Current Drug Therapy - Volume 16, Issue 2, 2021

Background: Heparin is the most commonly used injectable anticoagulant for many indications, ranging from the treatment of atrial fibrillation to the prevention of clotting in patients undergoing surgery. Currently, only argatroban and bivalirudin are FDA approved for the management of heparin induced thrombocytopenia (HIT) in the United States, both of which are direct thrombin inhibitors. The agents being reviewed, apixaban and rivaroxaban, are oral direct factor Xa (FXa) inhibitors. Currently, neither has FDA approval for use in HIT. The objective of this review is to summarize the current evidence available regarding the use of oral factor Xa inhibitors for the treatment of HIT. Methods: A literature search was conducted using Medline and Ovid Embase. Search terms included heparin-induced thrombocytopenia, HIT, apixaban, rivaroxaban, Xa Inhibitor, direct thrombin inhibitor, NOAC, and DOAC. Studies and case reports were included if they evaluated the efficacy and safety of oral FXa inhibitors for the treatment of HIT. Additional literature and case reports were found through bibliographic review. Results and Discussion: Currently, available literature includes an in vitro study with apixaban, case reports, and retrospective and prospective cohort studies. The in vitro study evaluated the interaction between apixaban and platelets in the presence of HIT antibodies, which assessed its potential for use in HIT management. Fourteen case reports and one case series were also identified, of which six described treatment with apixaban and eight with rivaroxaban. Lastly, four cohort studies were published evaluating the use of direct acting oral anticoagulants (DOACs), including oral factor Xa inhibitors in patients with HIT. Although there are no published randomized control trials evaluating the use of FXa inhibitors in the management of HIT, there are several findings that may guide clinicians on the use of these agents in practice. Conclusion: As indicated by the case reports, case series and cohort studies detailing clinical use and described in this manuscript, there are data and positive patient outcomes that support the potential use of these agents for HIT, and are an impetus for future studies.

Skin diseases remain a serious reason behind disability worldwide and they are ranked as the fourth most common cause of human illness affecting one-third of human population worldwide. Many conventional treatments are available for treating skin diseases but they have their own drawbacks. Currently, medicated foam serves the most effective purpose. The speedy development in the field of topical foams is because they are efficient and deliver instant absorption and have patient compliance. Various categories of drugs such as anti-inflammatory, anaesthetics, antifungal, skin emollients, antiseptics, antipruritics, etc. can be delivered in the form of medicated foams and have become very important delivery system for topically active agents in dermatology.

The human civilization is reeling under the COVID19 pandemic with no promising news of any effective treatment against the infection to date. A number of drugs have been repurposed without any remarkable efficacy. Amidst the crisis, utilising immunomodulators for boosting host immunity to mitigate disease severity and infectivity appears a viable option. In this article, we have explored the contemporary scientific evidence about levamisole for its potential use in COVID 19. Though the primary pharmacological use of the drug is as an anthelminthic, its immunostimulatory action has been shown to increase T-cell function, neutrophilic chemotaxis and immunoglobulin production both in vitro and in vivo. Clinically, the drug has been used with limited success in the treatment of herpes and HIV. The potential role of the drug in COVID 19 stems from the fact that the immunostimulant action can initiate a strong immune response and surmount the surreptitious virus, which evades host cell immunity. However, great caution has to be exercised in deciding the dosing schedule because the drug-disease interaction, especially the fatal hyperimmune response, is unknown and unpredictable. Being a widely available drug, enlisted in the WHO List of Essential Medicine, without any major safety issue, the drug is already in clinical trials carrying out worldwide. As the pandemic continues to ravage mankind with unabated intensity, any favourable outcome is eagerly awaited from the ongoing trials with levamisole and other drugs.

Background: Clinical competence of pharmacy students is better evaluated at their practice sites compared to the classroom. A clinical pharmacy competency evaluation rubric like that of the American College of Clinical Pharmacy (ACCP) is an effective assessment tool for clinical skills and can be used to show item reliability. The preceptors should be trained on how to use the rubrics as many inherent factors could influence inter-rater reliability. Objective: To evaluate inter-rater reliability among preceptors on evaluating clinical competence of pharmacy students, before and after a group discussion intervention. Materials and Methods: In this quasi-experimental study in a United Arab Emirates teaching hospital, Seven clinical pharmacy preceptors rated the clinical pharmacy competencies of ten recent PharmD graduates referring to their portfolios and preceptorship. Clinical pharmacy competencies were adopted from ACCP and mildly modified to be relevant for the local settings. Results: Inter-rater reliability (Cronbach's Alpha) among preceptors was reasonable being practitioners at a single site for 2-4 years. At domain level, inter-rater reliability ranged from 0.79 - 0.93 before intervention and 0.94 - 0.99 after intervention. No inter-rater reliability was observed in relation to certain competency elements ranging from 0.31 - 0.61 before the intervention, but improved to 0.79 - 0.97 after the intervention. Intra-class correlation coefficient improved among all individual preceptors being reliable with each other after group discussion though some had no reliability with each other before group discussion. Conclusion: Group discussion among preceptors at the training site was found to be effective in improving inter-rater reliability on all elements of the clinical pharmacy competency evaluation. Removing a preceptor from the analysis did not affect inter-rater reliability after group discussion.

Background: The multi particulate drug delivery system is preferred due to its numerous advantages but the batch to batch consistency and to achieve desired physical properties are the major challenges in the formulation of such dosage form. Objective: The objective of the present study was to explore the concept of quality by design for the development of galantamine HBr controlled release pellets using a modified palletization technique. Methods: Compritol 888 and Ethocel were chosen as hydrophobic release retardants, while Avicel was chosen as pelletization aid. A compatibility study was conducted between the drug and excipients. Drug loaded extrudes were prepared by using a mixture of isopropyl alcohol, and dichloromethane. Before converting the wet extrudes into pellets, pregelatinized starch was sprinkled on them to improve the physical properties of the pellets. The pellets were characterized for size, shape, and flow. The critical evaluation parameter was the drug dissolution pattern in distilled water. The dissolution data were treated with advanced data mining techniques. The in-vivo profile was predicted employing pharmacokinetic parameters of the drug and in-vitro drug release data of optimized batch pellets. Results: The failure mode and effect analysis revealed that the amount of Compritol 888 ATO and Ethocel were the most critical formulation parameters. The results of FTIR and DSC revealed compatibility between the drug and the excipients. The spherical pellets exhibited good flow. The drug dissolution studies of the batches, prepared according to the central composite design, revealed modified drug release. Multiple regression analysis and analysis of variance were performed to identify statistically significant factors. Contour plots demonstrated the impact of the amount of Compritol 888 and ethyl cellulose. The Design-Expert software was used to identify optimized formulation. The predicted in-vivo plasma concentration-time profile revealed the modified drug release up to 12h. Conclusion: Compritol and Ethocel were able to retard the drug release up to 12 hrs in distilled water. The innovative finding of this study is the use of a dry binder (pregelatinized starch) to improve the characteristics of pellets. Other dry binders are expected to show a similar effect. The newer processing technique can be of use in the industry.

Background: Response surface methodology is a unique tool for the optimization of Solid lipid Nanoparticles and Nanostructured lipid carriers by developing the relationship between dependent and independent variables and exploring their interactions. Methods: Central Composite Design and Box Benkhen Design were used to develop optimized formulations of Gefitinib [GEF] Solid Lipid Nanoparticles [SLN] and Nanostructured Lipidic Carriers [NLC]. In the design matrix, the independent variables chosen were the amount of Solid Lipid, Liquid Lipid, and Surfactant and the dependent variables were Particle Size and Poly Dispersity Index. Results: The GEF-SLN under optimized conditions gave rise to Particle size (187.9 nm ± 1.15), PDI (0.318 ± 0.006), %EE (95.38%±0.14), Zeta Potential (-8.75 mv ±0.18) and GEF-NLC under optimized conditions gave rise to Particle size (188.6 nm± 1.12), PDI (0.395± 0.004), %EE (97.46%± 0.33), Zeta Potential (-5.72 mv± 0.04) respectively. SEM of the Freeze-dried optimized lipidic carriers showed spherical particles. The in vitro experiments proved that Gefitinib in the lipidic carriers is released gradually throughout 24 h. Conclusion: This study showed that the response surface methodology could be efficiently applied for the modeling of GEF-SLN & GEF-NLC.

Objective: Adequate glycemic control in diabetes patients requires oral combination therapy. Saxagliptin is a dipeptidyl peptidase-4 inhibitor having fewer adverse effects, and metformin is the first-line medicine for diabetes treatment. The aim of this research work is to develop a bilayer tablet of saxagliptin and metformin in fixed-dose combination (FDC) using quality by design (QbD) to acquire the immediate release of saxagliptin and sustained release of metformin from bilayer tablet to ultimately achieve superior patient compliance. Methods: The development of the bilayer tablet was done in four stages using QbD. In the first step, quality target product profile (QTPP) of bilayer tablet was defined, and critical quality attributes (CQAs) were identified by risk estimation matrix and taguchi design; an immediate release saxagliptin layer was optimized in the second step, optimization of sustained-release metformin layer was carried out in the third step, and in the final step, bilayer tablet was prepared and characterized. The effect of independent parameters, i.e., magnesium stearate level (X1), kneading time (X2) and lubrication time (X3) on Carr’s Index (Y1), percentage relative standard deviation of content uniformity (Y2) and drug release at 30 minutes (Y3), were estimated for optimization of immediate release saxagliptin layer using Box-Behnken design (BBD). The effect of independent parameters, i.e., hydroxypropyl methylcellulose level (X4), compritol level (X5) and magnesium stearate level (X6) on Carr’s Index (Y4), drug release at 2 h (Y5), drug release at 5 h (Y6) and drug release at 10 h (Y7) were estimated for optimization of sustained-release metformin layer using BBD. Results: The optimized composition of immediate release saxagliptin layer estimated using numerical optimization by Design expert was 0.88% (X1), 15 minutes (X2) and 3.85 minutes (X3) with predicted variables, i.e., 10.59% (Y1), 3.16% (Y2) and 85% (Y3). The optimized composition of sustained- release saxagliptin layer predicted through numerical optimization was 30% (X4), 3.36% (X5) and 0.9% (X6) having 10.89% (Y4), 43.44% (Y5), 60% (Y6) and 85.14% (Y7). In-vitro dissolution study of bilayer tablet showed immediate release of Saxagliptin (approximately 85% in 30 minutes) and sustained release of metformin illustrating 43.21±1.21, 60.86±2.96 and 86.26±1.38% drug release at 2, 5 and 10 h, respectively. The release exponent for the Korsmeyer-Peppas model for Saxagliptin and metformin was 0.237 (<0.45) and 1.536 (n>0.85), indicating Fickian and super case II transport drug release behavior, respectively. Conclusion: By QbD approach, bilayer tablet containing saxagliptin and metformin was successfully developed, and influence of various formulation parameters on CQAs of drug products was understood with fewer experiments. This leads to the conclusion that cost can be reduced using QbD in the development of FDC for improving patient compliance.

Background: Flexible rectosigmoidoscopy is an easy and accessible exam to diagnose distal colon diseases, although many patients refuse to undergo it due to pain and discomfort during the procedure. Studies show that the application of local lidocaine, as an analgesic has no effect on pain relief in patients undergoing rectosigmoidoscopy. The current study aims at comparing the effects of diltiazem gel, an antispasmoic drug with local pain-reducing effects, with lidocaine gel in patients undergoing flexible rectosigmoidoscopy. Materials and Methods: The current double-blinded, randomized, clinical trial was performed to compare the effect of two topical drugs, lidocaine and diltiazem, on pain relief in patients undergoing rectosigmoidoscopy. A total of 80 patients who were potential candidates for rectosigmoidoscopy were enrolled in the study after obtaining the informed consent and then randomly assigned to one of the lidocaine gel (2 mL) or diltiazem gel (2 mL) group, 10 minutes prior to rectosigmoidoscopy. The level of pain in the patients during the procedure was measured using the visual analogue scale (VAS) and the results were recorded. The data were analyzed using paired samples ttest and independent t-test as well as analysis of covariance (ANOVA) with SPSS version 18. P-value <0.05 was considered the level of significance. Results: Of 80 patients, 35 (43.75%) were male and 45 (56.25%) female. The mean age and body mass index (BMI) of the patients were 51.45 ± 15.21 years and 25.95 ± 7.47 kg/m2, respectively, and there was no significant difference between the groups. The most frequent indications for rectosigmoidoscopy were abdominal pain (46.3%) and rectorrhagia (31.3%). The mean VAS score for pain reported by the patients in the lidocaine and diltiazem groups was 3.97 ± 2.89 and 2.60 ± 2.36, respectively. The VAS score for pain in the diltiazem group was significantly lower than lidocaine group (P = 0.023). Conclusion: The application of local diltiazem gel around the anus, in spite of no side effects, can effectively reduce the pain and discomfort in patients during rectosigmoidoscopy. Iranian Registry of Clinical Trials (Reg. No 31055).