Pharmacogenetics of chronic cardiovascular drugs: applications and implications

Cardiovascular disease continues to be a tremendous worldwide problem, and drug therapy is a major modality to attenuate its burden. At present, conditions such as hypertension, dyslipidaemia and heart failure are pharmacologically managed with an empirical trial-and-error approach. However, it has been suggested that this approach fails to adequately address the therapeutic needs of many patients, and pharmacogenetics has been offered as a tool to enhance patient-specific drug therapy. This review outlines pharmacogenetic studies of common cardiovascular drugs, such as diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins and warfarin, ultimately highlighting considerations for future research and practice.     

Recent overview of ocular patents

Ocular drug therapy has always been considered as a major challenge in the field of drug delivery. The presence of blood ocular barriers and efflux pumps has imposed a great concern as well. Various vision threatening disorders require a long term therapy of drug molecules, especially for the diseases that affect the posterior segment. Pharmaceutical companies and other research institutes have adopted a multidisciplinary approach to meet the current challenges which is evidenced by the trends seen in the published and filed U.S. patents. Various strategies have been employed to achieve long term sustained and targeted delivery for both the anterior and the posterior segments of the ocular diseases. These strategies include formulating drugs into implant, micro or nanoparticulate systems and hydrogel-based systems. Transporter targeted approach has also allowed scientists to deliver drugs to both the segments of the eye. Recent developments such as delivery of drugs utilizing ultrasound, iontophoresis and microneedle based devices have been promising. Genebased therapeutics has opened a new avenue for vision threatening disorders. In all, the current developments in the entire field have been very exciting for finding out new strategies to treat vision threatening disorders.     

Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps

Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens or Pluronics can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed.     

Clinical pharmacology: principles and practice of drug therapy in medical education

Educational reform has taken place in many Medical Schools. A traditional passive approach has been replaced by a more active, student-centred approach, founded on Problem-Based Learning. This has not been without risk because many well-structured courses have been abandoned, and this is of particular significance to the principles and practice of drug therapy. Here we outline an approach which could be incorporated into a medical curriculum and suggest some guidelines and a list of questions that should be asked in clinical situations involving drug therapy.     

Current pharmacological treatment approaches to central nervous system leukaemia.

Significant advances in the treatment and prevention of meningeal leukaemia have been made in the past 3 decades. This progress has resulted from the development of innovative approaches to treatment as well as a better understanding of the pharmacokinetics and pharmacodynamics of the commonly used antileukaemic agents. Intrathecal therapy, via the intralumbar or intraventricular route, is a form of regional therapy that results in the delivery of very high drug concentrations to the principle target tumour site (the meninges) using a relatively small drug dose, thereby minimising both systemic drug exposure and systemic toxicity. The dosage and schedules, clinical pharmacology and toxicities of the commonly used intrathecal agents, methotrexate and cytarabine (cytosine arabinoside; Ara-C) are discussed in detail. Another approach which has been used to overcome the poor penetration of antileukaemic drugs into the CNS has been the use of high-dose systemic therapy. This strategy has been successfully applied in the treatment of meningeal leukaemia using both high-dose methotrexate and high-dose cytarabine. The clinical pharmacology, toxicities, and potential limitations of this approach are outlined. Finally, new agents that are currently undergoing clinical evaluation and future directions for research are also discussed.     

Drug treatment of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is defined as a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, and with features of disordered defecation and distension. The irritable bowel syndrome occurs in 10 to 20% of people worldwide and is very commonly encountered in clinical practice. This has encouraged the pharmaceutical industry to search for effective drug therapy. So far, a universally effective agent has not been found, and since this is a chronic, benign disorder, beginning in youth, long term drug use should be avoided. Nevertheless, if a specific IBS symptom, such as constipation or abdominal pain dominates, a specific drug may be helpful. However, tests and treatment should be minimised or even avoided in order to do no harm. A largely nonpharmaceutical approach to IBS should be taken. This approach employs drugs sparingly and then only targeted at specific and resistant symptoms.     

A novel approach for delivery of enzyme drugs: preliminary demonstration of feasibility and utility in vitro

A novel heparin/protamine-based approach for delivery of enzyme drugs without associated toxic effects has been proposed. This approach would allow an enzyme drug to be administered in an inactive (i.e. pro-drug) form and then released at the target site in an active form using protamine as the triggering agent. The pro-drug and the triggered release features of this approach would permit the enzyme drug to act specifically and only on its target substrates while sparing normal substrates, thereby alleviating unwanted toxic effects. The in vitro feasibility of the approach has been successfully demonstrated using trypsin as the model protease drug. In addition, the utility of the approach has also been demonstrated by applying the system in delivering streptokinase, one of the most widely used clinical drugs in thrombolytic therapy. This approach may open up the possibility of developing a wide range of new catalytic drugs that are initially thought to be impossible for therapeutic use due to their potent toxic effects.     

Targeted prodrug design to optimize drug delivery

Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.     

Personal Construct Theory and constructivist drug education

In recent years drug education has come under scrutiny. Research has found that drug education is having minimal impact. Questions have been raised as to the appropriateness of theories underpinning drug education programmes as well as the aims and purpose of programmes. As such, there is a call for new approaches. This paper explores the potential of a personal construct approach to drug education. Personal Construct Theory (PCT) has been used to understand drug use and treatment as well as an approach to education and training. Although generally thought of as an individualistic approach, there are also social, interpersonal as well as educational aspects to the theory. In this paper, we argue that drug education needs to remove itself from the political and moral arena and ground itself in a theory that relates to young people and drug use in today's society. In so doing it should aim to facilitate and educate young people in making informed and healthy choices. PCT offers one such approach. [Mallick J, Watts M. Personal Construct Theory and constructivist drug education. Drug Alcohol Rev 2007;26:595 - 603]     

Antisense-based cancer therapeutics: are we there yet?

Despite significant advances that have been made in recent years, there is still an urgent need for novel, more effective and less toxic therapeutics for human cancer. Among many new molecular therapeutics being explored for cancer therapy, antisense oligonucleotides are a promising nucleic acid-based approach, with numerous antisense agents being evaluated in preclinical studies and several anticancer antisense drugs in clinical trials. Although there are still a few problems facing the development of antisense strategies for cancer therapy, with progress made in chemical modifications, target selection and drug delivery systems, antisense oligonucleotides are emerging as a novel approach to cancer therapy used alone or in combination with conventional treatments such as chemotherapy and radiation therapy.     

Antisense-based cancer therapeutics: are we there yet?

Despite significant advances that have been made in recent years, there is still an urgent need for novel, more effective and less toxic therapeutics for human cancer. Among many new molecular therapeutics being explored for cancer therapy, antisense oligonucleotides are a promising nucleic acid-based approach, with numerous antisense agents being evaluated in preclinical studies and several anticancer antisense drugs in clinical trials. Although there are still a few problems facing the development of antisense strategies for cancer therapy, with progress made in chemical modifications, target selection and drug delivery systems, antisense oligonucleotides are emerging as a novel approach to cancer therapy used alone or in combination with conventional treatments such as chemotherapy and radiation therapy.     

Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment.

Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs.

Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.     

Dry Powder Antibiotic Aerosol Product Development: Inhaled Therapy for Tuberculosis

Inhaled therapies offer a unique approach to the treatment of tuberculosis (TB) using a relevant target organ system as a route of administration. The number of research reports on this topic has been increasing exponentially in the last decade but studies of clinical efficacy have been rare in recent times. The challenge is to take many research findings and translate them into a strategy for product development. Dry powder inhalers are the dominant drug product under consideration by those interested in the inhaled therapy for TB. A range of factors including candidate drug, formulation, device selection, drug product testing for proof of concept, and preclinical and clinical purposes all demand different considerations. The following review is intended to raise awareness of a growing body of evidence, suggesting that inhaled therapy for TB is possible and desirable. In addition, it is intended to outline key elements of the product‐development activity for this particular application that has not been discussed elsewhere in the literature. Hopefully, this will encourage those with development expertise to seriously contemplate the steps required to bring such products forward. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3900–3907, 2013     

Combining polymeric devices and stem cells for the treatment of neurological disorders: a promising therapeutic approach

Cell therapy will probably become a major therapeutic strategy for neuronal disorders in the coming years. Nevertheless, due to poor survival of grafted cells and limited differentiation and integration in the host tissue, certain ameliorations must be envisaged. To address these difficulties, several strategies have been developed and among them, two methods seem particularly promising : in situ controlled drug delivery and implantation of cells adhered on biomaterial-based scaffolds. Indeed, the ability of drugs, such as growth factors, to regulate neuronal survival and/or plasticity infers the use of these molecules to treat neurodegeneration associated with human diseases. Moreover, the synthesis of cell scaffolds which mimic the extra-cellular matrix can help guide morphogenesis and tissue repair. Furthermore, cells can be cultivated on these matrices that may eventually make graft therapy a more practical approach for the treatment of neurological diseases. Nevertheless, for those two encouraging approaches multiple parameters have to be considered, such as the drug targeting strategy, but also the physical and morphological characteristics of the scaffold and the type of cells to be conveyed. This review thus focuses on those two promising strategies and also on their possible association to improve stem cell therapy of neurodegenerative disorders. Indeed, tissue replacement by grafting cells within or adhered onto drug delivering biomaterial-based devices, has recently been reported and seems to be very promising.     

Evaluation and treatment of ventricular arrhythmias: an update

An overall approach to evaluating and treating ventricular arrhythmias based on objective monitoring criteria is described. A clinically useful system classifies patients based on whether their ventricular arrhythmias are benign, potentially lethal, or lethal. Some clinicians believe that antiarrhythmic drug therapy improves survival in patients with potentially lethal arrhythmias. However, disappointing results from the Cardiac Arrhythmia Suppression Trial have led to a greater awareness of the potential adverse effects of antiarrhythmics. Various risk factors for arrhythmia-related death have been identified, such as the presence of frequent and complex ventricular ectopy, abnormal signal-averaged electrocardiography (SAECG) tracings, and poor left ventricular ejection fraction (LVEF). Antiarrhythmic drugs remain the primary mode of therapy for patients with recurrent symptomatic tachycardias. Antiarrhythmic drug efficacy has been evaluated by methods including symptom assessment, continuous ambulatory electrocardiographic monitoring (Holter monitoring), exercise testing, and invasive electrophysiologic testing. There may be an extremely wide range of effective serum concentrations for the class IA agents. Individual target concentrations of antiarrhythmic agents may be determined for individual patients and should assist the clinician in optimizing long-term antiarrhythmic drug therapy. The risk-to-benefit ratio of treatment should be weighed before antiarrhythmic drug therapy is begun, and careful, objective monitoring of drug efficacy should be performed. When pharmacologic treatment of ventricular arrhythmias is considered, treatment algorithms that incorporate LVEF measurements, Holter monitor recordings, and SAECG may aid the clinician.     

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for. Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy, with potentially lower overall costs and shorter timelines. Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers, with the aid of some new emerging technologies, such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing. Therefore, in this review, we focus on summarizing the therapeutic potential of non-oncology drugs, including cardiovascular drugs, microbiological drugs, small-molecule antibiotics, anti-viral drugs, anti-inflammatory drugs, anti-neurodegenerative drugs, antipsychotic drugs, antidepressants, and other drugs in human cancers. We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies. Taken together, these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.     

Recent advances in solid organ transplantation

Advances in organ transplantation have come rapidly and consistently in recent years as the result of improved surgical techniques and immunosuppressive drug therapies. Experience gained in renal transplantation over the past 30 years has made this a standard therapeutic approach for treating chronic renal failure. This knowledge has been successfully applied to the transplantation of other organs to produce steadily increasing survival rates and improved quality of life. This article reviews the advances that have been made in solid organ transplantation and immunosuppressive drug therapy.     

Goal-oriented, model-based drug regimens: setting individualized goals for each patient

Serum drug concentrations have commonly been described in terms of therapeutic ranges within which most patients have a therapeutic effect and a low incidence of toxicity. However, truly individualized drug dosage regimens cannot be developed without first setting a specific individualized target goal, such as a target serum drug concentration, at a desired target time after the dose (usually at a peak or trough), for each patient. For example, it is well known that the dosage of digoxin, or of any drug with a narrow therapeutic range, should somehow be individualized. One can begin this process by considering each patient as an individual, with his/her own individual need for the drug. If the need is small, so is the upper acceptable risk of toxicity. This would lead to a gently regimen, adjusted to the patient's body weight and renal function, to best achieve that specific target goal. Alternatively, if previous therapy has not sufficed and a significant or urgent need exists, then a higher goal may justifiably be selected, a greater risk of toxicity accepted, and a dosage regimen developed to meet that greater need. After such an individualized target goal is chosen, it should be achieved as precisely as possible. After the regimen is given, serum levels need to be measured and an individualized, patient-specific pharmacokinetic model should be made. Without the model, with only the raw serum level data, one cannot perceive the important exchanges that occur between serum and nonserum compartments of the drug, and we lack the precision given by the combination of the assay and the model to evaluate properly, optimally, the patient's clinical sensitivity to the drug. These concepts have been discussed here for digoxin, but they are general and apply to all drugs. This approach has also been applied to therapy with aminoglycoside antibiotics, vancomycin, lidocaine, theophylline, antiviral agents, a variety of anesthetic agents, psychiatric drugs, and anticancer agents.