Current clinical pharmacology最新文献

Background: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options.

Methods: The Italian Association of Thoracic Oncology (AIOT) organized five meetings in different Italian regions representing North, Middle and South of the country in order to discuss the issue.

Results: In light of these new approvals, it is valuable to understand the uptake of these new therapies in routine clinical practice and their impact on patient care. With these treatment options to define an appropriate algorythm is object of debate.

Conclusion: The present paper discusses the old and new treatment opportunities, proposing a shared algorithm for second-line setting in advanced NSCLC.

Background: Sodium-Glucose Cotransporter 2 (SGTL-2) inhibitors are a new class of antidiabetics, which have been approved for the treatment of patients with Type 2 Diabetes Mellitus (T2DM). Besides their beneficial metabolic effects, they exert favourable results in cardiovascular events and risk factors along with renoprotection. However, SGLT-2 inhibitors have not been yet approved as an adjunct therapy to insulin in patients with Type 1 Diabetes Mellitus (T1DM). This review aims at presenting both clinical and experimental data that reinforce the role of SGLT-2 inhibitors as adjunctive treatment in patients with T1DM along with the main restrictions of their use, namely Diabetic Ketoacidosis (DKA).

Methods: We conducted a comprehensive research of the relevant literature regarding the off-label use of SGLT-2 inhibitors in clinical practice, presenting the major benefits and the potential risks.

Results: SGLT-2 inhibitors are associated with improved glycemic control, reduction in body weight, and decrease in insulin dosage, along with their beneficial cardiovascular and renal effects. However, we cannot overlook the association with increased incidence of DKA events, in the presence of well known predisposing factors. Further investigation is required, in order to establish them as adjunctive treatment in those patients.

Conclusion: This novel class of antidiabetics seems to be a very attractive treatment option in patients with T1DM, due to their multiple beneficial effects, but the increased risk of DKA should be taken into account.

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.

Objective: The aim of present research work was to develop a herbal fast disintegrating tablet containing Fagonia schweinfurthii Hadidi dried extract and determining its antihistaminic activity using guinea pig ileum.

Method: The tablets were formulated by wet granulation technique using three different superdisintegrants (croscarmillose, crospovidone and sodium starch glycolate) at three different levels. The tablets were evaluated for various physical properties like hardness, friability weight variation etc. and various mechanical properties like disintegration time, wetting time to select the best superdisintegrant. The selected superdisintegrant was further used as intra as well as extra granulating agent to develop fast disintegrating tablets of Fagonia schweinfurthii Hadidi dried extract. The optimized formulation was subjected to stability study as per the ICH guidelines. Finally, Ex-vivo antihistaminic study was conducted on guinea pig ileum for optimized formulation and compared with marketed tablet containing cetrizine HCl as API (Stanhist-10, Ranbaxy, Pvt. Ltd).

Results: Physical properties of all tablet batches were found to be acceptable and comply with various official specifications. The disintegration time and wetting time of optimized formulation (F'3) were found to be 1.15±0.08 and 0.56±0.04 min respectively. Results of Ex-vivo study showed a comparable histamine inhibition between optimized tablet (15%) and marketed tablet formulation (18.8%) in a dose of 5 µg/ml.

Conclusion: On the basis of in-vitro and Ex-vivo studies, it was concluded that prepared herbal fast disintegrating tablets were stable and had potent antihistaminic activity.

Background: Prostatitis is a recurrent urinary infection in males and is often difficult to cure. The aim of the study was to examine whether anti-inflammatory effects of enhanced drainage of prostatic secretions, obtained through two months treatment with a proteolytic enzyme mucoactive (PEM) compound (Serrazyme and other constituents), influenced qualitative or quantitative expressions of bacterial growth in seminal cultures.

Method: 450 patients with prostatitis syndromes were randomized either to PEM therapy (intervention group) or to no treatment group. All patients were followed at the end of a 2-month PEM continuous treatment period (T2) and further two months after withdrawal (T4).

Results: After treatment, 15 out of 107 (14.1%) patients with Chronic Bacterial Prostatitis (CBP) showed negative seminal cultures, while in patients with cat NIH-IIIA prostatitis seminal cultures became positive in 33.3% cases with low bacteriospermia. After two months from withdrawal, although among CBP patients the total number of isolates and colony forming units (CFU) counts showed not significant changes compared to matched-values observed at T2, microbial parameters varied significantly among inflammatory prostatitis patients.

Conclusion: The results of the present study showed that 2 months of treatment with PEM, decreasing bacterial adherence and inflammatory prostatitis, reveals a subgroup of apparent inflammation associated with infection that microbial biofilms likely mask in inflammatory prostatitis patients.

Cancer is one of the deadly diseases which is characterized by unchecked cell division or abnormal cell growth due to the incapability of cell cycle arrest. As the treatment for this is to kill the cancerous cells, the main challenge for scientists is to direct the cell killing to cancerous cells while leaving the normal cells unharmed. Antibody-Drug Conjugates (ADC) are one such targeted anti-cancer therapy. It is an effective drug delivery system that utilizes the targeting action of antibody along with cell death by potent cytotoxic agent, linked up with one another by a linker molecule and thus helps to reduce toxicity to non-target cells, ensure broad therapeutic window and overcome multi-drug resistance. Multiple parameters like total antibody (conjugated and unconjugated antibody), conjugated antibody, conjugated drug, unconjugated antibody and unconjugated (free) drug are needed to be analyzed to find out the behavior as well as safety and efficacy of ADCs. With 2 FDA approved drugs (Kadcylca and Adcetris) and more than 40 drugs undergoing clinical trial, this field has gained pace in recent years. Some challenges still persist in this field like reducing immunogenic response to antibodies, ensuring the ADC homogeneity and antibody-drug ratio, selection of appropriate targets, successful conjugation of drug to antibody, securing the stability of linkers in systemic circulation as well as improvement of oral bioavailability. With the advent of stable linkers, cytotoxic drugs having higher potency and better conjugation capability with the linker and antibodies having high specificity, these ADCs can overcome the limitations of cancer treatment. This review focuses on the criteria for proper construction of ADC, conjugation techniques, the target choices, the underlying mechanism of action and pharmacokinetic considerations associated with ADC.

Background: A questionnaire is a commonly used data collection method and is a very crucial part of the research. However, designing a questionnaire can be a daunting task for postgraduate students.

Methods: This manuscript illustrates the various steps required in questionnaire designing and provides an insight into the essentials of questionnaire construction and validation. Data from a questionnaire should be able to comprehend the objectives of the study; else it may lead to wrong interpretation or bias, decreased power of study and inability to generalize the study results.

Conclusion: Since it is equally important to verify the usefulness of the designed questionnaire, the article briefly describes the process of psychometric evaluation of a questionnaire.

Background: In the pharmaceutical sectors, the computer plays a crucial role as a commander of all the theoretical aspects and provides a workbench to improve the overall quality of pharmaceutical research and development. The aim of this article is to provide a computational approach to the development of numerous technology of computer software in the field of clinical pharmacokinetics. The computational technique practised by clinical pharmacist and scientist with the applied knowledge and skills in dealing with clinical pharmacokinetics problems can be applied in routine clinical practices.

Methods: To solve the various complicated pharmacokinetic equations and modeling of pharmacokinetic processes, various software were used like Population pharmacokinetics, Individual pharmacokinetics, Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetics, in - silico pharmacokinetics like Window-Based Non-linear model fitting (WinNonlin), Statistical Analysis Software (SAS), Non-linear Mixed Effects Modelling (NONMEM), PK Solution etc. Results: Various software's which was described in this paper help in the development of experimental study designs, statistical treatment of data and various simulation studies, etc. A robust software solution should be easy to use and address the three main parts of the PK-PD workflow like data management, analysis, and reporting. PK-PD software's allow researchers to predict ADME properties of new drug entity. For the study of the pharmacokinetic, the best software is WINBUGS where there is no limitation of dimensional array and size of the problem. The best software to be used for individual pharmacokinetics is T.D.M.S in which, we can apply Bayesian and least square method for curve fitting and it can be used for both linear and non-linear pharmacokinetic data.

Conclusion: Various software were discussed here. This software not only help in knowing the history of the software but also help in gaining more knowledge about pharmacokinetics and pharmacodynamics simulation. Different software such as population pharmacokinetic, individual pharmacokinetic and others discussed in this article will help in the reporting and analyzing of data. The important points to be considered while selecting the software is also discussed which will help in easy accessing of software.

Background: Postpartum haemorrhage (PPH) is an important cause of early maternal death which needs to be controlled.

Objective: This study was designed to compare the effect of intravenous tranexamic acid (TXA) and prostaglandin analogue on reducing PPH resulted from uterine atony in women undergoing C section or vaginal delivery.

Method: A randomized, triple-blind, placebo-controlled study was conducted on 248 pregnant women with PPH due to uterine atony who were randomly assigned into two groups of TXA as the intervention group (n=124) and prostaglandin analogue as the control group (n=124). The intervention group received 4 g TXA for an hour and then 1 g over 6 hours infusion intravenously and the control group received prostaglandin analogue.

Results: Postoperative bleeding did not significantly differ between the two groups (68.2±6.1 ml and 69.1±175.73 ml, respectively, P =0.6). Moreover, hemoglobin declines were 1±0.4 g/dl and 1.2±0.5 g/dL in TXA and prostaglandin group respectively, indicating that the difference was not statistically significant (P =0.7).

Conclusion: The results of the present study showed that administrating intravenous TXA had comparable effects with prostaglandin analogue on reducing PPH in women with uterine atony and in those undergoing C section or vaginal delivery. Therefore, TXA can be used instead of prostaglandin in managing such patients.

Background: Over the last three decades, monoclonal antibodies (MAbs) have made a striking transformation from scientific tools to powerful human therapeutics. Muromonab CD3 a murine MAb was the first FDA approved therapeutic MAb for the prevention of kidney transplant rejection. Since its approval in 1986, there has been a decline in further application and approvals until the late 1990s when the first chimeric Mab, Rituximab was approved for the treatment of lowgrade B cell lymphoma in 1997. With the approval by licensing authorities of chimeric, followed by humanized and then fully human monoclonal antibodies, the rate of approval and monoclonal antibodies available in the market for the treatment of various diseases has increased dramatically. As of March 2017, FDA has approved approximately 60 therapeutic MAbs which are currently under evaluation in various phases of clinical trials.

Objective: MAbs are approved for the treatment of diseases belonging to various systems like cardiovascular, respiratory, hematology, kidney, immunology and oncology. MAbs are approved for the treatment of orphan diseases or indications such as paroxysmal nocturnal hemoglobinuria as well as cancers and multiple sclerosis where hundreds of patients are treated and even diseases such as breast cancer, asthma and rheumatoid arthritis where millions are being treated. This review focuses briefly on types, molecular targets, mechanism of actions and therapeutic indications of FDA approved MAb products that are currently available in the market.

Conclusion: With the advent of fully human MAbs, the efficacy and safety have improved in the treatment of various cardiovascular, cancer, respiratory, hematology, autoimmune diseases and infections. The introduction of biosimilars will increase the affordability and utilization of MAbs in the treatment of various diseases.