Effective Drug Therapy Research Articles

Advances in Pathophysiology of Calcific Aortic Valve Disease Propose Novel Molecular Therapeutic Targets.

Calcific Aortic Valve Disease (CAVD) is the most common heart valve disease and its incidence is expected to rise with aging population. No medical treatment so far has shown slowing progression of CAVD progression. Surgery remains to this day the only way to treat it. Effective drug therapy can only be achieved through a better insight into the pathogenic mechanisms underlying CAVD. The cellular and molecular events leading to leaflets calcification are complex. Upon endothelium cell damage, oxidized LDLs trigger a proinflammatory response disrupting healthy cross-talk between valve endothelial and interstitial cells. Therefore, valve interstitial cells transform into osteoblasts and mineralize the leaflets. Studies have investigated signaling pathways driving and connecting lipid metabolism, inflammation and osteogenesis. This review draws a summary of the recent advances and discusses their exploitation as promising therapeutic targets to treat CAVD and reduce valve replacement.

Lipomatoses.

Lipomatoses are benign proliferations of adipose tissue, often with typical distribution patterns, which usually occur without clear causes. In contrast to circumscribed lipomas, they develop diffusely and symmetrically and are not surrounded by a fibrous pseudocapsule. The most common form is benign symmetric lipomatosis (BSL; Launois-Bensaude syndrome), of which four types are distinguished based on the distribution pattern of hyperplastic adipose tissue. The etiology and pathogenesis of the disease are still largely unknown, although some forms appear to have a hereditary basis or to be associated with increased alcohol consumption. In some cases, mitochondrial dysfunctions have been detected. Lipomatoses may be solitary, but may also be associated with other symptoms or illnesses (comorbidity). Effective drug therapies are not known, but surgical procedures can alleviate the symptoms. Lipomatosis dolorosa, which can be distinguished from BSL, occurs predominantly in middle-aged women and is characterized by proliferation of adipose tissue and severe pain in the affected areas. Various differential diagnoses and concomitant illnesses need to be considered, in particular depression. There are no evidence-based recommendations for therapy. Repetitive lidocaine infusions can achieve temporary improvement. Recurrence after surgical intervention is not uncommon, but long-term success is also possible.

Vinorelbine Potently Induces Placental Cell Death, Does Not Harm Fertility and is a Potential Treatment for Ectopic Pregnancy

Ectopic pregnancies complicate 1–2 pregnancies and are a leading cause of maternal death. An effective oral drug therapy that replaces surgery might make its treatment safer, cheaper, simpler and therefore more widely accessible. The only current medical treatment offered to women is intramuscular methotrexate, but this only reliably resolves smaller ectopic pregnancies. As such, many ectopic pregnancies require surgical excision. We show that vinorelbine, an orally available chemotherapeutic agent, potently induced placental cell death but did not harm fertility in mice. Vinorelbine was 100–1000 times more potent than methotrexate in inducing placental cell death in vitro, and more potent than combination methotrexate and gefitinib (another proposed treatment for ectopic pregnancy being evaluated in phase III trials). Mechanistically, it caused microtubule condensation, blocked mitosis and activated the apoptosis cascade in placental cells. Vinorelbine was more efficacious than methotrexate±gefitinib in reducing the volume of placental cell tumors xenografted subcutaneously in SCID mice. Mice exposed to vinorelbine and allowed to breed, following a four week washout period, displayed normal fertility, however long-term fertility was not assessed. Human Fallopian tubes treated with vinorelbine did not exhibit up-regulation of apoptosis molecules. Our findings show that placental cells appear sensitive to vinorelbine and it has potential as a tablet-only approach to treat ectopic pregnancy.

Patient at intermediate cardiovascular risk: statins, yes! - antihypertensive therapy, maybe.

Patient at intermediate cardiovascular risk: statins, yes! - antihypertensive therapy, maybe.

Efficacy of essential oil of Syzygium aromaticum alone and in combination with benznidazole on murine oral infection with Trypanosoma cruzi IV

Chagas disease (CD), caused by Trypanosoma cruzi, remains a serious public health problem. One of the causes of the high morbidity and mortality in patients is the lack of an effective drug therapy. Thus, the aim of this study was to evaluate the efficacy of the essential oil of Syzygium aromaticum alone and in combination with benznidazole (BZ) in mice orally inoculated with strain of T. cruzi IV obtained from oral CD outbreak occurred in Western Brazilian Amazonia. All the animals inoculated with metacyclic trypomastigote forms (AM14 strain, BZ resistant), derived from the insect Rhodnius robustus, became infected and there was no difference in the mortality rate between the experimental groups. When compared with untreated control animals (UTC), the treatment with essential oil of S. aromaticum (EOSA) alone promoted reduction in 1/5 parameters derived from the parasitemia curve, whereas the treatments with BZ alone or in combination (BZ + EOSA) promoted reduction in 4/5 of those parameters, presenting similar profiles of parasitemia curve. The animals treated with BZ and with the combination BZ + EOSA presented lower patency periods in comparison with the animals in EOSA group, and lower positivity of blood cultures when compared with the UTC group. The results of molecular analysis by qPCR in both blood and cardiac tissue did not show differences between the groups. The cure rates obtained with the different treatments presented the following ascending order: EOSA = 12.5% (1/8), BZ = 25.0% (2/8) and BZ + EOSA = 37.5% (3/8). Although there are no significant differences between them, these results claims that the use of this essential oil could be of interest for treatment of Chagas disease.

Computational Modeling of the Staphylococcal Enterotoxins and Their Interaction with Natural Antitoxin Compounds

Staphylococcus aureus is an opportunistic bacterium that produces various types of toxins, resulting in serious food poisoning. Staphylococcal enterotoxins (SEs) are heat-stable and resistant to hydrolysis by digestive enzymes, representing a potential hazard for consumers worldwide. In the present study, we used amino-acid sequences encoding SEA and SEB-like to identify their respective template structure and build the three-dimensional (3-D) models using homology modeling method. Two natural compounds, Betulin and 28-Norolean-12-en-3-one, were selected for docking study on the basis of the criteria that they satisfied the Lipinski’s Rule-of-Five. A total of 14 and 13 amino-acid residues were present in the best binding site predicted in the SEA and SEB-like, respectively, using the Computer Atlas of Surface Topology of Proteins (CASTp). Among these residues, the docking study with natural compounds Betulin and 28-Norolean-12-en-3-one revealed that GLN43 and GLY227 in the binding site of the SEA, each formed a hydrogen-bond interaction with 28-Norolean-12-en-3-one; while GLY227 residue established a hydrogen bond with Betulin. In the case of SEB-like, the docking study demonstrated that ASN87 and TYR88 residues in its binding site formed hydrogen bonds with Betulin; whereas HIS59 in the binding site formed a hydrogen-bond interaction with 28-Norolean-12-en-3-one. Our results demonstrate that the toxic effects of these two SEs can be effectively treated with antitoxins like Betulin and 28-Norolean-12-en-3-one, which could provide an effective drug therapy for this pathogen.

Therapy in Amyotrophic Lateral Sclerosis (ALS): an unexpected evolving scenario.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease resulting in increasing disability, being uniformly fatal. Since its approval in the 1990s, riluzole remained for long time the unique treatment, offering modest survival benefit. Most recently a second drug has been approved by the US Food and Drug Administration for treatment of ALS: edaravone. Significant advances have been made in the symptomatic management of the disease but more effective drug therapy targeting disease progression is still dreadfully needed, the success appearing almost a miracle. Recent discoveries related to genetics indicate divergent mechanisms of disease encouraging precision medicine leading to molecularly tailored interventions. The search for effective therapy still faces important challenges in the areas of both basic science and animal research, adequate translation of results into human clinical trials, inherent bias in human studies, and issues related to delays in clinical diagnosis. It is interesting to point out that ALS research may speed up drug development not only for this disease, but also for other more prevalent neurodegenerative diseases: the reverse is also conceivable.

Size and Taste Matters: Recent Progress in the Development of Age-Appropriate Medicines for Children

Drug therapy for children is one of the cornerstone developments that have sharply reduced childhood mortality. Despite this, many challenges remain in ensuring that children receive safe and effective drug therapy. There are unique issues in treating children with oral medication relating to development, existing formulations and medication acceptability. Medication acceptability in children is complex relating to a wide range of factors, including drug palatability. Over the past decade there has been an increasing interest in and research as to how to improve and enhance child-specific drug formulations including the development of specific instruments for assessing drug palatability in children and new approaches to teaching medication literacy to families. Approaches to enhancing drug acceptability have also included organoleptic (taste masking) strategies as well as the creation of a number of innovative taste-blocking strategies and new technologies for formulation preparation. Polymer coating, microencapsulation and heat melt technologies have resulted in drug formulations that are now being assessed in children while soft melt and gel formulations are now commonly used. Mini-tablets offer the potential of using solid delivery systems in even very young infants. This work has resulted in a number of highly promising developments that are being evaluated for clinical use as well as providing insights into new directions in pursuit of the common goal of effective and safe drug therapy for children. On-going challenges include the need for drug regulatory agencies to work closely with drug regulatory agencies in facilitating innovation in formulation design and approval.

Analysis of TSC1 mutation spectrum in mucosal melanoma.

Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma. We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1. The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0months, P = 0.007). Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.

Differential prioritization of therapies to subtypes of triple negative breast cancer using a systems medicine method.

Triple negative breast cancer (TNBC) is a group of cancers whose heterogeneity and shortage of effective drug therapies has prompted efforts to divide these cancers into molecular subtypes. Our computational platform, entitled GenEx-TNBC, applies concepts in systems biology and polypharmacology to prioritize thousands of approved and experimental drugs for therapeutic potential against each molecular subtype of TNBC. Using patient-based and cell line-based gene expression data, we constructed networks to describe the biological perturbation associated with each TNBC subtype at multiple levels of biological action. These networks were analyzed for statistical coincidence with drug action networks stemming from known drug-protein targets, while accounting for the direction of disease modulation for coinciding entities. GenEx-TNBC successfully designated drugs, and drug classes, that were previously shown to be broadly effective or subtype-specific against TNBC, as well as novel agents. We further performed biological validation of the platform by testing the relative sensitivities of three cell lines, representing three distinct TNBC subtypes, to several small molecules according to the degree of predicted biological coincidence with each subtype. GenEx-TNBC is the first computational platform to associate drugs to diseases based on inverse relationships with multi-scale disease mechanisms mapped from global gene expression of a disease. This method may be useful for directing current efforts in preclinical drug development surrounding TNBC, and may offer insights into the targetable mechanisms of each TNBC subtype.

Drug therapy targeting pyrophosphate slows the ossification of spinal ligaments in twy mice.

The lack of an effective drug therapy against ossification of spinal ligament (OSL) warrants investigation into the therapeutic target of this disease. An endogenous inhibitor of biomineralization, pyrophosphate (PPi) is a potential therapy for ectopic ossification; however, exogenous PPi is rapidly hydrolyzed by tissue non-specific alkaline phosphatase (TNAP) present in body fluids. In this study, we examined whether a drug therapy targeting PPi is efficacious for the treatment of OSL using the Enpp1ttw/ttw (twy) mouse model. Twenty male twy mice were randomized into four groups: (i) vehicle (Control); (ii) alkaline phosphatase inhibitor levamisole (5 mg/kg/day sc continuously); (iii) levamisole + exogenous PPi (160 µmol/kg/day sc continuously); and (iv) nuclear retinoic acid receptor-γ (RARγ) agonist (6 µg/kg sc daily). The RARγ agonist, which is a proven inhibitor of ectopic endochondral ossification, was used as a positive control. Treatments commenced when the mice were 5 weeks of age and continued for 4 weeks. Longitudinal micro-computed tomography and postmortem histological analysis were performed. Administration of levamisole alone and in combination with PPi increased serum PPi concentration by 17% and 52%, respectively, compared to that in vehicle-treated mice. The development of OSL in twy mice was suppressed by levamisole + PPi and RARγ agonist treatments, but not by levamisole alone. The levamisole + PPi therapy did not cause osteoporosis, whereas RARγ agonist-treated mice developed osteoporosis. Treatment of twy mice with levamisole in combination with exogenous PPi increased serum PPi level, which slowed the progression of OSL without producing adverse effect on bone. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1256-1261, 2018.

Effect of Euphorbia Prostrata on the Wound Healing in Excisional Wound Model in Rats

Background-Euphorbia prostrata possesses many actions one of which is wound healing. Skin wound healing is a significant health care problem which clinician faces still. Hence this study was planned to evaluate effect of euphorbia prostrata on skin wound healing. Material and methods-This study was conducted among randomly selected wistar rats (n=6 per group). Group A and Group B had Cream and 1% euphorbia prostrate cream applied topically on the excisional wound respectively. Wound healing and epithelisation was assessed on Days 4,8,12,16,20. Results: Group A showed an average wound size of 348±13.0 on day 4, 278±10.5 on day 8, 119±9.8 on day 12, 86±9.2 on day 16 and 100% wound healing was observed day 20 onwards. Group B showed an average wound size of 296±11.0 on day 4, 147±9.5 on day 8 and complete wound healing was observed day 12 onwards in the test group. Conclusion: Euphorbia prostrata holds promise as effective drug therapy for wound healing.

PP-44 Developing a paediatric drug formulary for the netherlands

<h3>Background</h3> As many drugs in paediatrics are used of off-label, prescribers face a lack of evidence-based dosing guidelines. Current knowledge on paediatric pharmacotherapy is empirical, practice based, and seldom systematically collected and disseminated.The overall aim was to develop an openly accessible, web based formulary con-taining best evidence based, referenced and up-to-date drug-specific information, which was acceptable to paediatricians, hospital pharmacists and general practitioners. <h3>Methods</h3> The work was done by a team of a coordinat-ing paediatrician (0.2 fulltime equivalent (fte)), project manager (0.8 fte) and pharmacist (1.0 fte) and the multidisciplanary editorial board of 35 members. The overall budget on an annual basis was € 250 000 in the first 2 years, and currently € 220 000. The formulary started as a consensus-based formulary. From this point onwards, a dedicated pharmacist searched the available scientific literature following and assessed the risks and benefits of use in the paediatric population. The evidence is de-scribed in a risk analysis document and summarised in a drug monograph and reviewed by the editorial board before publication. <h3>Results</h3> A framework was developed to provide dosing guidelines based on best available evidence from reg-istration data, published investigator-initiated research, guidelines, clinical experience and consensus. Dissem-ination of these dosing guidelines was established by developing an open-access online database (http://www.kinderformularium.nl/). The development has resulted in the revision of many earlier consensus-based dose rec-ommendations, clarified the scientific grounds of drug use for children and ensured uniformity in prescribing habits in the Netherlands. Also, additional projects to fur-ther improve the information and usability of the formu-lary were initiated, including dosing guidelines for renal dysfunction, a dosing calculator and parent/patient drug information leaflets. <h3>Discussion</h3> It is almost impossible to make a paediatric risk-benefit assessment based on the same standards that are mandatory when assessing adult drug use. We are aware that many of our dosing recommendations there-fore still bear a varying degree of uncertainty. ‘Best-evidence’ means that we do know the scientific background that supports paediatric use. This also implies that, in the face of low-quality evidence, expert opinion or a consen-sus of a group of experts is important. It is a common misconception that a recommendation supported by low-quality evidence implies a recommendation against use. The Dutch Paediatric Formulary deliberately chose to give insights in the limited amount of evidence available and create awareness rather than to reject paediatric use because of limited evidence. <h3>Conclusion</h3> The Dutch Paediatric Formulary is a proof of concept in creating a knowledge-based paediatric formulary. The formulary has also been of great value in timely translating scientific research knowledge to daily practice. We believe that the Dutch approach in creating a knowledge-based paediatric formulary was successful and could be used as basis for similar initiatives world-wide, preferably in a concerted effort to ultimately pro-vide children with effective and safe drug therapy.

Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy.

The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb. The mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation. H37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 μM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation. MGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.

Taurine and tea polyphenols combination ameliorate nonalcoholic steatohepatitis in rats

BackgroundNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, for which there is currently no safe and effective drug for therapy. In this study, we explored the effects of taurine, tea polyphenols (TPs), or a combination thereof, on NASH rats.MethodsRats were divided into a normal group, a high-fat diet induced model group and a treatment group (including taurine, TPs, or taurine + TPs treatment for 8 weeks). Twelve weeks later, all rats were sacrificed, and serum transaminase, lipid and lipopolysaccharide levels and hepatic oxidative stress levels were determined. Histological changes were evaluated.ResultsIn NASH rats, hepatocyte damage, lipid disturbance, oxidative stress and elevated lipopolysaccharide levels were confirmed. Taurine treatment alleviated hepatocyte damage and oxidative stress. TPs treatment improved lipid metabolism and increased hepatic antioxidant activity. The therapeutic effects of taurine + TPs treatment on hepatocyte damage, lipid disturbance, and oxidative stress were superior to those of taurine and TPs treatment, respectively. Taurine, TPs and their combination all decreased serum lipopolysaccharide levels in NASH rats, but the combination of the compounds caused these levels to decrease more significantly than taurine or TPs treatment alone.ConclusionTaurine combined with TPs treatment could relieve NASH by alleviating hepatocyte damage, decreasing oxidative stress and improving lipid metabolism and gut flora disturbance partly. Taurine and TPs combination may act as a new effective medicine for treating NASH patients.

Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study.

Ankylosing spondylitis (AS) is an autoimmune disease characterized by fibroblasts ossification. However, effective drug therapy for AS is lacking. As an antidiabetic drug, metformin has demonstrated an antiosteogenic effect on osteoblasts in vitro. And it is also a kind of specific agonists for adenosine 5'-monophosphate activated protein kinase (AMPK), which is blocked in the process of AS. Given the role in antiosteogenesis and AMPK activating, metformin was investigated of its effect on fibroblasts harvested from capsular ligament of patients with femoral neck fracture and AS. Osteogenic specific makers (Alp, Bglap, Runx2, Bmp2, and Col1) in fibroblasts administered with metformin (20 μg/mL) were detected by ALP staining, alizarin red staining, qPCR, and Western blotting after 7 and 14 days of culture. Inflammation genes (il1-β and il6) and pathway (Pi3k, Akt, and Ampk) associated markers were also evaluated. Our results showed that osteogenic specific markers were greatly downregulated and ossification was effectively inhibited in AS fibroblasts after addition of metformin. Levels of inflammation markers were also decreased by metformin. Thus, metformin exerts potent effect on suppression of ossification and inflammation in AS fibroblasts via the activation of Pi3k/Akt and AMPK pathways, which may be developed as a potential agent for treatment of AS.

VIPAR, a quantitative approach to 3D histopathology applied to lymphatic malformations

Lack of investigatory and diagnostic tools has been a major contributing factor to the failure to mechanistically understand lymphedema and other lymphatic disorders in order to develop effective drug and surgical therapies. One difficulty has been understanding the true changes in lymph vessel pathology from standard 2D tissue sections. VIPAR (volume information-based histopathological analysis by 3D reconstruction and data extraction), a light-sheet microscopy-based approach for the analysis of tissue biopsies, is based on digital reconstruction and visualization of microscopic image stacks. VIPAR allows semiautomated segmentation of the vasculature and subsequent nonbiased extraction of characteristic vessel shape and connectivity parameters. We applied VIPAR to analyze biopsies from healthy lymphedematous and lymphangiomatous skin. Digital 3D reconstruction provided a directly visually interpretable, comprehensive representation of the lymphatic and blood vessels in the analyzed tissue volumes. The most conspicuous features were disrupted lymphatic vessels in lymphedematous skin and a hyperplasia (4.36-fold lymphatic vessel volume increase) in the lymphangiomatous skin. Both abnormalities were detected by the connectivity analysis based on extracted vessel shape and structure data. The quantitative evaluation of extracted data revealed a significant reduction of lymphatic segment length (51.3% and 54.2%) and straightness (89.2% and 83.7%) for lymphedematous and lymphangiomatous skin, respectively. Blood vessel length was significantly increased in the lymphangiomatous sample (239.3%). VIPAR is a volume-based tissue reconstruction data extraction and analysis approach that successfully distinguished healthy from lymphedematous and lymphangiomatous skin. Its application is not limited to the vascular systems or skin. Max Planck Society, DFG (SFB 656), and Cells-in-Motion Cluster of Excellence EXC 1003.

PHARMACIST LEAD PATIENT COUNSELLING: IMPACT ON QUALITY OF LIFE IN ASTHMA PATIENTS

Safe and effective drug therapy depends on patients being well informed about their medication. The proper use of drugs and patient education are vital for asthma management. Increasing patient’s knowl-edge about their asthma therapy is a necessary component of asthma management. This study was carried out to assess the patient counseling impact on quality of life (QOL) in asthma patients using SF 36questionnaire. In this study a total of hundred patients diagnosed with asthma were enrolled by considering the inclusion and exclusion criteria. Out of this, 50 (50%) patients were in intervention and 50 (50%) patients in the control group. As per our study it was found that the predominant risk factor for Asthma was fumes and smoking was found to be the major risk factor in males. After patient counseling intervention group showed improvement in QOL from the baseline to1st and 2nd follow-ups. But control group doesn’t show significant improvement in the QOL from the baseline to 1st and 2nd follow-ups. Physical activity and daily activity was also found to be increased during second follow-up in intervention group than in control group. Our study concluded that continuous education programs and counseling should be conducted for chronic diseases to emphasize and re-emphasize the importance of Quality of Life, to prevent recurrences, reduce progression of disease and ultimately minimize the hospitalization and there is a need of continuous pharmaceutical care services/ monitoring to improve the better quality of life.

Larrea tridentata: A novel source for anti-parasitic agents active against Entamoeba histolytica, Giardia lamblia and Naegleria fowleri.

Protozoan parasites infect and kill millions of people worldwide every year, particularly in developing countries where access to clean fresh water is limited. Among the most common are intestinal parasites, including Giardia lamblia and Entamoeba histolytica. These parasites wreak havoc on the epithelium lining the small intestines (G. lamblia) and colon (E. histolytica) causing giardiasis and amebiasis, respectively. In addition, there are less common but far more deadly pathogens such as Naegleria fowleri that thrive in warm waters and infect the central nervous systems of their victims via the nasal passages. Despite their prevalence and associated high mortality rates, there remains an unmet need to identify more effective therapeutics for people infected with these opportunistic parasites. To address this unmet need, we have surveyed plants and traditional herbal medicines known throughout the world to identify novel antiparasitic agents with activity against G. lamblia, E. histolytica, and N. fowleri. Herein, we report Larrea tridentata, known as creosote bush, as a novel source for secondary metabolites that display antiparasitic activity against all three pathogens. This report also characterizes the lignan compound classes, nordihydroguairetic acid and demethoxyisoguaiacin, as novel antiparasitic lead agents to further develop more effective drug therapy options for millions of people worldwide.

Blood-Brain Barrier Driven Pharmacoresistance in Amyotrophic Lateral Sclerosis and Challenges for Effective Drug Therapies.

The blood-brain barrier (BBB) is essential for proper neuronal function, homeostasis, and protection of the central nervous system (CNS) microenvironment from blood-borne pathogens and neurotoxins. The BBB is also an impediment for CNS penetration of drugs. In some neurologic conditions, such as epilepsy and brain tumors, overexpression of P-glycoprotein, an efflux transporter whose physiological function is to expel catabolites and xenobiotics from the CNS into the blood stream, has been reported. Recent studies reported that overexpression of P-glycoprotein and increase in its activity at the BBB drives a progressive resistance to CNS penetration and persistence of riluzole, the only drug approved thus far for treatment of amyotrophic lateral sclerosis (ALS), rapidly progressive and mostly fatal neurologic disease. This review will discuss the impact of transporter-mediated pharmacoresistance for ALS drug therapy and the potential therapeutic strategies to improve the outcome of ALS clinical trials and efficacy of current and future drug treatments.