Cardiovascular & Haematological Disorders - Drug Targets - Volume 17, Issue 2, 2017

Background: Segmental medial arteriolysis (SAM) is a unique arteriopathy highlighted by significant lytic changes in the medial wall of the blood vessels and can present from vague gastrointestinal discomfort to catastrophic abdominal bleeding and shock. We hereby present a concise review of this rare phenomenon with historic perspectives, epidemiology, and current concepts of etiology, pathogenesis, relevant clinical associations, treatment modalities, prognosis and future directions in SAM. Conclusion: In addition, we present an interesting occurrence of this intriguing phenomenon in a forty-eight year old lady at our institution who presented with vague symptomatology and was an extremely challenging diagnosis. This highlights the importance of timely detection and institution of therapeutic or preventive strategies to minimize future catastrophic events.

Background: Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure (HF) cases and has similar outcomes compared to heart failure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge and approach to treatment. HFpEF is diagnosed using the following criteria: symptoms, preserved ejection fraction (greater than 50%), and evidence of abnormal left ventricular filling or relaxation, or diastolic distensibility or stiffness. Studies conducted to examine the efficacy of angiotensin receptor blockers (ARB) (irbesartan and candesartan), thiazide diuretics (chlorthalidone), and angiotensin converting enzyme inhibitors (ACEI) (perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear benefit. Recently, the FDA has approved a novel drug, which combines an angiotensin receptor neprilysin inhibitor and ARB (valsartan) named LCZ696 (entresto) for possible treatment of HFrEF. Conclusion: In this article, we will discuss the failure of previous treatment modalities and the promise that LCZ696 (entresto) may hold for treating patients with HFpEF.

Background: The serotonin 2B receptor subtype (5-HT2BR), located in central nervous system (CNS), cardiovascular system (CVS) and the gastrointestinal tract (GIT), is an important target for the treatment of migraine, obesity and irritable bowel syndrome. 5-HT2BR is necessary for the myocardial cell proliferation and differentiation at the embroyonic stage for healthy development of heart. Recently, its involvement in drug induced valvulopathy and other myocardial disorders, have paved a way for selective antagonist for the treatment of cardiac disorders. Conclusion: The current review summarizes the limited progress made in the past decade for design and development of 5-HT2BR antagonists for the treatment of disorders related to heart. We focus primarily on the different scaffolds reported in both manuscripts and patents, that have led to selectivity for 5-HT2B over subtype 5-HT2A/2C. Opportunities in cardiovascular drug development for novel 5-HT2BR antagonists are also presented.

Background: Approximately 3% of Tuberculosis (TB) patients have a venous thromboembolic events (VTE). The use of Vitamin K antagonists (VKAs), as anticoagulant, in patients receiving anti TB antimicrobials is often complicated by drug interactions, especially with rifampicin. These patients require frequent monitoring of the International Normalized Ratio (INR), and it is reported that warfarin can not achieve a therapeutic INR. In such cases, abruptly stopping the rifampicin once the course of anti TB antimicrobials is not completed is potentially hazardous. The most recent alternative to prevent thrombotic episodes by using oral agents is represented by novel oral anticoagulants (NOAs) an important breakthrough since they do not require strict laboratory monitoring, frequent dosing adjustments, or dietary restrictions; moreover, they and they are linked with far fewer drug-drug interactions. Objective: We have performed a Systematic Review to retrieve information about studies that have assessed the effect of NOAs administered in combination with anti TB antimicrobials in order to investigate if NOAs could be used in TB patients with VTE that do not achieve a therapeutic INR with VKAs. Method: The MEDLINE and Google Scholar databases were screened from the inception to 5th of February 2017, using two search strategies: the first one was antimicrobials AND novel oral anticoagulants; the second was antibiotics AND novel oral anticoagulants. Results: 1011 titles were identified on PubMed and Google Scholar published from the inception to February 5, 2017, of these 17 studies were included in the qualitative synthesis Conclusion: No published data were found that properly assessed the effect of NOAs administered in combination with anti TB antimicrobials. Further studies are needed to establish the safety of NOAs in this clinical scenario. In the meanwhile, a viable alternative to VKAs, in order to prevent complications of VTE related to TB, may be represented by Low Molecular Weight Heparin (LMWH), notwithstanding the limitation of the parental route of administration.

Background: Hemophilic arthropathy (HA) of the ankle is prevalent in people with hemophilia (PWH). It is frequently severe and incapacitating, due to recurrent bleeding into the ankle articulation during infancy. Around 50% of hemophilic patients suffer from ankle pain and radiological signs of HA. Objective: To review current treatment of HA of the ankle in PWH. Method: A literature review of hemophilic ankle arthropathy in PWH was performed utilizing MEDLINE (PubMed) and the Cochrane Library. Results: Primary hematologic prophylaxis could keep away from the development of ankle HA if the level of the patient's deficient factor is prevented from dropping below 1% of normal. Recurrent articular bleeding can be prevented by the intravenous infusion of clotting factor concentrates (prophylaxis). Major articular bleeds and chronic hemophilic synovitis should be managed fiercely to prevent ankle HA. In the circumstance of advancing articular involvement, some noninvasive and invasive procedures can procure symptomatic mitigation and ameliorate the patient’s function and quality of life. Conclusion: The ideal treatment for the hemophilic ankle when hematologic prophylaxis fails includes physical medicine and rehabilitation, orthoses, radiosynovectomy, arthroscopic ankle debridement (in the initial stages of cartilage degeneration), and ankle distraction, ankle fusion or total ankle replacement (in advanced stages of cartilage degeneration).

Background: Atherosclerosis is a chronic inflammatory condition causing very high morbidity and mortality. It is characterized by accumulation of plaques within arteries. Nanomedicine is an emerging field of medicine utilizing nanotechnology for advanced imaging and therapy. Nanomedicine has led to significant developments in the field of cardiovascular diseases, including atherosclerosis. Many nanoformulations have been developed with anti-atherosclerotic effects. Nanomedicine tools have been used in the imaging of atherosclerosis. Various nanocarriers have been employed for successful localization in atherosclerotic lesions. The biggest challenge for such delivery vehicles has been localization to atherosclerosis lesions. Several strategies have been employed to overcome these defects. Strategies have also been developed for stabilization of atherosclerotic lesions. Conclusion: Nanotechnology is also an important tool for the development of novel biomarkers. At the same time there are also potential limitations. Toxicity, lack of translation from preclinical phase to clinical development, and the inability to address the chronic phase of atherosclerosis are the most important among them. Future toxicity studies shall enlighten us further on this exciting research area.

Background: Ultrasound-assisted, catheter-directed thrombolysis (UA-CDT) relieves right ventricular stress without a significant increase in the risk of bleeding compared to systemic thrombolysis. Although concomitant anticoagulation is provided to prevent thrombus expansion, the optimal anticoagulation regimen in patients receiving UA-CDT remains unknown. Objective: We sought to describe anticoagulation practices for patients receiving UA-CDT. Methods: Patients receiving UA-CDT for acute pulmonary embolism (PE) between Jan 1, 2013 to Sept 30, 2014 at a single center were analyzed. We collected patient characteristics, fibrinolytic and anticoagulant usage as well as clinical outcomes. Results: Fourteen patients were included in the final analysis. The mean alteplase dose was 16.8 ± 5.6 mg and 24.3 ± 3.4 mg in unilateral and bilateral PE, respectively. Mean unfractionated heparin (UFH) rates were 7.4 (±2.17) IU/kg/hr and 12.4 (±3.1) IU/kg/hr during and after fibrinolytic therapy, respectively. The median aPTT was 42.4 sec [IQR 34.5-51.8] and 77.9 sec [IQR 66.5-96.8] during and after fibrinolytic therapy, respectively. There were no recurrent VTE within 30 days of hospital discharge. One patient had a major bleeding event (intracranial hemorrhage). Conclusion: In patients with acute PE, our institution utilized low levels of anticoagulation during fibrinolytic administration and therapeutic doses after completion of fibrinolytic infusion. Standardized protocols for anticoagulation during UA-CDT are warranted.

Objective: The aim was to report a new family with congenital FX deficiency. Patients and Methods: The proposita is a 41 year old female with a moderate bleeding tendency (easy bruising, menorrhagia). Parents were not consanguineous. Family history was positive for a mild bleeding tendency. Results: Coagulation and genetics studies revealed that the proposita and two of her siblings were heterozygotes for a new mutation Cys241Gly in exon 6 but had different FX level (2-3% of normal in the proposita and about 50% in the two siblings. The same was true for one of her three children. The mother and the other two children of the proposita had also slightly decreased FX levels but no mutation. On the suspicion that the proposita was carrying another defect which had escaped the Sanger method, we carried out a whole exome analysis and discovered that the proposita and one of her siblings were also homozygous for a mutation of a known polymorphism (c.503-57C>T). The daughter of the proposita was instead, besides being a carrier of the missense new mutation Cys241Gly, heterozygous for the same polymorphism. The mother and two other daughters were also heterozygous for the polymorphism. There were no deletions or duplications. Conclusion: The polymorphism present in the family seems to be capable of potentiating the defect induced by the new mutation. This, safe for epigenetics phenomena, is the only possible explanation for the discrepancy found in the FX level between mother and daughter despite the fact that both carried the same new mutation.

Background: Buxus sempervirens L. (Boxwood) is a medicinal plant used in Moroccan traditional medicine for diabetes treatment in Morocco. However; there is no experimental support of this ethnopharmacological use. Methods: The present investigation is aimed at studying the antidiabetic and the preliminary phytochemical of the aqueous extract of the leaves of Buxus sempervirens (AELBS). AELBS (5 mg/kg) was administered by gavage to normal and streptozotocin-induced diabetic rats and blood glucose levels were measured for 6 hours (acute study) and 15 days (chronic study). Oral glucose test tolerance (OGTT) and histopathological examination of liver and pancreas were carried out using standard methods. Furthermore, preliminary phytochemical screening and quantification of phenolic and flavonoid contents were also realized. Results: AELBS reduced the blood glucose of both healthy and diabetic rats. This extract was also able to improve oral glucose tolerance in diabetic rats and it ameliorated hepatic histology, however, no enhancement was noticed in pancreatic histology. Preliminary phytochemical study revealed that AELBS possesses many chemical compounds such as alkaloids, phenolic compounds (flavonoids, tannins, and cyanidins), carbohydrates, reducing sugars and mucilage. Additionally, this extract is rich in phenolic compounds including flavonoids. Conclusion: According to all these findings, we conclude that AELBS at a low dose demonstrated a potent antihyperglycemic effect in streptozotocin rats and further investigations should be necessary for supporting the use of this plant in the management of diabetes by the Moroccan population.