the type, severity, and setting of the event (inpatient versus outpatient). Diabetes is an increasing public health burden with 9.9% of Canadians expected to be diagnosed with it in 2020. A prominent change with respect to treatment options since the publication of the revised Diabetes Canada guidelines in May 2016 concerned the SGLT2 inhibitors. Their favorable clinical profile has increased interest among clinicians, but there is still reason for caution. Because these drugs are new, the balance of benefits versus risks is not well understood. We conducted a cross-sectional survey of all in-practice physicians (excluding pediatricians). Data were collected through an online survey. Our survey identified 154 physicians who have identified one or more adverse drug reactions (ADRs) related to SGLT2 inhibitor use. A total of 173 ADRs were identified. In total, 20.6% of family physician respondents had witnessed one or more ADRs. The most common complication is mycotic infection (82 cases) with 47% identified as a low level of severity and occurring mostly in the outpatient setting. The second most common complication is diabetic ketoacidosis (43 cases) with 67% identified as a high level of severity and occurring mostly in the inpatient setting. Other identified complications include hyperkalemia (6 cases), renal insufficiency (15 cases), and even amputation (2 cases). Our survey is the first to document real-world complications from SGLT2 inhibitors. In the outpatient setting, mycotic infections are most common and most often benign. In the inpatient setting, diabetic ketoacidosis is the most common and is severe. This is an important take-home message for family physicians to tailor their practice and vigilance according to the practice setting.

5HT6 Antagonists in the Treatment of Alzheimer's Dementia: Current Progress.

Alzheimer’s disease is an important condition with a considerable and unmet disease burden in large need of continued research and more treatment options. The 5HT6 antagonists are a new class of medications to be offered. Because they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increasing acetylcholine in the central nervous system (CNS). Early trials of the 5HT6 antagonists showed improvements in cognition and activities of daily living when used as adjuncts to current therapies for Alzheimer’s dementia. However, recent phase III trials have failed to show a statistically significant improvement in cognitive function. This article will provide a comprehensive review of 5HT6 antagonists in drug development, including some that have been recently discontinued. We will discuss both the successes and failures of this drug class and provide rationale for their continued research and development.

CV3 - Comparative Effectiveness of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation

Atrial fibrillation (AF) management focuses on the prevention of blood clots to reduce the risk of stroke. Warfarin has successfully reduced the risk of stroke and mortality. Since 2010, a new class of medications, direct oral anticoagulants (DOACs), entered the market. Clinical trials provide good evidence that DOACs compare favorably to warfarin on a variety of outcomes, including mortality. Initial observational studies have concluded these medications may also be cost-effective. Our research objective was to compare the effectiveness of DOACs to warfarin in clinical practice. This is a retrospective observational study of data from patient-level administrative and claims data from the Veterans Health Administration (VHA) and Medicare. We identified patients with a new diagnosis of AF who initiated warfarin or a DOAC between 2011 and 2015 (N=35,478). We examined the relationship between initiating warfarin or a DOAC on mortality using a two-stage residual inclusion approach, using facility-level prescribing patterns as an instrumental variable. Models controlled for facility quality measures, patient demographic variables, comorbidities, and stroke risk. Eighty percent of the sample initiated warfarin with the remainder initiating the DOACs. The average follow-up time was 1.97 years. In the first stage model, facility prescribing patterns significantly predicted the likelihood of receiving a DOAC (OR=6.04, 95% CI=2.5-13.8). In the second-stage, Cox proportional hazard models that control for selection bias, Veterans who started on a DOAC had significantly lower risk of mortality (hazard ratio=0.34, C.I.=0.22-0.53). Naïve models and propensity score models that don’t explicitly account for unobserved selection bias have hazard ratios of 0.66 (CI=0.61-0.71) and 0.70 (CI=0.65-0.76), respectively. Veterans who initiate a DOAC compared to warfarin have significantly lower risk of death. The ease of administration and monitoring advantages for DOACs suggest these drugs may be the preferred option for treatment in clinical populations with significant comorbidities.

New Developments in the Medical Treatment of Glaucoma

To focus on new medical therapies that lower intraocular pressure in glaucoma. We summarize new classes of medications to help treat open-angle glaucoma and ocular hypertension, including modified prostaglandin analogues, such as latanoprostene bunod, and prostanoid receptor agonists, ONO-9054 and DE-117. We summarize the differences among the Rho kinase inhibitors that modulate the actin cytoskeleton. We present preclinical and clinical data on the adenosine receptor agonist, trabodenoson, and the RNAi-based compound, bamosiran. Several promising drugs with novel mechanisms of action are in development to lower intraocular pressure in glaucoma. The Food and Drug Administration approved latanoprostene bunod and netasurdil for commercial use in late 2017. These drugs mark the first new compounds to treat glaucoma in over two decades.

Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications. Develop evidence-based guidelines for CFTR modulator therapy in patients with CF. A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, a medical librarian, and a biostatistician were recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis. For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV1) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatment with IVA for 1) children aged 12-17 years with an FEV1 greater than 90% predicted, and 2) children less than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV1 less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and children aged 12 years or older with an FEV1 greater than 90% predicted, and 2) children aged 6-11 years. Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.

Cyclic AMP-dependent protein kinase catalytic subunit A (PRKACA): the expected, the unexpected, and what might be next.

Protein kinase A (PKA) or cyclic-AMP (cAMP)-dependent kinase was among the first serine-threonine kinases to be molecularly and functionally characterized. For years, it was investigated as the enzyme that mediates cAMP functions in almost all cell systems and organisms studied to date. Despite PKA's critical role in signaling and the long history of investigations of cAMP in oncogenesis (dating back to the 1970s), it was not until relatively recently that PKA defects were found to be directly involved in tumor predisposition. First, PKA's main regulatory subunit, PRKAR1A, was found to be mutated in Carney complex, a genetic syndrome that predisposes to heart tumors (cardiac myxomas) and a variety of other lesions of the endocrine system, including the adrenal cortex, and several cancers, including liver carcinoma. Then, PKA's main catalytic subunit, PRKACA, was found to be mutated in sporadic adrenal tumors and fibrolamellar liver carcinoma. Not surprisingly, therefore, a new research study published in The Journal of Pathology showed PRKACA mutations in sporadic cardiac myxomas. The real question is what other pathologies will be found to be due to PRKACA (or other PKA subunit) defects. The possibilities abound and may show the way for a totally new class of medications that target cAMP signaling to be useful in fighting the corresponding tumors. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Sodium-Glucose Transporter Inhibitors and Diabetic Nephropathy in Humans and Animal Model

Diabetic nephropathy as the leading cause for end stage renal disease and replacement therapy is increasing every year. Treatment of T2DM with the present oral blood glucose lowering drugs and insulin is challenging, with an enormous number of patients are able to achieve the target glycaemic control (HbA1C<6.5%). Despite the use of new Insulin compounds and different recommended combination of oral anti-diabetic drugs, the benefits of these recommendations are offset by side effects such as weight gain and recurrent hypoglycaemia. Therefore, the need for new agents that control blood glucose strictly and have other proactive cellular pathways is challenging. The sodium glucose transporter protein 2 (SGLT2) inhibitors, are recently being widely used. The main therapeutic effect of these new drugs, SGLT2 inhibitors (SGLT2-I), is lowering the blood glucose levels via inhibitory effect on the transport of glucose and sodium in the proximal tubular cells by sodium glucose transport 1. SGLT2-I reduce plasma sodium level by natriuretic and diuresis, with decreasing blood pressure and body weight. These new medications can be used as first and second lines of treatment especially in patients with normal glomerular filtration rate, with or without cardiovascular complications. The most effective combination of SGLT2I is Metformin especially in albuminuria and slowing the progression of diabetic nephropathy especially if initiated in early stages of DM. The new class of medication (SGLT2I) are less effective in patients with moderate CKD (eGFR<45 ml/min). This review will focus on the new pathways such autophagy as a new pathway where SGLT2 are involved with protective effects.

Unusual case of immune-related colitis

The cancer immunotherapy field has had many promising developments in recent years. Checkpoint inhibitors are good examples of that. This new class of medications comes with a new constellation of...

DVT Prevention in Stroke.

The purpose of this review is to discuss the prevention of venous thromboembolism (VTE) in stroke patients. We discuss use of oral anticoagulation and other interventions for the prevention of VTE. A new class of medications, non-vitamin K antagonist oral anticoagulants (NOACs), have been successfully trialed for the prevention of VTE. We review the data and guidance statements for VTE prevention. Warfarin and vitamin K antagonist drugs have been the mainstay of VTE prevention for decades. More recently, NOACs have become available for both stroke and systemic embolism prevention in nonvalvular atrial fibrillation and for VTE treatment or prevention. NOACs have been shown to be at least noninferior for VTE prevention and treatment when compared with warfarin, and have a good safety profile. Other approaches include use of graduated compression stockings, intermittent compression stockings, inferior vena cava filters, and heparins. Selection of the appropriate VTE prophylaxis in stroke patients is important to reduce associated morbidity and mortality.

CORR Insights®: Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors?

CORR Insights®: Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors?

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data.

Atherosclerotic cardiovascular disease (ASCVD) remains the number one killer in the western world. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and ezetimibe has been shown to reduce the risk of cardiovascular events. Now, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mabs) are available for high-risk individuals with ASCVD or familial hypercholesterolemia on maximally tolerated statin therapy but requiring greater LDL-C reduction. PCSK9 mab outcome trial results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk (FOURIER) study, which was presented at the American College of Cardiology in March 2017, which demonstrated a decrease of 15% in primary and 20% secondary end points over a 2-year period [1••]. These results firmly demonstrated additional benefit beyond maximally tolerated statin therapy in high-risk individuals. Thus, management of LDL-C will soon become more complex, as a new class of medication is added to our standard armamentarium. This review explores the discovery of PCSK9, its biology and physiology, and the development of the PCSK9 mabs.

Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported "AKI" actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.

Interleukin-5 Antagonists Usher in a New Generation of Asthma Therapy.

Asthma is the most common chronic respiratory disease in the USA. A subset of patients with asthma have refractory symptoms, persistent eosinophilic inflammation, and recurrent exacerbations despite maximal medical therapy. The monoclonal antibodies targeting the IL-5 pathway are a new class of medications designed to target severe eosinophilic asthma. There are two medications clinically available: mepolizumab and reslizumab, both of which target IL-5. A third medication, benralizumab, is currently under development and targets the IL-5 receptor. Clinical data suggest these medications can reduce asthma exacerbations and improve lung function in patients with peripheral eosinophilia and poorly controlled asthma despite maximal medical therapy. The anti-IL-5 medications are among the first targeted molecular therapies for asthma and will usher in an exciting new era in the treatment of severe asthma.

Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant.

Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

Monoclonal Antibodies for Lipid Management.

In recent years, biochemical and genetic studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a major mediator of low-density lipoprotein cholesterol (LDL-c) levels and thereby a potential novel target for reducing risk of coronary heart disease (CHD). These observations led to the development of PCSK9 inhibitors, which lower LDL-c levels more than any other non-invasive lipid-lowering therapy presently available. The PCSK9 inhibitors furthest along in clinical trials are subcutaneously injected monoclonal antibodies. These PCSK9 inhibitors have demonstrated LDL-c-lowering efficacy with acceptable safety in phase III clinical trials and may offer a useful therapy in addition to maximally tolerated HMG-CoA reductase inhibitors (statins) in certain patient groups. Longer-term data are required to ensure sustained efficacy and safety of this new class of medications. This review provides an overview of the biology, genetics, development, and clinical trials of monoclonal antibodies designed to inhibit PCSK9.

Strontium ranelate increases osteoblast activity.

Strontium ranelate (SR) is the first generation of a new class of medication for osteoporosis, which is capable of inducing bone formation and, to a certain extent, inhibiting bone resorption. The aim of this study was to evaluate the in vitro effects of SR on osteoblastic cell cultures. MC3TE-E1 cells were seeded in 24-well plates at a density of 2×10(4) cells/well and exposed to SR at 0.05, 0.1, and 0.5mM. The following parameters were assayed: 1) Cell proliferation by hemocytometer counting after 24, 48 and 72h, 2) Cell viability by MTT assay after 24, 48 and 72h, 3) Type I Collagen and Osteopontin (OPN) quantification by Western Blotting, ELISA, and Real Time PCR after 48h, 3) Immunolocalization of fibronectin (FN) by epifluorescence, and 4) matrix mineralization by Alizarin Red staining after 14days. After 24, 48 and 72h, the cell proliferation and viability were not affected by SR at 0.05 and 0.1mM (p>0.05). However, cell cultures exposed to SR at 0.5mM exhibited a decrease in both cell proliferation and cell viability in all time points assayed (p<0.05). High levels of protein and mRNA for Type I Collagen and OPN were detected in cultures exposed to SR, particularly at 0.5mM (p<0.05). SR allowed the expression of FN in osteoblastic cell cultures as observed by epifluorescence analysis. The mineralized bone-like nodule formation was affected in a concentration-dependent manner by SR, with large bone-like nodules being detected in osteoblastic cell cultures exposed to SR at 0.5mM. In conclusion, these results suggest that SR can accelerate acquisition of the osteoblastic phenotype, which explains, at least in part, the rebalancing of bone turnover in favor of bone formation.

Novel Oral Anticoagulants for Venous Thromboembolism with Special Emphasis on Risk of Hemorrhagic Complications and Reversal Agents.

Warfarin was the only oral anticoagulant available for the treatment of venous thromboembolism for about half a century until the recent approval of novel oral agents dabigatran, rivoraxaban and apixaban. This presents new classes of medications less cumbersome to use. They do not require frequent laboratory monitoring or have nurmerous drug interactions. On the other hand it also poses a challenge to the physicians deciding which agent to use in specific patient populations, how to predict the bleeding risk compared to warfarin and between the different novel agents and how to manage bleeding with relatively recent discovery of few potential antidotes. This review summarizes the major trials that led to the approval of these agents and their exclusion criteria helping physicians understand which patient types might not benefit from these agents. It provides clinical pearls invaluable in everyday practice such as transitioning between traditional and novel anticoagulants, dose adjustments for high risk populations, drug interactions and cost analysis. Futhermore, the review provides direct comparisons with warfarin and indirect comparisons among the novel agents in terms of efficacy and bleeding risk narrating the numbers of patients with intracranial, gastrointestinal and fatal hemorrhages in each of the major trials. We hope that this review will help the physicians inform their patients about the benefits and risks of these agents and enable them to make an informed selection of the most appropriate anticoagulant.

The New Face of Hyperlipidemia Management: Proprotein Convertase Subtilisin/Kexin Inhibitors (PCSK-9) and Their Emergent Role As An Alternative To Statin Therapy.

This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha). This article will overview this medication class, describe their pathophysiology, and analyze the clinical data from the numerous studies and trials done on both of these medications for their efficacy and safety outcomes. Data compiled on this new class of medications support the research that PCSK-9 inhibitors are both a safe and effective means of lowering the LDL levels of resistant or otherwise currently unmanaged hypercholesterolemia patients.

Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.

Denosumab Related Osteonecrosis of the Jaw with Spontaneous Necrosis of the Soft Palate: Report of a Life Threatening Case

Bisphosphonates have been used for years in the treatment of patients with distant bony metastasis and in the prevention of osteoporosis. One of main side effects of these medications is the development of bisphosphonate related osteonecrosis of the jaw (BRONJ) in a small subset of patients. A new class of medications with a shorter half-life, known as receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, was introduced with the hopes of avoiding this side effect. However, reports of osteonecrosis of the jaw after the use of RANKL inhibitors have also been documented. We report on a patient who developed a life threatening osteonecrosis of the jaw with sepsis shortly after switching from a bisphosphonate to a RANKL inhibitor for osteoporosis treatment. This patient developed several soft tissue defects including spontaneous necrosis of the soft palate. To our knowledge this is the first time this presentation has been described.