Current Clinical Pharmacology - Volume 13, Issue 1, 2018

Background: Lupus nephritis (LN) is a common complication in many patients with systemic lupus erythematosus, although renal-limited lupus nephritis has been reported as well. Early diagnosis of lupus nephritis is critical as early detection and effective treatment can improve renal outcomes in such patients. Objective: The treatment of lupus nephritis is largely determined based on the histological class present on the renal biopsy specimen. In most cases, Class I and II of lupus nephritis do not require any specific treatment, but class III and IV lupus nephritis require immunosuppressive therapy. Treatment of Class V and VI remains controversial. In 2012, six guidelines were introduced for the management of lupus nephritis. These guidelines offer comprehensive treatment plans for each class of Lupus nephritis but differ from each other in many aspects. The purpose of this article is to review the current literature of the available pharmacological treatments used in the six classes of lupus nephritis as well as resistant lupus nephritis, strategies to address the problems of inadequate therapeutic response, medication related side effects, relapses of lupus nephritis, and some future treatment options. Methods: We reviewed the available literature and treatment guidelines on lupus nephritis in detail to present a comprehensive review of the available treatment options for different classes of lupus nephritis. Conclusion: Lupus nephritis which does not respond to initial treatment is associated with worse renal outcomes. Several therapeutic approaches are available for the induction and maintenance immunosuppression of the different classes of LN. Management of LN should be individualized for each patient based on their risk-benefit profile.

Background: There is an increasing need to face regulatory aspects as well as ethics and scientific ones in the pharmaceutical research phase after the authorization of a drug. Traditionally, Phase IV studies, after the authorization of a drug to be marketed by the Competent Authority like the Food and Drug Administration (FDA) (in Europe, European Medicine Agency – EMA- through National Procedures or Community Procedures) have been considered mainly aimed to the assessment of the new drug safety profile. However, the sample size calculation for such aim is still an open issue. Moreover, the benefit/risk assessment is a compelling global need. Methods: This editorial aims to give a fairly exhaustive overview of the main topics currently present in the pharmaceutical research phase after the authorization of a drug. FDA and EMA guidelines are considered under a comparative perspective with a focus on the perspective of “Post Authorization Safety Studies (PASS)” and “Post Authorization Efficacy Studies (PAES)” with critical considerations. Then, the approach of “Explanatory Trials” and “Pragmatic Trials” is proposed under the horizon of Health Technology Assessment (HTA). Conclusion: Critical remarks are raised against the pure commercial perspective in the proposal of PASS and PAES and on the design of registries which should be planned with relevant objectives to be pursued by appropriate statistical analyses reported in the Statistical Analysis Plan (SAP) of the study protocol. Finally, a particular focus is placed on the work of the Ethical Committees regarding the approval of the observational studies on the safety and the efficacy of the drugs in their pragmatic clinical use.

Background: The liver is the major metabolic clearance organ for chemical agents from the human body. Pregnancy is associated with several physiological changes that may affect one or more of these factors, and also induces changes in the hepatic clearance of certain drugs. The aim of this paper was to review some of the currently available information in the field to provide some insights about the relevance of these changes on the clearance of some drugs. Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1970 first semester. Results: Gestational Diabetes Mellitus (GDM) is a frequent disease commonly associated with other entities as obesity, hypertension, dyslipidemia, non-alcoholic fatty liver disease, prothrombotic conditions, changes in intestinal microbiome. These entities, together with the glycemic fluctuations associated with GDM might affect the determinants of the hepatic clearance (hepatic blood flow, the unbound fraction of drugs, and the hepatic intrinsic clearance). GDM is frequently associated with multi-drug treatments. While many of these drugs are cleared by the liver, little is known about the clinical relevance of these GDM associated pharmacokinetic changes. Conclusion: Considering the frequency of the disease and the effects that these pharmacokinetic changes might have on the mother and child, the need for further research seems advisable. In the meantime, cautious clinical judgment in the management of drug administration in women affected by this disease is recommended.

Background: Knowledge of drugs safety collected during the pre-marketing phase is inevitably limited because the randomized clinical trials (RCTs) are rarely designed to evaluate safety. The small and selective groups of enrolled individuals and the limited duration of trials may hamper the ability to characterize fully the safety profiles of drugs. Additionally, information about rare adverse drug reactions (ADRs) in special groups is often incomplete or not available for most of the drugs commonly used in the daily clinical practice. In the paediatric setting several highimpact safety issues have emerged. Hence, in recent years, there has been a call for improved post-marketing pharmacoepidemiological studies, in which cohorts of patients are monitored for sufficient time in order to determine the precise risk-benefit ratio. Objective: In this review, we discuss the current available strategies enhancing the post-marketing monitoring activities of the drugs in the paediatric setting and define criteria whereby they can provide valuable information to improve the management of therapy in daily clinical practice including both safety and efficacy aspects. The strategies we cover include the signal detection using international pharmacovigilance and/or healthcare databases, the promotion of active surveillance initiatives which can generate complete, informative data sets for the signal detection and systematic review/meta-analysis. Conclusion: Together, these methods provide a comprehensive picture of causality and risk improving the management of therapy in a paediatric setting and they should be considered as a unique tool to be integrated with post-marketing activities.

Background: Epileptic children and adolescent have a significantly low serum level of vitamin D due to the effect of antiepileptic drugs on the vitamin D metabolism. Those patients are at risk of cardiovascular events. Objective: This study aimed to show that epileptic patients who treated with antiepileptic drugs supplemented with vitamin D are free from the electrocardiograph changes compared with those treated with antiepileptic drugs. Method: This cross-sectional study included, 121 epileptic patients aged < 18 years of both genders with a history of idiopathic generalized tonic clonic seizure. They grouped into Group I (n=20) patients without medical treatment, Group II (n=76) patients treated with antiepileptic drugs, and vitamin D Group III (n=25) patients treated with antiepileptic drugs supplemented with vitamin D3 vitamin D. Each participant subjected to the electrocardiogram investigation at the time of entry into the study. Results: Group III patients had a significant decrease of QRS complex, QRS dispersion QTcorrected, and TQ duration compared with Group II. Group I patients, had a significant increase of QRS complex duration, compared with Group II patients. Four patients of Group II showed a significant prolonged QT-interval in the QT nomogram. Three patients had a JT index (an indicator of ventricular hyperpolarization) more than the normal cutoff level of 112. The area under the curve of receiving operating characteristics showed significant favorable effects of vitamin D supplementation on the different variables of electrocardiograph. Conclusion: Vitamin D supplementation may correct the changes in the electrocardiograph observed in idiopathic generalized tonic clonic seizure treated with antiepileptic medicines, and our observations warrant larger studies.

Introduction: Pharmacovigilance (PV) is the science responsible for ADRs reporting and accordingly medication safety. Pediatrics age group is a special concern as they have a higher risk of developing ADRs; this put more burden on pediatricians for early detection and reporting of ADRs. The present study aims to explore pediatricians' knowledge, attitude, and practices of pharmacovigilance. Method: A structured validated questionnaire was designed to achieve the study goals. A convenient sample of 142 pediatricians took part in the study. Results: The majority of pediatricians had a poor knowledge score about pharmacovigiliance and ADRs reporting. On the other hand, 71% of respondents had a good attitude score towards reporting ADRs. When exploring their own practice, pediatricians have a low reporting rate. Conclusion: The results of the present study reveal that pediatricians lack knowledge of PV and ADRs reporting. However, they have a good attitude towards ADRs reporting and enhancing their PV practice. This is still not reflected in their own practice. Further training and education about ADRs reporting are very important to move toward safer medications in children.

Background: Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct targeting CD3 on T cells and CD19 on B cells. We describe the relationship between pharmacokinetics (PK) of blinatumomab and pharmacodynamic (PD) changes in peripheral lymphocytes, serum cytokines, and tumor size in patients with non-Hodgkin lymphoma (NHL). Methods: In a phase 1 study, 76 patients with relapsed/refractory NHL received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 μg/m2/day). PD changes were analyzed with respect to dose, blinatumomab concentration at steady state (Css), and cumulative area under the concentration-versus-time curve (AUCcum). Results: B-cell depletion occurred within 48 hours at doses ≥5 μg/m2/day, followed first-order kinetics, and was blinatumomab exposure-dependent. Change in tumor size depended on systemic blinatumomab exposure and treatment duration and could be fitted to an Emax model, which predicted a 50% reduction in tumor size at AUCcum of ≥1,340 hg/L and Css of ≥1,830 pg/mL, corresponding to a blinatumomab dose of 47 μg/m2/day for 28 days. The magnitude of transient cytokine elevation, observed within 1-2 days of infusion start, was dose-dependent, with less pronounced elevation at low starting doses. Conclusion: B-lymphocyte depletion following blinatumomab infusion was exposure-dependent. Transient cytokine elevation increased with dose; it was less pronounced at low starting doses. Tumor response was a function of exposure, suggesting utility for the PK/PD relationship in dose selection for future studies, including NHL and other malignant settings.

Introduction: Anxiety and negative sensations due to alcohol withdrawal are factors leading to alcohol relapse and addiction. Minocycline, an antibiotic, can decrease alcohol consumption in rats, however, its effects on alcohol withdrawal anxiety and relapse have not been studied. Material and Methods: Part 1: Forced alcohol drinking in gradually increasing concentration was administered till day 22 in rats. Effect of drugs on anxiety was assessed using elevated plus maze (EPM) and two-chambered box apparatus, after removal of alcohol. Part 2: For relapse, an alcohol deprivation effect model was used, rats were continuously offered alcohol and water for 4 consecutive weeks in a two-bottle choice paradigm, followed by 2 weeks of alcohol deprivation. Effect of drugs on alcohol consumption during the first hour of alcohol reintroduction was assessed. Animals were sacrificed and whole brain Tumor Necrosis Factor (TNF) α was estimated. Results: Part 1: Anxiety at 3 hours was significantly lower following minocycline (20 mg/kg i.p.) or diazepam compared to vehicle control. Part 2: Acute administration of minocycline (5,10 and 20 mg/kg, i.p.) suppressed alcohol consumption significantly (p value<0.05) as compared to vehicle control. A significant decrease in whole brain TNF α was observed in animals treated with minocycline compared to untreated animals. Conclusion: Minocycline attenuates alcohol withdrawal anxiety and disrupts alcohol relapse.

Background: The causal link between upper limb restlessness and cervical disc prolapsus is still unclear, and the exact role of the spinal cord in the origination of limb restlessness is not yet completely understood. Methods: Here we have evaluated the therapeutic effect of pramipexole (0.5 mg/kg) in a 47-year old male with cervical disc prolapsus who described restlessness in his upper limb and neck. Results: The patient felt significantly better, and his symptoms improved near to complete after five days when we initiated 0.5 mg/day pramipexole treatment. Conclusion: In our present paper, we provide more evidence for the role of pramipexole (0.5 mg/day) in limb restlessness which is associated with cervical disc herniation. In this context, we also have discussed the underlying pathophysiology which seems to be responsible for the restlessness symptoms of the patients.