Current Clinical Pharmacology - Volume 14, Issue 2, 2019

Diabetic nephropathy is defined as a decline in the renal function and an increase in the amount of albuminuria (>300 mg/day). The interruption of the renin-angiotensin-aldosterone system (RAAS) by well-established therapies such as angiotensin-converting enzyme inhibitor, angiotensin receptor blockers, calcium channel blockers or diuretics has been beneficial in reducing the progression of renal diseases; however, there is an increase in the levels of aldosterone due to the aldosterone escape phenomenon. Newer and novel approaches to counteract this aldosterone breakthrough while accentuating the anti-hypertensive and anti-proteinuric effects of these agents would be ideal and mineralocorticoid receptor antagonists fit in this slot perfectly. This review attempted to evaluate the safety and efficacy of and mineralocorticoid receptor antagonists for diabetic nephropathy. Presently mineralocorticoid receptor antagonists such as spironolactone, eplerenone and finerenone are being investigated as both monotherapies and as additional therapies. Clinical studies have shown that these drugs have been effective in the reduction of blood pressure, urinaryalbumin- excretion and estimated glomerular filtration rate. The commonly observed adverse effects are hyperkalemia, gynaecomastia and vaginal bleeding, that are bothersome with spironolactone seems to be avoidable if these patients are switched to non-steroidal and mineralocorticoid receptor antagonists such as finerenone and eplerenone. Most of the studies have only evaluated the shortterm effects of mineralocorticoid receptor antagonists on diabetic nephropathy. Hard outcomes such as cardiovascular events, creatinine doubling, progression to end-stage renal disease, mortality and the need for temporary or permanent dialysis need to be studied with these molecules.

Aim: Multiple drug intolerance syndrome (MDIS) is a unique clinical entity distinct from other drug hypersensitivity syndromes. The aim of this review was to critically appraise the various aspects of MDIS. Methods: A review was conducted to search for the causes, mechanism, clinical features, and management of MDIS. Results: The most common cause of MDIS is antibiotics followed by non-steroidal antiinflammatory drugs (NSAIDs). Although some non-specific immunological mechanisms are involved, the immunological tests for MDIS are negative. Rashes, gastrointestinal reflux, headache, cough, muscle ache, fever, dermatitis, hypertension, and psychiatric symptoms are the usual manifestations. Treatment is mostly symptomatic with the withdrawal of the offending drug. Drug rechallenges and desensitization may be required for the management of this syndrome. Conclusion: MDIS occurs by a nonimmune mechanism which requires a prompt withdrawal of the offending drug(s), and in some cases may require drug re-challenge and desensitization.

Background: muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. Methods: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment. The characteristics of screened papers were described using the mentioned conceptual framework. Results: Muscarinic antagonists and agonists have been assayed for the treatment of tumors established in lung, brain and breast with beneficial effects. We described an up-regulation of mAChRs in mammary tumors and the lack of expression in non-tumorigenic breast cells and normal mammary tissues. We and others demonstrated that muscarinic agonists can trigger anti-tumor actions in a dose-dependent manner on tumors originated in different organs like brain or breast. At pharmacological concentrations, they exert similar effects to traditional chemotherapeutic agents. Metronomic chemotherapy refers to the administration of anti-cancer drugs at low doses with short intervals among them, and it is a different regimen applied in cancer treatment reducing malignant growth and angiogenesis, and very low incidence of adverse effects. Conclusion: The usage of subthreshold concentrations of muscarinic agonists combined with conventional chemotherapeutic agents could be a promising tool for breast cancer therapy.

Background: Antipsychotic drugs are the cornerstone of schizophrenia treatment and are also indicated for other psychotic and mood disorders. Different antipsychotic drugs and their formulations are available, though liquid forms have been overlooked. Methods: Herein the added value of liquid antipsychotics is reviewed, with a focus on the recently introduced liquid quetiapine, a frequently used antipsychotic. Results: Liquid antipsychotics are easily administrated via the preferable oral route, while compliance under supervised administration is transparent. Liquid forms could be preferred in patients with swallowing difficulties, which are common in elderly patients and often concealed. In this population, the availability of liquid antipsychotics could prevent errors in medication administration, which could possibly render caregivers labile to any harm caused to the patient. Aspiration, however, remains a risk with liquid formulations. Common errors in medication administration are the omission of treatment and alteration of solid oral formulations. Regarding quetiapine, omission of treatment could be associated with non-adherence as well as discontinuation symptoms, while alteration of extended release formulation could alter its pharmacokinetics. Mildly agitated and cooperative patients are another target population of liquid antipsychotics, which can induce fast sedation avoiding involuntary intramuscular injections. The combination of sedative properties and low incidence of extrapyramidal symptoms makes liquid quetiapine a valuable option for these patients, yet the current evidence is limited. Conclusion: The liquid form of quetiapine can facilitate pharmacotherapy of schizophrenia and can be defined as value added medicine bringing key benefits not only to the patients and caregivers but also to the health care system.

Background: Prostate cancer is the sixth leading cause of death, among all cancer deaths By 2030, this burden is expected to increase with 1.7 million new cases and 499,000 new deaths. We aimed to evaluate the efficacy and safety of Nilutamide in metastatic prostate cancer (mPCa) patients who underwent orchiectomy. Methods: A comprehensive search was conducted in the Medline/PubMed and Cochrane Library. References from included studies and studies from clinicaltrials.gov were explored without language and date restrictions. We included only randomized controlled trials, comparing the safety and efficacy of Nilutamide in Metastatic Prostate Cancer (mPCa) patients who underwent orchiectomy with placebo. The outcomes of concerns were survival and the response of drug and safety.. Quality of the included studies was assessed using the Cochrane Risk of Bias Tool. Two authors were independently involved in the study selection, data extraction and quality assessment. Disagreements between the two reviewers were resolved by consulting a third reviewer. Results: A total of five out of 244 studies were included in meta-analysis involving1637 participants. Nilutamide group showed improved response rate (RR=1.77, 95%CI 1.46-2.14, p<0.00001), disease progression (RR=0.59, 95%CI 0.47-0.73, p<0.00001), complete response (RR=2.13, 95%CI 1.40-3.23, p=0.003) and clinical benefit (RR=1.23, 95%CI 1.13-1.34, p<0.00001) when compared to placebo; however, stable disease favored the control group (RR=0.80, 95%CI 0.68-0.94, p=0.007). In addition, patients on Nilutamide showed prolonged progression-free survival and overall survival. Nausea and vomiting were the most common adverse events reported in Nilutamide group. Conclusion: Evidence suggests that patients with mPCa who underwent orchiectomy receiving Nilutamide showed significant improvement in progression-free survival and overall survival response rate and clinical benefits in comparison with the placebo group.

Background: Opioid analgesics are commonly used along with propofol during general anesthesia. Due to the dearth of data on the quality of anesthesia achieved with this combination, the present meta-analysis was carried out. Methods: Electronic databases were searched for appropriate studies using a suitable search strategy. Randomized clinical trials comparing the combination of remifentanil/sufentanil/alfentanil with propofol with fentanyl and propofol, were included. The outcome measures were as follows: total propofol dose to achieve the desired general anesthesia; time of onset and duration of general anesthesia; depth of general anesthesia; and recovery time (time for eye-opening and time taken for extubation). Risk of bias was assessed and Forest plots were generated for eligible outcomes. The weighted mean difference [95% confidence intervals] was used as the effect estimate. Results: Fourteen studies were included in the systematic review and 13 were included in the metaanalysis. Statistically significant differences were observed for remifentanil in comparison to fentanyl when combined with propofol: Propofol dose (in mg) -76.18 [-94.72, -57.64]; time of onset of anesthesia (min) -0.44 [-0.74, -0.15]; time taken for eye-opening (min) -3.95 [-4.8, -3.1]; and time for extubation (min) -3.53 [-4.37, -2.7]. No significant differences were observed for either sufentanil or alfentanil about the dose of propofol required and due to scanty data, pooling of the data could not be attempted for other outcome measures for either sufentanil or alfentanil. Conclusion: To conclude, we found that remifentanil has a statistically significant anesthetic profile than fentanyl when combined with propofol. Scanty evidence for both alfentanil and sufentanil precludes any such confirmation.

Background: Psychostimulants can induce behavioral sensitization by their chronic use. The main target for the action of these drugs is dopamine, neither epinephrine nor serotonin transporters. Serotonin is synthesized by the precursor L-tryptophan. Tryptophan and methylphenidate being 5-HT agonists, both increase the level of serotonin thereby causing desensitization of 5-HT1a receptors. The present study investigated whether behavioral sensitization induced by Methylphenidate is decreased in tryptophan administrated animals. Methods: The Experiment was divided into 2 phases (1). Behavioral effects of repeated administration of TRP 100 mg/kg and MPD for 14 days in three groups; (i) water (ii) MPD 1.0 mg/kg (iii) TRP. To explore the locomotor effects of treatment, the activity was monitored in a familiar and novel environment. (2) Behavioral consequences of repeatedly administrated MPD (1.0 mg/kg) on pretreated TRP (100 mg/kg) and MPD (1.0 mg/kg) animals following Co-MPD and TRP for 14 days, rats were divided in three groups (i) water, (ii) MPD and (iii) TRP as mentioned in Experiment no 1. After two weeks six subgroups were assigned i.e. (i) water-saline, (ii) water- MPD, (iii) TRP-saline (iv) TRP-MPD (v) MPD-saline and (vi) MPD-MPD+TRP and treated for further 14 days. Locomotor behavior was monitored in familiar environment on the next day and in novel environment on alternate days of each administration. Results: The Results from phase 1 showed increased activity in both (TRP and MPD) treatments. However, the results of phase 2 showed significant decrease in methylphenidate-induced behavioral sensitization by both pretreatment and co-administration with TRP. Conclusion: The present study suggests the potential of tryptophan to decrease the risk of behavioral sensitization induced by methylphenidate.

Background: Recombinant human keratinocyte growth factor (rHuKGF) has gained considerable attention by researchers as epithelial cells proliferating agent. Moreover, intravenous truncated rHuKGF (palifermin) has been approved by Food and Drug Administration (FDA) to treat and prevent chemotherapy-induced oral mucositis and small intestine ulceration. The labile structure and short circulation time of rHuKGF in-vivo are the main obstacles that reduce the oral bioactivity and dosage of such proteins at the target site. Objective: Formulation of methacrylic acid-methyl methacrylate copolymer-coated capsules filled with chitosan nanoparticles loaded with rHuKGF for oral delivery. Methods: We report on chitosan nanoparticles (CNPs) with diameter < 200 nm, prepared by ionic gelation, loaded with rHuKGF and filled in methacrylic acid-methyl methacrylate copolymercoated capsules for oral delivery. The pharmacokinetic parameters were determined based on the serum levels of rHuKGF, following a single intravenous (IV) or oral dosages using a rabbit model. Furthermore, fluorescent microscope imaging was conducted to investigate the cellular uptake of the rhodamine-labelled rHuKGF-loaded nanoparticles. The proliferation effect of the formulation on FHs 74 Int cells was studied as well by MTT assay. Results: The mucoadhesive and absorption enhancement properties of chitosan and the protective effect of methacrylic acid-methyl methacrylate copolymer against rHuKGF release at the stomach, low pH, were combined to promote and ensure rHuKGF intestinal delivery and increase serum levels of rHuKGF. In addition, in-vitro studies revealed the protein bioactivity since rHuKGFloaded CNPs significantly increased the proliferation of FHs 74 Int cells. Conclusion: The study revealed that oral administration of rHuKGF–loaded CNPs in methacrylic acid-methyl methacrylate copolymer-coated capsules is practically alternative to the IV administration since the absolute bioavailability of the orally administered rHuKGF–loaded CNPs, using the rabbit as animal model, was 69%. Fluorescent microscope imaging revealed that rhodaminelabelled rHuKGF-loaded CNPs were taken up by FHs 74 Int cells, after 6 hours’ incubation time, followed by increase in the proliferation rate.

Background: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC. Methods: The toxicity of aspirin and aspirin derivatives to OC and a CRC cell line were investigated in the presence and absence of platins. Results: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 colorectal cancer (CRC) cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line. Conclusion: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins.

Background: Therapeutic drug monitoring is a relevant tool in drug treatment of elderly patients. The aim of this study was to assess the possibility of therapeutic drug monitoring of the most important potential interactions in nursing homes. Methods: A material of prescribed drugs to 446 patients in three nursing homes in Bergen, Norway from a single day in March 2016 was analysed. Clinically relevant drug interactions (pharmacodynamic or pharmacokinetic) were identified and classified with Stockley`s Interaction Alerts. The most important interaction among several in each patient were ranked by recommended action > severity > evidence according to Stockley`s. The possibility of therapeutic drug monitoring of drug combinations involved in the most important interactions was retrieved from a database of all laboratories performing clinical pharmacology in Norway (the Pharmacology Portal). Results: Two or more drugs were used by 443 (99.3%) of 446 patients. Three-hundred and eightyfour patients (86.1%) had > 1 interaction. About 95% of the most important interactions were pharmacodynamic. In 280 (72.9%) of these interactions, Stockley`s recommended adjust dose or monitoring. Among the 384 most important interactions, 93% involved one drug and 41% involved two drugs available for therapeutic drug monitoring. Conclusion: In this pilot study, therapeutic drug monitoring was possible in the majority of the most important interactions in Norwegian nursing homes. This option is of importance since adjust dose or monitoring were frequently recommended actions associated with these interactions.

Background: In this study, we aimed to detect the changes in the level of interleukin (IL)-4 and IL-13 cytokines and their downstream genes including interleukin-13 receptor subunit alpha-2 (IL13Ra2), interleukin-4 receptor subunit alpha-1 (IL4Ra1), dual oxidase 1 (DUOX1) and dual oxidase 2 (DUOX2). The protective effects of Selenium-L-methionine on radiation-induced histopathological damages and changes in the level of these cytokines and genes were detected. Methods: Four groups of 20 rats (5 rats in each) namely, control; Selenium-L-methionine, radiation and radiation plus Selenium-L-methionine were used in this study. 4 mg/kg of Selenium-Lmethionine was administered 1 day before irradiation and five consecutive days after irradiation. Irradiation was done using a dose of 15 Gy 60Co gamma rays at 109 cGy/min. All rats were sacrificed 10 weeks after irradiation for detecting changes in IL-4 and IL-13 cytokines, the expressions of IL13Ra2, IL4Ra1, Duox1 and Duox2 and histopathological changes. Results: The level of IL-4 but not IL-13 increased after irradiation. This was associated with increased expression of IL4Ra1, Duox1 and Duox2, in addition to changes in morphological properties. Selenium-L-methionine could attenuate all injury markers following lung irradiation. Conclusion: Selenium-L-methionine can protect lung tissues against toxic effects of ionizing radiation. It is possible that the modulation of immune responses and redox interactions are involved in the radioprotective effect of this agent.