Current Clinical Pharmacology - Volume 12, Issue 1, 2017

Lung cancer is the main reason of cancer death worldwide. About 30% of non-small-cell lung cancer (NSCLC) cases are diagnosed with locally advanced disease (stage III). This is a mixed population including patients who have far more extensive and bulky disease than others. Management of these patients continue to be a challenge; frequently, patients have both local recurrence and distant metastases in this stage and the prognosis is very poor with a 5-year overall survival estimated between 3% and 7% for inoperable disease. The standard treatment for these patients is concurrent chemo-radiotherapy (CRT) improving survival when compared to sequential combination as shown in several metanalysis. Recently, immune-therapies, including checkpoint inhibitor, such as monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have shown to enhance survival compared to chemotherapy in patients with advanced NSCLC. The integration of radiotherapy with immunotherapy is a conceptually promising strategy and several preclinical experiments have further developed the rationale for combining them. Radiotherapy has the capacity to overcome a lot of tumor immune escape mechanisms through the liberation of immunogenic private antigens showing a better local control and augmenting the immune response of systemic agents. This manuscript discusses the potential clinical interest for the combination of radiation and immunotherapy in locally advanced NSCLC.

Background: Previous reports have shown inadequate response to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in 5-30% of patients undergoing percutaneous coronary interventions (PCI), due mostly to clopidogrel resistance. This prevalence increases up to 66% in patients undergoing neurointerventional procedures. However, clinical significance of CYP2C19 genotypes in neurointerventional procedures or carotid artery stenting (CAS) is unknown. Objective: The purpose of this review is to update our current knowledge and understanding of the pharmacogenetic basis for poor clopidogrel responsiveness in patients undergoing CAS and endovascular interventions as well as to explore usefulness of genotyping to reduce the rate of procedure-related thrombosis that results in ischemic complications. Method: A literature search for pharmacogenetic studies in cerebral endovascular interventions and CAS was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers. Results: The review included 7 papers involving 3 genetic polymorphisms on CYP2C19 and 442 subjects. Patients harboring at least one loss-of-function CYP2C19 polymorphism (e.g., CYP2C19*2 and *3) are at an increased risk of thromboembolic complications such as stent thrombosis following neurointerventional procedures. Notably, patients who carry the gain-of-function CYP2C19*17 allele may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. Conclusion: Studies assessing the influence of CYP2C19 polymorphisms on high on-treatment platelet reactivity in CAS and cerebrovascular disease patients are still limited and need further validation in large multicenter studies. This review covers an important topic in the field of antiplatelet therapy for cerebral endovascular procedures and CAS.

Background: Worldwide, in the absence of standard pediatric prescribing information, clinicians often use medicines in children in a dosage form or for an indication that has not been approved for use. Inadequate clinical trials increase exposure to drugs that lack safety-efficacy data in pediatric population. Hence, off-label and unlicensed drug use must be regarded as a patient safety-issue that is known to be associated with increased risks of adverse drug reactions apart from under- or overdosing due to lack of pharmacokinetic data. This review aims to give an overview of the worldwide reported rates of off-label and unlicensed drug use in different patient populations in pediatric settings, with a brief summary of the related adverse drug reactions (ADRs) and a discussion of the existing regulatory provisions and possible solutions for ensuring safe use of medicines in children. Method: Literature searches were conducted and we included studies that evaluated unlicensed or off-label drug use in various pediatric patient populations. The definition of off-label drug use and unlicensed drug varied between different studies. Results: Fourteen studies from different countries were included in the review and were grouped as: studies conducted in the patients admitted in neonatal intensive care units, in pediatric wards, in hospitalized children and in pediatric outpatient settings. The number of patients studied ranged from 34 in neonatal intensive care units to 355 409 hospitalized children. Many studies reported high rates of off-label (9% to 78.7%) and unlicensed (0.3% to 35%) drug use in different pediatric patient settings. Conclusion: Given the prevalence of unlicensed and off-label drug use, the cooperation of various stakeholders including health professionals, pediatric population and their parents/caregivers, regulatory authorities, and the pharmaceutical industry is integral to instituting individual measures to avoid exposing children to unnecessary risks and avoid depriving them of potentially effective pharmacotherapy. Initiatives to encourage clinical trials for licensing drug use in children by providing market exclusivity and patent extension could aid in bridging the gap between approval and contemporary drug prescribing practices. Enforcement of legislations in the drug development process and subsequent pharmacovigilance could improve the quality of information and accountability of pharmaceutical industry to support and facilitate drug research in children.

Over one million people die from malaria each year, mainly in the world’s tropical and sub-tropical areas. Several research efforts have been devoted to the design of new therapeutic targets for disease control, as drug resistance is one of the greatest challenges in malaria eradication. Carbohydrate recognition in Plasmodium-host interactions is one area for potential targets against disease. The glycan derivatives interfere with replication and invasion of Plasmodium falciparum. Sulfated glycosaminoglycans (GAGs) are known to block merozoite and sporozoite invasion. Heparin is a GAG that has been shown blocking the invasion by binding to the specific domain of merozoites surface (MSP) termed MSP-1. Although MSP does not bind to heparin-like GAG oligosaccharides, its ability to bind to small molecules has not yet been investigated. Besides this, the red blood cell also has glycans on the surface that mediate parasites-cell and cell-cell interactions. In this review, we aim to discuss drug mechanisms that act in carbohydrate synthesis targets in malaria disease.

Background: Androgenetic alopecia is a common condition characterized by thinning of scalp hair. Conversion of testosterone to dihydrotestosterone, a more potent androgen, by the enzyme 5-α-reductase is responsible for underlying pathogenesis. Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type-1 and type-2 isoenzymes of 5-α-reductase. Finasteride and minoxidil are the only approved drugs for androgenetic alopecia. Dutasteride has been demonstrated to be effective in several randomized, double-blind, placebo controlled trials in androgenetic alopecia. In this review, after the pharmacology of dutasteride, the authors have discussed the status of dutasteride in androgenetic alopecia and have compared its efficacy with that of finasteride. Objective: This article aims to review the current status of dutasteride in androgenetic alopecia. The structure, mechanism of action, pharmacokinetics and side effects are discussed along with its comparison with finasteride in androgenetic alopecia. Method: The main sources of our information were Medline Pubmed, Google scholar and Scopus including original articles and review articles. The keywords 'dutasteride', 'dutasteride in androgenetic alopecia' were used for search. Conclusion: Like finasteride, dutasteride is now becoming popular treatment option in AGA, due to its good response shown by various randomized control studies and meta-analysis. Also, in most of these studies, dutasteride was found to be better than finasteride with comparable adverse effects. Therefore, dutasteride could become a treatment of choice for AGA in near future.

Migraine is a recurrent, disabling, complex and highly prevalent neurological disorder. The mystery behind the cause of migraine is continuously evolving, according to the scientific understanding of the disease. This growing understanding helps to identify novel therapeutic targets for the management of migraine to treat the ailing migraineurs. The role of serotonin (5HT) in migraine is recognized to be the cornerstone for the currently available therapeutic options namely ergot alkaloids and triptans. The role of mediators such as Calcitonin Gene-Related Peptide (CGRP), nitric oxide and excitatory neurotransmitter glutamate, has been realized and ignited the development of drugs targeting these factors. Lasmiditan, known as a Neurally Active Anti- Migraine Agent (NAAMA) is a specific 5HT1F agonist, developed as a new group named as ‘ditans’. The drug was designed and developed to meet the unmet needs of currently available medications to circumvent the vascular adverse effects. Having a group of drugs with a nonvascular mechanism of action, devoid of unwanted effects with a different spectrum of indication and contraindications, is the need of the hour to expand the armamentarium available to tackle acute migraine attack.

Background: Millions of people today use herbs either as food or in the form of medicine along with other medications. Many of the herbs can interact with these medications, causing either potentially dangerous side effects or improved or reduced benefits from the medication. Objective: The present study was performed to determine the influence of cinnamon, on the pharmacokinetics and pharmacodynamics of pioglitazone. Method: Studies were conducted in normal and alloxan induced diabetic rats and rabbits with oral administration of selected doses of pioglitazone, cinnamon and their combination. Blood samples were collected at regular intervals of time and were analysed for glucose by GOD/POD method and for pioglitazone by HPLC method respectively. Body weights were also measured every week. Results: Significant differences were seen in pharmacokinetic parameters of pioglitazone like AUC, t1/2, Ke, Cl/F, Vd/F when given in combination with cinnamon in normal and diabetic rabbits. The combination of pioglitazone and cinnamon was found to reduce the glucose levels and body weights significantly than pioglitazone. The results indicating increased AUC of pioglitazone on pretreatment with cinnamon suggest an interaction indicating decreased metabolism of pioglitazone as a result of CYP 3A4 inhibition and thereby producing a potentiating effect. Conclusion: Cinnamon enhanced the bioavailability of pioglitazone by inhibiting the CYP3A4 enzyme. Hence, cinnamon might be beneficial when used in combination with pioglitazone in diabetic patients and an adjustment of dose of pioglitazone may be necessary.

Background: In patients with the Congenital Sucrase-Isomaltase Deficiency (CSID), who lack intestinal sucrase-isomaltase enzyme, a suspension of yeast sucrase is applied as a drug to compensate the enzyme deficiency. While antipsychotic drugs are used for the treatment of schizophrenia, administering multiple drugs at the same time may counteract each other. Methods: In this study, the interaction between trifluoperazine and haloperidol as antipsychotic drugs on oral drug yeast sucrase was investigated. In this regard, the kinetic parameters of enzyme were determined in the presence or absence of the drugs. The kinetic parameters of the drugs such as Ki and IC50 were also calculated. Lineweaver - Burk plot was used to reveal the type of inhibition. Results: The results showed that both drugs could reduce sucrase activity and decrease the Vmax of the enzyme by non-competitive inhibition. The IC50 and Ki values of the drugs were determined to be 0.7 and 0.068 mM and 0.45 and 0.063 mM for haloperidol and trifluoperazine, respectively. The results suggested that trifluoperazine binds to the enzyme with higher affinity than haloperidol. Fluorescence measurement was used for conformational investigations of the drugs and sucrase interaction. It was shown that the drugs bind to free enzyme and enzyme-substrate complex which are accompanied with hyperchromicity. This suggests that tryptophan residues of the enzyme transferred to hydrophobic medium after binding of the drugs to the enzyme. Conclusion: The finding of this research revealed that both trifluoperazine and haloperidol could inhibit sucrase in non-competitive manner. The kinetic parameters and conformational changes due to binding of trifluoperazine to the enzyme were different from that of haloperidol.

Background: Migraine is not curable, but preventive treatments are usually used to decrease the intensity and frequency of headache attacks. Different therapeutic options are widely studied for chronic migraine (CM), but all of them have different inefficacies. Objective: The aim of this study was to compare the efficacy of levetiracetam versus sodium valproate in the treatment of CM. Methods: A randomized controlled clinical trial was conducted on 62 patients with chronic migraine (30 patients in intervention group-treated with levetiracetam and 32 patients in control group- treated with sodium valproate). The treatment regimen consisted of initial dose of levetiracetam or sodium valproate 500 mg daily which increased to 500 mg two times a day after two weeks. The treatment response was evaluated by measuring pain frequency, pain severity, and the MIDAS (migraine disability assessment) score over three months follow-up. Results: During a three-month follow-up, the mean of headache frequency, severity, and MIDAS score were changed significantly. The rate of decrease in headache frequency was higher in control group than intervention group ((6.7±2.7 and 14.4±5.3 day/month, respectively) (P<0.001). Also, headache severity and MIDAS score significantly decreased in the control group than intervention group (3.4±1.1 and 5.7±1.6, respectively P<0.001, 16.7 ± 6.1 and 30.2±9.8, respectively (P<0.001). Conclusions: According to our findings, levetiracetam offered improvement in headache frequency, severity, and MIDAS score in patients with CM. However, levetiracetam was not effective enough for chronic migraine as valproate, despite some significant effect. Thus levetiracetam can be one of the choices for limited chronic migraine subjects who are in contraindication of Valproate.