Modern Advances in Pharmaceutical Research Vol. 2

Drug Delivery Approaches

Wajd Amly, Rafik Karaman — Sat, 26 Oct 2019 00:00:00 +0000

This review discusses the different biological barriers that affect the delivery of therapeutic agents through membranes, such as intestinal mucosa, Brain Blood Barrier (BBB), and mediators of transport such as efflux transporters and the approaches for overcoming such barriers. The approaches illustrated in this review include: utilizing natural occurring transporters to deliver drugs specifically to their targets, nucleoside analogues delivery, CYP-activated prodrugs that target drugs to the liver, modification of passive diffusion by efflux pumps, intestinal transporters such as PEPT1 and GLUT1, Carrier Mediated Transport (CMT) systems for transporting nutrients, vitamins or hormones into the central nervous system, tissue selective drug delivery, administration of an exogenous enzyme to reach the tumor site which is followed by systemic administration of non-toxic prodrugs (ADEPT, GDEPT and VDEPT), enzymes involve in the bioconversion of ester-based prodrugs for activation (hydrolysis) of prodrugs to their active forms, brain targeted Chemical Delivery Systems (CDS), amino acid prodrugs to improve oral bioavailability, sustained drug delivery and intravenous drug delivery. Furthermore, Receptor-Mediated Transcytosis (RMT) for efficacious delivery of Nano particles via the intestinal mucosa and BBB, and the prodrug chemical approach based on intra molecularity to deliver anti-cancer drugs is discussed.

Graphical Abstract

Conversion of the cyclic peptide prodrug to the parent peptide by the action of esterase enzymes

Perceptions of the Traditional Medical Practitioners of North-Western Nigeria on Malaria Treatment and the Potential Antiplasmodial Properties of Plumeria rubra Stem-Bark

Sat, 26 Oct 2019 00:00:00 +0000

Aims: The apparent lack of scientific proof of efficacies claimed by the traditional medical practitioners (TMPs) (locally known as Magori/’Yan-ganye, in Hausa language) of North-Western Nigeria with respect to malaria and the many drawbacks of the current antimalarial drugs stimulated this study. The study was carried out to evaluate the perception of the TMPs on the causes, diagnosis and treatment of malaria and evaluate the potential antiplasmodial properties (in-vivo in Albino mice) of Plumeria rubra Linn. (Apocynaceae) commonly used in traditional treatment of malaria in North-Western Nigeria. The study was aimed at providing scientific basis for use of traditional health knowledge and use of medicinal plant resources in the treatment of malaria.

Study Design: Using an ethno-medical survey, information was obtained from the TMPs relating to identification of plants, their medicinal uses and the mode of preparations of remedies on traditional treatment of malaria.

Place and Duration of Study: The ethno-medicinal survey was carried out at the premises of TMPs from December, 2005 to May, 2008. The laboratory work was carried out at the Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria from July, 2008 to February, 2010.

Methodology: An ethno-medical survey was conducted in twenty Local Government Areas across four States (Kaduna, Kano, Katsina and Jigawa) in North-Western Nigeria. The communities covered in the survey were selected on the basis of their reputation for being homes to a number of TMPs. The plant used was selected on the basis of ethno-medical information obtained from the TMPs using an exclusion criterion based on claim for activity score. The preferable solvent used by the local people was found to be mostly water and/or alcohol, the plant material was therefore extracted by maceration technique using 70% v/v aqueous-ethanol. The metabolites profiles of the extracts were determined using thin layer chromatographic (TLC) technique on commercially prepared silica gel pre-coated flexible plates.

Results: The TMPs were able to define, diagnose and presumably treat malaria using the indigenous medicines. Median lethal dose (LD₅₀) was established to be greater than 5 gkg^-1 for the aqueous extract and 3.8 gkg^-1 for the chloroform extract orally in mice respectively. Antiplasmodial evaluation of the two extracts revealed that the two extracts exhibited dose-dependent in-vivo suppressive, curative and prophylactive properties on the development of parasitaemia in Albino mice using a chloroquine sensitive strain of Plasmodium berghei (NK-65). TLC profile fingerprints of the aqueous extract revealed three distinct spots with R_f values of 0.23, 0.39 and 0.75 whereas that the chloroform extract revealed three distinct spots with R_f values of 0.33, 0.42 and 0.55 when it was developed in ethyl acetate: ethanol: water: ammonia (65:25:9:1).

Conclusion: These results represented the first conducted evaluation of the perception of TMPs of North-Western Nigeria on the causes, diagnosis and treatment of malaria, antiplasmodial and thin layer chromatographic profile fingerprinting studies on Plumeria rubra bark found in North-Western Nigeria. The findings are therefore expected to provide the necessary scientific basis for rational use of traditional health knowledge and use of medicinal plant resources of North-Western Nigeria in the treatment of malaria.

The Future of Prodrugs Design

Rafik Karaman — Sat, 26 Oct 2019 00:00:00 +0000

When knowledge fails to provide answers to important questions such as how to improve the bioavailability of vital medications, “Imagination is more important than knowledge,” as Albert Einstein once said. Ingenuity in the design of effective prodrugs has been lacking in quantity and quality. The reasons behind the low quality of ingenuity could be related to the fact that medicinal chemists have expertise in organic and organometalic chemistry not in biochemistry and biology. On the other hand, pharmaceutical chemists, biologists and biochemists do not have the expertise to make sophisticated chemical devices. Therefore, in order for a prodrug strategy to work, a team consisting of all this expertise is necessary.

In vitro and ex vivo Studies of Nonionic Surfactant Vesicles Using 23 Factorial Design: Metoprolol Tartrate Used as Model Drug

Sat, 26 Oct 2019 00:00:00 +0000

The purpose of this study was to formulate and investigate metoprolol tartrate (MT) loaded non-ionic surfactant vesicles using 2³ factorial designs. Preparation of niosomal drug delivery of MT increased its bioavailability which led to being better therapeutic effects, reduced the frequency of dosing and decreased side effects of hypertensive patients. Ether injection method (EIM) and thin film hydration method (TFHM) were used for the preparation of all formulations as per full factorial design to study the effect of two independent variables X1 (amount of span-60), and X2 (amount of cholesterol) on three dependent variable Y1 (percent drug entrapment efficiency), Y2 (percent drug content) and Y3 (percent cumulative drug release) respectively. The relation between the dependent and independent variables was drawn out from the mathematical equation and response surface methodology (RSM). Statistical analysis was performed using ANOVA. Microscopic observation confirmed that all particles were uniform in size and shape. The particle size of niosomes measured by SEM was between 3 μm to 4.5 μm that given the evidence of large uni-lamellar vesicles formed by EIM and TFHM. The percent drug entrapment efficiency was found to be highest for formulations MTEIM-8 and MTTFHM-8 with values 97.11% and 95.56% respectively. In vitro dissolution studies were carried out in phosphate buffer (pH 6.8) for 8 hours at 100 rpm and maintained at 37 ± 0.5°C according to USP-II paddle method and absorbance was taken at 226 nm. The probable drug release mechanism may be fickian (class I) diffusion as the correlation coefficient (????²) best fitted with zero order and release exponent (n) was less than 0.43. The FTIR studies have been done to confirm no interaction along with drug and polymer. In vitro and ex vivo comparative studies showed that non-ionic surfactant vesicle had controlled the release of drug for a longer period. Finally, it can be concluded that non-ionic surfactant vesicle could be an effective for delivery of MT with increased bioavailability.

Prodrugs Designed by DFT and Molecular Mechanics Methods

Rafik Karaman — Sat, 26 Oct 2019 00:00:00 +0000

The accumulation of knowledge on intramolecular processes, enzymes and transporters along with the vast progress in molecular revolution have accelerated the search for prodrugs having the capability to replace their corresponding current marketed drugs and to provide therapeutics with better pharmacological profiles. Utilizing the different available computational methods has led to the design and synthesis of a variety of prodrugs to replace their corresponding parent drugs.

It has been proven that prodrugs can significantly improve the life quality of patients.

The directed enzyme prodrug therapy (DEPT) approach to employ the design of artificial enzymes to activate prodrugs at specific sites along with use of intramolecular processes to design prodrugs are the most attractive strategies to obtain more efficient therapeutics.

Pharmacological Profile and Indications of Non-Vitamin K Antagonist Oral Anticoagulants: Updated Review

Rose Mary Ferreira Lisboa da Silva — Sat, 26 Oct 2019 00:00:00 +0000

The non-vitamin K antagonist oral anticoagulants have been approved since 2008 for the prevention of systemic embolism and stroke in patients with non-valvular atrial fibrillation with prior stroke, transient ischemic attack, or CHA₂DS₂-VASc score ≥2. According to the latest guidelines, if CHA₂DS₂-VASc score ≥2 for all male patients or if CHA₂DS₂-VASc score ≥3 for all female patients, oral anticoagulants are recommended, and considering shared decision between doctor and patient. However, they are contraindicated in patients with mechanical prosthetic valve and in patients with moderate-to-severe mitral stenosis and atrial fibrillation. They have also been approved for prevention and treatment of deep vein thrombosis and pulmonary embolism. Dabigatran, a direct thrombin inhibitor, was the first to be approved, followed by the factor Xa inhibitors, rivaroxaban, apixaban, and in 2015, edoxaban. They have advantages such as the use of fixed-dose, with infrequent drug interaction, rapid onset of action and do not require monitoring of their anticoagulant action. Nonetheless, they have different half-lives, the need for dose adjustment according to renal function, weight and age of the patient. Its use in pregnant women and children or adolescents is not well established. There are also peculiarities about the risks of bleeding, effects on coagulation tests and specific antidotes. Through this review we discuss the pharmacokinetics and pharmacodynamics characteristics of direct oral anticoagulants, its indications, interactions and contraindications. Analysis of its efficacy, safety, risk-benefit ratio and costs will also be addressed.

The Question of Prodrug Naming

Rafik Karaman — Sat, 26 Oct 2019 00:00:00 +0000

Prodrug is a term used to define a pharmacologically inactive chemical entity that can be used to temporarily alter the physicochemical properties of a drug to increase its usefulness and decrease its associated toxicity. According to the definition, the inactive prodrug converts to its active parent drug and a non-toxic linker upon exposure to a physiological environment. Albert stated in his Selective Toxicity book, that the term prodrug is incorrect and should be replaced with the term predug. He apologized for having invented the term, however, now it is too widely used to alter.

TNF-α Inhibitor Treatment for Crohn’s Disease: Comparative Review of Post Therapy Malignancy between Infliximab and Adalimumab

Danil Hammoudi, Adekunle Sanyaolu, Nirav Nagarsheth, Jason Kimbel, Amos Abioye — Sat, 26 Oct 2019 00:00:00 +0000

The association between chronic inflammatory disease and cancer has been well established through years of research. In corollary, progressive resistance to chimeric monoclonal antibodies has been reported in literature. The purpose of this investigation was to establish the overall trend of the chimeric monoclonal antibody (Infliximab) failure compared with human monoclonal antibody (Adalimumab). It was opined that this failure may result in subclinical yet cancer-inducing inflammation that could be measurable in patient populations undergoing the therapy by examining cancer prevalence. An overall trend of increased incidence of new malignancy in patient populations on Infliximab compared with Adalimumab was confirmed from the literature reviewed. There was also a significant trend of developing Gastrointestinal (GI) related cancer in patients on Infliximab, which corresponds with the majority of the progression process in Crohn’s disease. It was opined that future observations in clinical practice will lead to the phasing out of Infliximab as a front-line monoclonal antibody in the treatment of Crohn’s disease in favor of less immunogenic monoclonal antibodies. In conclusion an increased incidence of both general and GI malignancies has been widely reported in patient populations undergoing Infliximab therapy than with Adalimumab.

Spectrum of Thyroid Diseases in Makurdi, Benue State of Nigeria: A Review of 94 Consecutive Cases

B. A. Eke, B. A. Ojo, A. Adekwu, M. Efu, E. I. Ogwuche, P. Abayol — Sat, 26 Oct 2019 00:00:00 +0000

This study aims to review the spectrum of thyroid diseases in Makurdi, Benue State of Nigeria through a histopathological survey. It is a retrospective study covering 1^st January, 2005 to 31^st December, 2016.

Ninety four (94) consecutive cases of thyroidectomy specimens collected from Holy Trinity Specialist Hospital, Makurdi, Nigeria a private hospital and Benue State University Teaching Hospital, Makurdi, Nigeria between January 1^st, 2005 to December 31^st, 2016 were examined histologically and analyzed with regards to age and sex.

There were 7 male specimens as against 87 female specimens giving a male: female ratio of 1:12.43. Nodular colloid goiter was the commonest histological lesion accounting for 72%, followed by thyroid carcinoma which accounted for 11.66%, adenoma 10.60%. Thyroiditis, 5.30% was the fourth commonest pathology and thyroglossal cyst/duct accounted for 1.06%. Follicular carcinoma was the commonest malignancy seen accounting for 7.51% of all specimens and most occurred in females. However, most of these thyroid malignancies occurred in younger age groups (20-49years) compared to other studies in Nigeria and Africa. There is need for a large scale study in Makurdi on the relatively younger age of our thyroid malignancies, higher incidence of follicular carcinoma when compared to other African studies and the relatively high incident of thyroiditis found in this study.

Role and Effectiveness of Simulation-based Training in Raising Family Medicine Residents’ Clinical Resuscitation and Critical Care Skills

Sat, 26 Oct 2019 00:00:00 +0000

Background: Family medicine (FM) physicians are bound to providing healthcare services at a variety of clinical and community settings. They should be equipped to competently handle health emergencies in a multitude of professional procedures. Medical education on patients often raises safety issues; simulation-based medical education (SBME) was a solution enabling education in a risk free environment.

Aim: To analyze the impact of a SBME on Family medicine residents’ performance in critical resuscitation procedures.

Methods: A systematic review of published articles between 1996 and 2016 was conducted. Systematized literature search through ranked search engines was done. All original research articles on SBME published between 1997 and 2012 were examined.

Results: The analysis included 6 relevant studies selected. The studies’ venues included either academic or healthcare settings in Netherlands, Switzerland; Greece, and Canada. The studies’ populations were mainly family medicine, and general practitioner, residents who participated in simulated resuscitation/life support educational activities. The number of participants in each SBME activity ranged between 28 and 72. The study of the Greek experiment included 434 residents. An interventional design was advocated, and a self-reported questionnaire to evaluate participants’ skills pursuant to SBME activities before and/or after the learning activities was unanimously utilized. The main SBME focus involved patient resuscitation and critical event care. Most studies came to significantly positive conclusions about SBME in raising residents’ resuscitation knowledge, skill, and behavior.

Conclusions: The role of interactive SBM teaching in preparing FM residents to rescuing and resuscitating the critically ill independently is now sufficiently evident. Despite such success potential, methods to achieve improved critical care competence advocating low cost simulated medical education solutions in low economic circumstances should be sought.

Prodrugs Design

Rafik Karaman — Sat, 26 Oct 2019 00:00:00 +0000

Prodrug design can be used in the following cases: improving active drug solubility and consequently bioavailability, increasing permeability and absorption and modifying the drug’s distribution profile. In the prodrug design, a computational approach consisting of calculations using Molecular Orbital (MO) and Molecular Mechanics (MM) methods and correlations between experimental and calculated values can be utilized.

Effectiveness and Properties of Hydrazide Drugs that Inhibit Growth of Mycobacterium tuberculosis

Ronald Bartzatt — Sat, 26 Oct 2019 00:00:00 +0000

Aims: To examine the properties of hydrazide compounds shown to inhibit Mycobacterium tuberculosis. To identify properties that affect efficiency of bacterial inhibition.

Study Design: Utilizing data from previous studies of compounds that inhibit Mycobacterium tuberculosis, then statistical and pattern recognition methods are applied to identify interrelationships.

Place and Duration of Study: Department of Chemistry, Durham Science Center, University of Nebraska at Omaha, from January 2016 to July 2016.

Methodology: Interrelationships of pharmacological properties were identified by use of various pattern recognition techniques, such as hierarchical cluster analysis and path analysis. Molecular properties and descriptors for all compounds were determined, with additional characteristics such as structure scaffolding and functional group position was accomplished. Statistical analysis, including Pearson r correlation, Mann-Whitney test, one-way ANOVA, Kruskal-Wallis, and descriptive statistics were determined. Multiple regression analysis of molecular property values allows prediction of similar compounds. Determination of any numerical outliers was accomplished by applying Grubb’s test.

Results: Compounds inhibiting the growth of Mycobacterium tuberculosis contained an aromatic ring or were non-aromatic structures (no ring). There was weak negative correlation of MIC to formula weight. The average formula weight, polar surface area, and Log P, is 183.55 grams/mole, 63.70 A², and 0.768, respectively. Values of MIC ranged from 14.7 µg/mL to 100 µg/mL. Extent of bacterial inhibition was similar between aromatics to non-aromatics. No outliers were identified by Grubb’s test for all values of MIC taken together. Path analysis showed polar surface area to have most effect on MIC.

Conclusion: The measured level of growth inhibition MIC, showed strong positive relationship to polar surface area, number of hydroxyl and amine groups, oxygen and nitrogen atoms. Two aromatic compounds having a pyridine ring were found to be most similar to isoniazid. Aromatic and non-aromatic compounds showed similar levels of bacterial inhibition overall.