Showing papers in "Expert Review of Clinical Pharmacology in 2015"

Homocysteine and the pathogenesis of atherosclerosis.

Abstract: The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques.

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems

Abstract: Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.

Pharmacovigilance in resource-limited countries.

Abstract: In the past 20 years, many low- and middle-income countries have created national pharmacovigilance (PV) systems and joined the WHO’s global PV network. However, very few of them have fully functional systems. Scientific evidence on the local burden of medicine-related harm and their preventability is missing. Legislation and regulatory framework as well as financial support to build sustainable PV systems are needed. Public health programs need to integrate PV to monitor new vaccines and medicines introduced through these programs. Signal analysis should focus on high-burden preventable adverse drug problems. Increased involvement of healthcare professionals from public and private sectors, pharmaceutical companies, academic institutions and the public at large is necessary to assure a safe environment for drug therapy. WHO has a major role in supporting and coordinating these developments.

Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms

Abstract: In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can

Leflunomide and teriflunomide: altering the metabolism of pyrimidines for the treatment of autoimmune diseases

Abstract: Leflunomide modulates T-cell responses and induces a shift from the Th1 to Th2 subpopulation. This process results in a beneficial effect in diseases in which there is good evidence that T cells play a major role in both initiation and perpetuation of the inflammatory condition. Leflunomide has been successfully used for treating rheumatoid arthritis and psoriatic arthritis for many years. The active metabolite of leflunomide is teriflunomide, which has been approved for treating multiple sclerosis. Teriflunomide, just like the mother drug, inhibits dihydro-orotate dehydrogenase and synthesis of pyrimidine. The present review presents and discusses the safety profiles of leflunomide and teriflunomide, two drugs that are indeed the same, considering that much can be learned from the reported side effects of both.

How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease

Abstract: We have provided a critical assessment of research on the reduction of cholesterol levels by statin treatment to reduce cardiovascular disease. Our opinion is that although statins are effective at reducing cholesterol levels, they have failed to substantially improve cardiovascular outcomes. We have described the deceptive approach statin advocates have deployed to create the appearance that cholesterol reduction results in an impressive reduction in cardiovascular disease outcomes through their use of a statistical tool called relative risk reduction (RRR), a method which amplifies the trivial beneficial effects of statins. We have also described how the directors of the clinical trials have succeeded in minimizing the significance of the numerous adverse effects of statin treatment.

Perampanel in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus

Abstract: Perampanel is the latest approved antiepileptic drug in focal and generalized epilepsies and has a distinct and selective mode of action on AMPA-receptors. Several thousand patients have received perampanel within randomized placebo-controlled trials, open-label extension trials and post-marketing observational studies. Significant median partial-onset seizure reduction rates of 23% for 4 mg/day, 26-31% for 8 mg/day and 18-35% for 12 mg/day were reported. Likewise 50 percent responder rates were 29% for 4 mg/day, 33-38% for 8 mg/day and 34-36% for 12 mg/day. Primary generalized tonic-clonic seizures were reduced by 76.5% (8 mg) vs 38.4% (placebo) in a recent controlled trial. Overall, perampanel is well tolerated and the main adverse events are dizziness, somnolence and fatigue. There are also anecdotal reports on use in progressive myoclonic epilepsies and status epilepticus. Perampanel will likely remain an important, possibly broad-spectrum AED with a significant market share, especially in patients with drug-refractory epilepsies.

The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women

Abstract: At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio.

Antiepileptic drugs influences on body weight in people with epilepsy.

Abstract: Data from clinical trials, retrospective and cross-sectional studies have quantified the metabolic changes associated with long-term use of antiepileptic drugs (AEDs). AEDs can be associated with weight gain or weight loss, although most are weight neutral. Weight gain is not only a cosmetic problem but also a risk for obesity-related vascular disorders. Weight loss may compromise growth in children/adolescents. This review discusses the possible contribution of peripheral and central hormones/neuropeptides (as leptin, insulin, adiponectin, neuropeptide-Y, ghrelin and galanin) and pathways that influence energy balance in the pathogenesis of weight changes with AEDs. As AEDs may influence weight, physicians have to properly select and characterize the suitable AED as an initial step or modify the existing AED if it compromises patient’s health.

Long-acting muscarinic antagonists

Abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients.

What lessons can be learned from failed Alzheimer’s disease trials?

Abstract: Trials missing primary efficacy end points raise the question of whether the choice of drug or the limitations of disease biology were at fault. In some trials, drugs appear not to have achieved biochemical effect thresholds sufficient for clinical benefit. This suggests the need for improved drugs that are more active at tolerated doses. In other trials, it is unclear how the observed biomarker changes are related to potential efficacy. However, hints of efficacy from exploratory analyses support the idea that starting treatment earlier in the course of the disease might be more effective. A closer look at the failed trials will help de-risk future trials.

Pharmacologic and clinical evaluation of posaconazole

Abstract: Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances.

The effect of antiepileptic drugs on thyroid hormonal function: causes and implications.

Abstract: Epilepsy is a chronic disease and its treatment is lifelong in one-third of patients. Data from cross-sectional and prospective studies have reviewed the influence of antiepileptic drugs (AEDs) on thyroid hormones. Thyroid abnormalities were reported in one-third of the patients on AEDs. Subclinical hypothyroidism, reduced thyroxine, triiodothyronine, free thyroxine, free triiodothyronine and thyroid binding globulin concentrations were reported with phenobarbital, phenytoin, carbamazepine, valproate and oxcarbazepine, but not with lamotrigine, levitracetam, tiagabine and vigabatrine. All reported patients were clinically euthyroid and hormonal changes were reversible after AED withdrawal. The mechanisms for thyroid dysfunction with AEDs include enhanced metabolism and/or altered protein binding or interference of hypothalamic-pituitary-thyroid axis function. This review focuses on the evidence, mechanisms of thyroid abnormalities with AEDs and their clinical implications. The associations between subclinical hypothyroidism and metabolic risks due to AEDs are also discussed.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits.

Abstract: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients.

Glutamatergic agents for schizophrenia: current evidence and perspectives.

Abstract: Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology, biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergic-modulating antipsychotics that fail to significantly improve negative and cognitive symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics modulate this system on several levels, as do mood stabilizers, including lamotrigine, topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to overcome for successfully leveraging glutamatergic agents for schizophrenia are patient selection, focus on positive symptoms and late disease stages, and dose-response relationships. Because glutamate guides pro...

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

Abstract: The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.

Conbercept (KH-902) for the treatment of neovascular age-related macular degeneration.

Abstract: Age-related macular degeneration (AMD) is a progressive, degenerative disease of the retina that occurs with increasing incidence with age and ranks third among the global causes of visual impairment. VEGF has been implicated in the development and progression of neovascular AMD. Drugs that block VEGF, leading to regression of the abnormal blood vessels, are the mainstay of treatment of neovascular AMD, particularly for subfoveal neovascular lesions. Anti-VEGF agents currently in use in neovascular AMD are pegaptanib (Macugen(®)), ranibizumab (Lucentis(®)), bevacizumab (Avastin(®)) and a soluble VEGF receptor decoy aflibercept (Eylea(®)). Recently, China Food and Drug Administration have approved conbercept for the treatment of neovascular AMD in China. Conbercept appears to offer yet another anti-VEGF drug for use in neovascular AMD. However, there is still a need for large, well-designed, randomized clinical trials to ensure its safety and efficacy.

Using real-world healthcare data for pharmacovigilance signal detection - the experience of the EU-ADR project.

Abstract: A prospective pharmacovigilance signal detection study, comparing the real-world healthcare data (EU-ADR) and two spontaneous reporting system (SRS) databases, US FDA's Adverse Event Reporting System and WHO's Vigibase is reported. The study compared drug safety signals found in the EU-ADR and SRS databases. The potential for signal detection in the EU-ADR system was found to be dependent on frequency of the event and utilization of drugs in the general population. The EU-ADR system may have a greater potential for detecting signals for events occurring at higher frequency in general population and those that are commonly not considered as potentially a drug-induced event. Factors influencing various differences between the datasets are discussed along with potential limitations and applications to pharmacovigilance practice.

Review of select causes of drug-induced AKI.

Abstract: Drug-induced acute kidney injury (AKI) is an important problem that is frequently encountered by clinicians [1]. Both prescribed and over-the-counter agents have the potential to injure all renal c...

Pharmacological strategies for prevention of postoperative atrial fibrillation.

Abstract: Atrial fibrillation (AF) complicating cardiac surgery continues to be a major problem that increases the postoperative risk of stroke, myocardial infarction, heart failure and costs and can affect long-term survival. The incidence of AF after surgery has not significantly changed over the last two decades, despite improvement in medical and surgical techniques. The mechanism and pathophysiology underlying postoperative AF (PoAF) is incompletely understood and results from a combination of acute and chronic factors, superimposed on an underlying abnormal atrial substrate with increased interstitial fibrosis. Several anti-arrhythmic and non-anti-arrhythmic medications have been used for the prevention of PoAF, but the effectiveness of these strategies has been limited due to a poor understanding of the basis for the increased susceptibility of the atria to AF in the postoperative setting. In this review, we summarize the pathophysiology underlying the development of PoAF and evidence behind pharmacological approaches used for its prevention in the postoperative setting.

Biosimilar regulation in the EU

Abstract: In the EU, the EMA has been working with biosimilars since 1998. This experience is crystallized in the extensive set of guidelines, which range from basic principles to details of clinical trials. While the guidance may appear complicated, it has enabled the development of biosimilars, of which 21 have managed to get marketing authorization. Currently marketed biosimilars in the EU have a good track record in safety and traceability. No biosimilars have been withdrawn from the market because of safety concerns. The most controversial issues with biosimilars are immunogenicity and extrapolation of therapeutic indications. The available data for these topics do not raise concerns among EU regulators. Interchangeability and substitution are regulated by individual EU member states.

Pharmacological treatment of attention-deficit/hyperactivity disorder: assessing outcomes

Abstract: A substantial body of evidence has supported the efficacy and safety of pharmacological treatment available for attention deficit/hyperactivity disorder (ADHD). There is increasing agreement that the important treatment outcomes for ADHD extend beyond improvement in core symptoms and that a more generic (or global) concept of remission is the overarching goal of treatment. However, there is no consensus on the best definition of remission or on how best to conceptualize and measure broader treatment outcomes. In this article, we provide an overview of the various methods and approaches to measuring treatment outcomes for ADHD with respect to symptoms, impairment, quality of life, adverse events and safety as well as cognition. We will describe the ways that they may be used within routine clinical practice and think ahead about the kinds of studies that are required to move the field forward.

Ceftazidime-avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections.

Abstract: Treatment of complicated urinary tract infections and complicated intra-abdominal infections is increasingly difficult due to the rising prevalence of multidrug-resistant Gram-negative bacteria. Ceftazidime-avibactam is a combination of the established third-generation cephalosporin ceftazidime with avibactam, a novel non-β-lactam β-lactamase inhibitor, which restores the activity of ceftazidime against many β-lactamase-producing Gram-negative bacteria, including extended-spectrum β-lactamases and Klebsiella pneumoniae carbapenemases. Clinical and nonclinical studies supporting the safety and efficacy of ceftazidime-avibactam include microbiological surveillance studies of clinically relevant pathogens, in vivo animal models of infection, pharmacokinetic/pharmacodynamic target attainment analyses, Phase I clinical pharmacology studies, and Phase II/III studies in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including patients with ceftazidime-nonsusceptible Gram-negative infections.

How to use vancomycin optimally in neonates: remaining questions

Abstract: In neonates, vancomycin, a narrow-spectrum antibiotic, is the first choice of treatment of late-onset sepsis predominantly caused by Gram-positive bacteria (coagulase-negative staphylococci and enterococci). Although it has been used for >50 years, prescribing the right dose and dosing regimen remains a challenge in neonatal intensive care units for many reasons including high pharmacokinetic variability, increase in the minimal inhibition concentration against staphylococci, lack of consensus on dosing regimen and way of administration (continuous or intermittent), duration of treatment, use of therapeutic drug monitoring, limited data on short- and long-term toxicity, risk of mutant selection and errors of administration linked to concentrated formulations. This article highlights and discusses future research directions, with specific attention given to dosing optimization of vancomycin, including the advantages of modeling and simulation approaches.

Current choice of treatments for neovascular AMD.

Abstract: Age-related macular degeneration is the leading cause of irreversible blindness in developed countries with the neovascular form accounting for the majority of severe vision loss in the disease. The management of wet age-related macular degeneration has improved drastically in the past decade as anti-VEGF agents took its place at the forefront of treatment. As the choice of therapy is based on a number of factors, this review summarizes the pivotal studies that brought these agents to use and compares the different agents currently available. This review also briefly describes the promising new therapies that are in development.

Colistin: efficacy and safety in different populations

Abstract: This article reviews mechanisms, incidences, risk factors and preventive modalities of colistin toxicity as well as colistin use in special populations and through special routes. All clinical studies that examined the pharmacokinetic/pharmacodynamic, efficacy and side effects of colistin in the management of multidrug-resistant organisms in different patient population including pediatrics, adults, obese, critically ill, burn or cancer patients with any route of drug administration were considered. Compared with older recommended doses, current dosing approach improves cure rate without significant increase in the rate of colistin-induced nephrotoxicity. Efficacy and safety of high doses of colistin should be considered in the future studies. Also comparing efficacy and safety of different doses of aerosolized colistin and defining the appropriate dose in different populations is another open area of future researches.

Indications of atypical antipsychotics in the elderly.

Abstract: Atypical antipsychotics (AAP) have become some of the most commonly prescribed medications in primary and specialist care settings. Off-label prescribing accounts for much of the expanded use of AAPs. This has become common in the elderly. Marketing by pharmaceutical companies appears to have contributed to the off-label use of AAPs, in situations where their safety and efficacy is far from established. Although evidence provides varying degrees of support for their use for behavioural and psychological symptoms of dementia, augmentation of antidepressants in depression, anxiety, insomnia and in the management of psychosis in Parkinson's Disease, there are a number of potential problems with their expanded use in the elderly. These include weight gain, type two diabetes mellitus, sudden cardiac death and increased mortality rates in the elderly with dementia. It is recommended that whenever AAPs are used off-label, a review date is identified, informed consent is obtained and treatment and side-effects are closely monitored.

Novel therapeutics in the field of capsaicin and pain.

Abstract: Capsaicin, a pharmacologically active agent found in chili peppers, causes burning and itching sensation due to binding at the transient receptor potential vanilloid-1 (TRPV-1) receptor, a polymodal receptor critical to the sensing of a variety of stimuli (e.g., noxious heat, bidirectional pH), and subsequent activation of polymodal C and A-δ nociceptive fibers. Acutely, TRPV-1 activation with peripheral capsaicin produces pronociceptive effects, which extends to the development of hyperalgesia and allodynia. However, capsaicin has been reported to display antinociceptive properties as well, largely through TRPV-1-dependent mechanisms. Local application of high concentration of capsaicin is used for neuropathic pain and repeated stimulation of TRPV-1 induced an improvement of epigastric pain in irritable bowel syndrome and dyspepsia patients by desensitization of nociceptive pathways. New TRPV-1 agonists are currently under preclinical study and TRPV-1 antagonists are in early clinical development as analgesics. The TRPV-1 pathway might be a novel target for therapeutics in pain sensitivity.

Adverse reactions to oncologic drugs: spontaneous reporting and signal detection.

Abstract: Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting.

Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail.

Abstract: Efinaconazole 10% topical solution is a new antifungal therapy for the topical treatment of mild to moderate toenail onychomycosis. In vitro and in vivo data have shown significant antifungal activity against dermatophytes, Candida spp. and nondermatophyte molds, and its mechanism of action is through inhibition of fungal lanosterol 14α-demethylase. In two parallel, double-blind, randomized, controlled, Phase III trials, complete cure rates were 17.8 and 15.2%, respectively, and mycological cure rates were 55.2 and 53.4%, respectively, for efinaconazole 10% topical solution, which were superior to vehicle, with minimal adverse events. This drug profile reviews the most recent basic science and clinical data for efinaconazole in the treatment of toenail onychomycosis.