Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 22, Issue 2, 2024

Herbal remedies are used by 80% of the Asian population in primary health care as per WHO. According to current research, the herbal medicine market was valued at nearly USD 166 billion in 2021 and is expected to reach approximately USD 348 billion by 2028. Increased incidence of chronic conditions such as diabetes, asthma, coronary artery disease, osteoarthritis, has fueled the growing interest in traditional herbal and plant-derived treatments among researchers. In addition, rural communities in developing nations have renewed interest in herbal treatments due to lower cost and easy availability.

Aim of the paper is to highlight the role of five of more commonly used herbal medicines that are Ginkgo biloba, Garlic, Flaxseed, Ginseng, Salvia miltiorrhiza in cardiovascular disorders.

A PubMed search was done using the keywords Herbal Medicine, Ginkgo biloba, Garlic, Flaxseed, Ginseng, Salvia miltiorrhiza. Articles which were available for free access were utilized. No formula inclusion or exclusion criteria was followed. A total of 42 papers were included for the study.

Although there have been encouraging outcomes with the use of these herbal medications, many of these products are poorly monitored and are yet to be studied in detail regarding their adverse effects. Moreover, these medicinal products are known to interact with various drugs. To compete with the expanding pharmaceutical industry, more medicinally helpful herbal items must be used and scientifically validated.

Advances in organ transplantation were made after the discovery of the pure form of cyclosporine by Dr Jean Borel in the 1970s. In fact, in clinical practice achieving a delicate balance in circulating immunosuppressive necessitate focus on the difficult task of post-transplant therapeutic drug monitoring.

The purpose of this study was to determine the pharmacologic properties of cyclosporine-tacrolimus, detection methods, and the effects on the activity of cytochrome P450 enzymes when prescribing the most efficient treatments in forms of polypharmacy for the recipients of heart transplantation.

Scientific literature on the interactions of tacrolimus and cyclosporine with human cytochrome P450 enzymes was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus.

Prescription immunosuppressive drugs based on polypharmacy accompanied by induction agents could result in hidden neurotoxicity and nephrotoxicity. A literature search shows that cyclosporine prescription with antihypertensives drugs needs close monitoring. Co-administration of tacrolimus and diltiazem or verapamil needs a decrease in the tacrolimus dose by 20-50%. Vigilant attention to the lowest possible statin dose is needed when coadministered with fluvastatin or pravastatin. Polypharmacy based on ticlopidine, clopidogrel, and cyclosporine or tacrolimus needs monitoring of immunosuppressive drug levels for several months. A prescription with clotrimazole or fluconazole needs close monitoring, and itraconazole or ketoconazole needs to reduce the initial dose by 50%. Combination with nefazodone needs to be avoided, and alternative drugs such as sertraline or citalopram could be prescribed in addition to further monitoring consideration. In prescription with phenytoin, the bound and free phenytoin levels need close monitoring.

Polypharmacy based on tacrolimus or cyclosporine needs vigilant therapeutic drug monitoring due to the cytochrome P450 enzymes associated with biochemical variables in metabolic pathways. Further attention to polypharmacy should be given to circulate drugs that could hide pharmacokinetics interactions associated with infections, malignancies, chronic kidney disease, and rejection after organ transplantation.

Cardiomyopathy is a global health crisis that affects people all over the world. Consequently, scientists felt compelled to look for and develop ever-more-powerful pharmaceuticals. For ATTR-CM, the only drug currently recommended by the European Society of Cardiology is Tafamidis.

The primary aim of this review article is to understand the chemistry, pharmacodynamic, pharmacokinetic, and bio-analytical methods available for Tafamidis.

A systematic review of the existing resources was accomplished up to 2022, comprising existing studies forming the database covering the existing resources from Web of Science, ScienceDirect, and PubMed.

The review was based on a systematic review of all the existing studies used to formulate the database. The study also illustrated the PRISMA design that systematically analyses the prevalent resources.

Minimal analytical techniques are observed for quantifying the Tafamidis and transthyretin kinetic stabiliser. Therapeutic, pharmacological, and analytical considerations for the novel drug Tafamidis are discussed in this review. Particular attention is paid to the many different analytical and bioanalytical methods currently available for estimating Tafamidis, and the need is highlighted to develop a straightforward, validated technique that meets green chemistry standards.

This study aimed to evaluate the hepatotoxicity of buprenorphine in lactating rat pups of buprenorphine-injected mothers. Buprenorphine (BUP), a semisynthetic opioid, is increasingly administrated as a first-line standard maintenance treatment for opioid dependence due to its high safety and efficacy compared to other opioids. Numerous studies have confirmed the safety of BUP maintenance treatment in addicted patients.

This study was designed to assess the effects of BUP on the activities of liver enzymes, oxidative parameters, and liver histopathological changes in pups born to a mother exposed to this drug during lactation.

BUP at a dose of 0.5 or 0.1 mg/kg was subcutaneously administrated to lactating rats for 28 days. At the end of the experiment, the pups were anesthetized, and blood samples were obtained from their hearts for measuring liver enzymes. Then the livers of the animals were dissected to measure oxidative stress parameters. In addition, the liver samples were fixed for histopathological evaluation.

The findings indicated a decrease in the activities of serum liver enzymes (ALT and AST) of the pups born to mothers exposed to 0.5 and 1 mg/kg of BUP during lactation. BUP could not change malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels, nor superoxide dismutase (SOD) activity in the liver tissue of animals. Some vacuolated hepatocytes with dark, eccentric nuclei, necrosis with karyolytic nuclei, mitotic figures, and multiple binucleated cells were seen in the pups which received 1 mg/kg of BUP.

In conclusion, BUP may induce liver dysfunction in pups born to mothers exposed to this drug during lactation.

Hypoglycemia and anemia are associated with diabetes mellitus. Medicinal plants and orthodox drugs have been used for the management of this disease. This study aimed to validate the ethnomedical claims of Terminalia catappa Linn. leaf extract in reducing hyperglycemia and hematological potentials in alloxan-induced diabetic rats and to identify likely antidiabetic compounds.

Ultra-high-performance liquid chromatography was used to identify the various phytochemical constituents. Male Wistar rats were randomly divided into five groups containing 6 rats per group. Group 1 (control) received 0.2 ml/kg of distilled water, group 2 received 130 mg/kg of T. catappa aqueous extract, groups 3-5 were diabetic and received 0.2 ml/g distilled water, 130 mg/kg T. catappa extract and 0.75 IU/kg insulin respectively for 14 days. Hematological parameters were measured and an oral glucose tolerance test was carried out using 2 g/kg body weight glucose. A histological analysis of the pancreas was done.

Twenty-five compounds identified as flavonoids, phenolic acids, tannins, and triterpenoids were detected. The blood glucose levels were significantly (p <0.05) elevated in DM groups but were significantly (p <0.05) reduced following Terminalia catappa leaves extract to DM groups. There was s significant (p <0.05) increase in insulin levels improved hematological parameters (RBC, WBC, and platelets), and increased islet population.

These results suggest that T. catappa extract has hypoglycemic, insulinogenic, and hematopoietic potentials in diabetic condition and offer protection to the pancreas which could be attributed to the phytochemical constituents thereby justifying its use in traditional therapy.

Sepsis is a significant cause of mortality worldwide. This study aimed to compare clinical and laboratory characteristics of sepsis in patients addicted to illicit drugs versus patients with no illicit drug addiction.

In this cross-sectional study, all patients hospitalized with sepsis diagnosis were recruited within six months from September to March 2019. Sixty patients for each group (illicit drug-addicted and non-addicted individuals) were selected. The data relating to illicit drug consumption, serum indices, the current focus of infection, duration of hospitalization, and disease outcomes were collected. Patients who had an illicit drug addiction were compared with non-addicted patients in terms of clinical and laboratory parameters. The data collected were analyzed using SPSS software (version 19).

The bacterial load in the urine culture was statistically significant in both groups and higher in the non-addicted group. The frequency distributions of focus of infection, duration of hospitalization, and outcome were not significantly different between the two groups. The serum sodium and total neutrophils were significantly higher in the addicted group. However, the MCHC level was significantly lower (p < 0.05).

Opium may have stimulated the immune system and reduced bacterial infection in septic patient users.

The study aimed to investigate the antihypertensive activity of Scorzonera undulata ssp. deliciosa.

Scorzonera undulata ssp deliciosa, locally known as “Guiz”, is used in traditional medicine in Morocco as a diuretic and mainly against snake bites.

This study investigated the possible antihypertensive effect of the aqueous extract of Scorzonera undulata (AESU).

In the present study, the antihypertensive activity of AESU was tested in normotensive and hypertensive rats.

The results indicated that AESU decreased the systolic, diastolic, and mean arterial blood pressure in hypertensive rats. The data revealed that AESU exerted its antihypertensive effect through vasodilatory properties. Interestingly, the study demonstrated that the vasorelaxation ability of AESU might be mediated through receptor-operated calcium channels (ROCCs). However, AESU dhad effect on inhibiting ACE-2.

The present study indicates the antihypertensive and vasorelaxant activities of AESU in hypertensive rats.

To assess acute lipid profiles, atrial fibrillation and other cardiovascular risk factors in patients undergoing treatments by thrombectomy (EVT) with acute ischemic stroke (AIS).

We performed a retrospective analysis of the lipid profile and vascular risk factor in 1639 consecutive patients with acute ischemic stroke between January 2016 and December 2021. To assess lipid profiles, laboratory tests, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were obtained the day after admission. We also examined the association between lipid profile, AF and EVT in multivariate logistic regression analysis.

Median age of patients was 74 years, 54.9% were males (95% CI 52.5-57.4%), and 26.8% (95% CI, 24.7-29.0%) had AF. EVT patients (n = 370; 22.57%; 95% CI, 20.6-24.7) showed no difference in age (median 73 years (IQR; 63-80) versus 74 years (ΙQR; 63-82)), HbA1c levels (median 5.8 (IQR; 5.4-6.2) versus 5.9 (IQR; 5.4-6.4)), TG/HDL ratio (median 2.40 (IQR; 1.65-3.48) versus 2.51 (IQR; 1.73-3.64)), diabetes (OR 0.82; 95% CI 0.61 to 1.08), hypertension (OR 0.87; 95% CI 0.68 to 1.12) and obesity (OR 1.06; 95% CI 0.78 to 1.42) compared to non-EVT patients. Conversely, EVT patients showed lower levels of TC (160 mg/dl (IQR; 139-187) versus 173 mg/dl (IQR; 148-202); p <0.001), LDL-C (105 mg/dl (IQR; 80-133) versus 113 mg/dl (IQR; 88-142); p <0.01), TG (98 mg/dl (IQR; 76-126) versus 107 mg/dl (IQR; 85-139); p <0.001), non-HDL-C (117 mg/dl (IQR; 94-145) versus 127 mg/dl (IQR; 103-154); p <0.001), HC (8.3 μmol/l (IQR; 6-11) versus 10 μmol/l (IQR; 7.3-13.5); p <0.001) than non-EVT patients. Multivariate logistic regression analysis showed an independent association of EVT with TC (OR 0.99, 95% CI 0.98-0.99), AF (OR 1.79, 95% CI 1.34-2.38), age (OR 0.98, 95% CI 0.96-0.99), and NIHSS (OR 1.17, 95% CI 0.14-1.19).

Total cholesterol and all cholesterol-related measures were significantly lower in patients undergoing thrombectomy than in other stroke patients. Conversely, we found that AF was significantly high in patients with EVT, suggesting that hypercholesterolemia could be mainly linked to small-vessel occlusion stroke while large vessel occlusion (LVO) stroke could show different causes. AIS patients may have different pathogenesis and their understanding may improve the discovery of specific and tailored preventive treatments.

Cardiovascular disease and diabetes mellitus are among the leading causes of mortality.

Our study evaluated endothelial function in patients with arterial hypertension, coronary heart disease, and diabetes mellitus.

This study aimed to assess the degree of endothelial dysfunction in individuals with cardiovascular risk factors older than 55 years of age.

A total of 112 patients were subdivided into three groups according to the existing disease; the first group consisted of 50 patients diagnosed with arterial hypertension (AH), the second group consisted of 30 patients with ischemic heart disease (IHD), and the third group included 20 patients with type 2 diabetes mellitus (DM). The control group included 12 practically healthy volunteers, comparable in age and sex. Exclusion criteria were age under 55 years, severe concomitant diseases in the acute phase or acute infectious diseases, and oncopathology. Considered factors of cardiovascular risk include dyslipidemia, elevated fasting blood glucose, hypertension, obesity, cigarette smoking, and heredity for CVD. Moreover, tests were conducted with the help of the device 'AngioScan-01' (LLC “AngioScan Electronics”). Endothelium-dependent vasodilation (EDV), the index of stiffness of the vascular wall (SI), and the atherogenic index (Log(𝑇G / HDL - X)) were evaluated. The analysis of the data obtained was carried out using the IBM SPSS Statistic program.

In the control group, the atherogenic index was in the range of 3.34 (the normal is up to 3.5). The highest atherogenic index, 4.01, was observed in the DM group (differences with the control group are statistically significant). In the AH and IHD groups, the atherogenic index was 3.57 and 3.65, respectively. In the control group, the level of glycemia was 4.45 mmol/l. The highest level of fasting glucose was reported in the DM group, i.e., 6.7 mmol/l (differences with the control group were statistically significant). In the first and second groups, the fasting glucose level was 5.07 mmol/l and 5.08 mmol/l, respectively. In the control group, the mean EDV score was 2,056 ± 0.757 mm, and the lowest EDV in the DM group was 1.365 ± 0.413, but in the AH and IHD groups, it was also significantly reduced by 1.404 ± 0.440 and 1.377 ± 0.390, respectively. The stiffness index in the control group was 6.725 ± 0.776 m/s. In the DM group, this parameter was 8.258 ± 0.656 m/s; in the AH and IHD groups, it was 7.398 ± 1.330 m/s and 7.486 ± 0.816 m/s, respectively.

In conclusion, the study of endothelial function using non-invasive angioscan reflects the influence of risk factors on the vascular wall. The most severe endothelial dysfunction is expressed in patients with diabetes. The results of endothelium-dependent vasodilation and the vascular wall stiffness index (SI) correspond to the scale of evaluation of the 10-year CVD mortality risk (SCORE). These results indicate a deterioration in the vascular ability to vasodilate in patients in response to mechanical deformation of the endothelium and the effect of NO on smooth muscle vascular cells.

Glioblastoma multiforme (GBM) is characterized by massive tumor-induced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumor-driven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.

We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using in silico tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.

Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski’s rule of five. Our in silico analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.

The present study showed TC to possess anti-angiogenic potential via the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.

Hospital-acquired venous thromboembolism (HA-VTE) is defined as cases of venous thromboembolism (VTE) that occur in a hospital and within ninety days of a hospital admission. Deep vein thromboses (DVTs) most commonly occur within the deep veins of the pelvis and legs. If the thrombus dislodges and travels to the lungs, it can result in a pulmonary embolus (PE). VTE is associated with significant morbidity and mortality, accounting for almost 10% of all hospital deaths. If risk factors are correctly identified and VTE prophylaxis is prescribed, VTE can be a preventable condition. In 2010, NHS England launched The National Venous Thromboembolism Prevention Programme. This included NICE guidance, and a VTE risk assessment tool, which must be completed for at least 95% of patients on admission. The National Thrombosis Survey, published by Thrombosis UK, studied how this program was implemented locally, and audited HA-VTE prevention strategies nationally.

Using the Thrombosis Survey and NICE guidance as an aide, this study collects data about hospital-acquired DVT (HA-DVT) at the Queen Elizabeth Hospital in Gateshead (QEH) and aims to:

1.    1.   Identify cases of HA-DVT and understand the clinical circumstances surrounding these cases
2.    2.   Assess the quality of VTE preventative measures at QEH
3.    3.   Outline potential improvement in reducing the incidence of HA-VTE at this hospital

This retrospective cohort study used electronic records to identify all cases of DVT between April 2019 and April 2022 at QEH. Cases of HA-DVT were defined as: a positive ultrasound doppler report and either the case occurring in the 90 days following an inpatient stay, or beyond two days into an admission. For these cases of HA-DVT, we recorded the: reason for admission; admitting specialty; presence of an underlying active cancer and deaths occurring within 90 days of diagnosis. We assessed the quality of VTE preventative measures, by recording the: completion of VTE risk assessments; prescription of weight-adjusted pharmacological VTE prophylaxis and provision of VTE prophylaxis on discharge. For HA-DVT cases occurring within 90 days of an inpatient stay, the preventative measures were assessed on the original admission. Electronic records were used to record the completion rate of the National VTE risk assessment tool for all inpatients during this time frame.

The VTE risk assessment tool was completed for 98.5% of all admissions. One hundred and thirty-five cases of HA-DVT were identified between April 2019 and April 2022. Sixteen patients with HA-DVT did not have VTE prophylaxis prescribed on admission. Eleven of these patients had a clearly documented reason why anticoagulation was avoided. In HA-DVT cases where pharmacological VTE prophylaxis was prescribed, 23% were prescribed an inappropriate dose for their weight. If anticoagulation was required on discharge, this was prescribed appropriately in 94% of cases. About 31% of the patients with HA-DVT had an underlying active malignancy. Thirty-nine patients died within 90 days of the DVT being diagnosed; in only 1 case was VTE thought to be a contributing factor to death.

The hospital exceeded the national standard of VTE risk assessment completion on admission (greater than 95%). For almost a quarter of patients with HA-DVT, the dose of thromboprophylaxis prescribed was not appropriate for weight. In five cases of HA-DVT, thromboprophylaxis was omitted with no clear justification. HA-DVT often affects the most clinically vulnerable patients and is associated with a high mortality.

Nattokinase (NK) is a naturally occurring fibrinolytic protease enzyme obtained from the traditional Japanese food called Natto and has several uses in the pharmaceutical and medical industries. Nowadays, the most often used thrombolytic agent in the clinical field is NK, in part because it is less expensive than other thrombolytic medicines.

The objective of this study is to investigate the screening, isolation and characterization of the NK enzyme-producing Bacillus strain from fermented Soya beans.

The sample of fermented soya beans were tested for the presence of fibrinolytic protease-producing bacteria, followed by the screening, extraction, characterization and clot lysis assays.

A total of three isolates were screened for caseinolytic activities by casein hydrolysis assay. Out of those isolates, MRS18 was found to be potent in producing the enzyme proteinase. To determine the taxonomy and phylogeny of these isolates, biochemical and molecular characterization has been carried out. Bacillus amyloliquefaciens MRS18 has been found with the highest caseinolytic activity. The clot lysing ability of the potent strain Bacillus amyloliquefaciens was found to be 61.7% after 120 min, and on further purification, by ammonium sulphate precipitation method, the lysis percentage was found to be 656% after 120 min.

From the results of the present study, we concluded that Bacillus amyloliquefaciens isolated from the fermented soya beans produced an NK enzyme that exhibits immense potential to lyse blood clots.

Plants have been used for ages in traditional medicine, and it is exciting to perceive how recent research has recognized the bioactive compounds liable for their beneficial effects. Green synthesis of metal nanoparticles is a hastily emergent research area in nanotechnology. This study describes the synthesis of silver nanoparticles (AgNPs) using Coriandrum sativum and Murraya koenigii leaf extract and its thrombolytic activity.

The aim of the study was to determine the clot lysis activity of Coriandrum sativum and Murraya koenigii synthesized silver nanoparticles.

Leaves of Coriandrum sativum and Murraya koenigii were collected. Methanolic extraction of the plant sample was done through a Soxhlet extractor. The methanolic extract obtained from both the leaves was subjected to GC-MS analysis. The synthesized NPs from leaf extracts were monitored for analysis, where the typical X-ray diffraction pattern and its diffraction peaks were identified. 3D image of the NPs was analysed by Atomic Force Microscopy. The surface charge of nanoparticles was identified by Zeta potential. The Clot lysis activity of Coriandrum sativum and Murraya koenigii synthesized silver nanoparticles were analysed by the modified Holmstorm method.

The thrombolytic property of the methanolic extract of plants Coriandrum sativum showed clot lysis activity at 2.5 mg/mL with 45.99% activity, and Murraya koenigii extract with 66.56% activity. The nanoparticles (Nps) from Coriandrum sativum showed clot lysis activity at 2.5 mg/mL with 58.29% activity, and NPs from Murraya koenigii with 54.04% activity. Coriandrum sativum in GC-MS exhibited 3 peaks, whereas Murraya koenigii extract showed five peaks with notable bioactive compounds.

These NPs were further used for biomedical applications after being fixed by an organic encapsulation agent. The present research reveals the usefulness of Coriandrum sativum and Murraya koenigii for the environmentally friendly manufacture of silver nanoparticles.

Myeloproliferative neoplasms (MPNs) are divided into BCR-ABL positive Chronic myeloid leukemia (CML) and BCR-ABL negative MPNs including Polycythemia vera (PV), Essential Thrombocythemia (ET) and Primary myelofibrosis (PMF). Evaluation of the Philadelphia chromosome in MPNs is a diagnostic requirement for classic CML.

In 2020, a 37-year-old woman with negative cytogenetic testing for Janus kinase2 (JAK2), Calreticulin (CALR), myeloproliferative leukemia virus oncogene (MPL), and positive for BCR-ABL1 mutation with reticular fibrosis in bone marrow was diagnosed as CML. Some years ago, the patient had been diagnosed with PMF with evidence of histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto disease (KFD). The BCR-ABL fusion gene was initially evaluated which was negative. Then, Cutaneous squamous cell carcinoma (cSCC) was confirmed by Dermatopathologist with palpable splenomegaly and high white blood cell (WBC) count with basophilia. Finally, BCR-ABL was detected positive by the fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (qRT-PCR). In fact, the co-occurrence of PMF with CML was identified.

This case study highlighted the importance of some cytogenetic methods in the detection and classification of MPNs. It is recommended that physicians pay more attention to it and be aware of the planning treatment.