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Fulltext Taking a Step Further in Identifying Ideal Blood Pressure Range Among Hemodialysis Patients: A Systematic Review and a Meta-Analysis

Aftab RA, Sellappans R, Ming CK, Shaik I

Front Pharmacol, 2020;11:729.
PMID: 32528285 DOI: 10.3389/fphar.2020.00729

Background: Hypertension is one of the primary predictor of mortality among end-stage renal disease (ESRD) patients on dialysis. However, there is no consensus on an ideal blood pressure range for this population.
Aims and Objective: To identify an ideal systolic blood pressure range based on optimal survival among ESRD patients on dialysis.
Method: A systematic search for clinical trials assessing the impact of different systolic blood pressure range on mortality among ESRD patients on hemodialysis was conducted through PubMed, EBSCOhost, Science Direct, Google Scholar, and Scopus. All randomized control trials (RCTs) involving ESRD patients on hemodialysis with primary or secondary outcome of assessing the impact different systolic blood pressure range (140 mm Hg) on all-cause mortality were included. The quality of reporting of the included studies was evaluated using the Jadad scale. Two researchers independently conducted eligibility assessment. Discrepancies were resolved by discussion and consultation with a third researcher when needed. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated.
Results: A total of 1,787 research articles were identified during the initial search, after which six RCTs met our inclusion criteria. According to the Jadad scale, all six RCTs scored 3 points each for quality of reporting. Four RCTs employed pharmacological intervention while two RCTs assessed non-pharmacological intervention. Of the six RCTs, two studies were able to achieve a systolic blood pressure of <140 mm Hg at the end of trial with a RR for reduction in mortality of 0.56 (95% CI, 0.3-1.07; P = 0.08). Four RCTs were able to achieve a systolic blood pressure of >140 mm Hg at the end of trial, with the RR for reduction of mortality of 0.72 (95% CI, 0.54-0.96; P = 0.003). Overall, pooled estimates of the six RCTs suggested the reduction in systolic blood pressure statistically reduce all cause of mortality (RR, 0.69%; 95% CI, 0.53-0.90; P = 0.006) among ESRD patients on hemodialysis.
Conclusion: Though not statically significant, the current study identifies <140 mm Hg as a promising blood pressure range for optimum survival among ESRD patients on hemodialysis. However, further studies are required to establish an ideal blood pressure range among hemodialysis patients.
Systematic Review Registration: The study protocol was registered under PROSPERO (CRD42019121102).
Fulltext The Adverse Cardiovascular Effects and Cardiotoxicity of Kratom (Mitragyna speciosa Korth.): A Comprehensive Review

Leong Bin Abdullah MFI, Singh D

Front Pharmacol, 2021;12:726003.
PMID: 34646135 DOI: 10.3389/fphar.2021.726003

Background: Kratom or Mitragyna speciosa (Korth.) has received overwhelming attention recently due to its alleged pain-relieving effects. Despite its potential therapeutic value, kratom use has been linked to many occurrences of multiorgan toxicity and cardiotoxicity. Accordingly, the current narrative review aimed to provide a detailed account of kratom's adverse cardiovascular effects and cardiotoxicity risk, based on in vitro studies, poison center reports, coroner and autopsy reports, clinical case reports, and clinical studies. Methods: An electronic search was conducted to identify all research articles published in English from 1950 to 2021 using the major research databases, such as Google Scholar, Web of Science, PubMed, Scopus, Mendeley, EMBASE, Cochrane Library, and Medline. We then analyzed the literature's discussion of adverse cardiovascular effects, toxicity, and mortality related to kratom use. Results: Our findings revealed that, although in vitro studies have found kratom preparations' most abundant alkaloid-mitragynine-to cause a prolonged QTc interval and an increased risk of torsades de pointes, a clinical study examining humans' regular consumption of kratom did not report such a risk. However, this latter study did show that regular kratom use could induce an increased QTc interval in a dose-dependent manner. A few case reports also highlighted that kratom consumption is associated with ventricular arrhythmia and cardiopulmonary arrest, but this association could have ensued when kratom was co-administered with another substance. Similarly, analyses of national poison data showed that kratom's most common adverse acute cardiovascular effects include tachycardia and hypertension. Meanwhile, coroner and autopsy reports indicated that kratom's cardiovascular sequelae encompass coronary atherosclerosis, myocardial infarction, hypertensive cardiovascular disease, left ventricular hypertrophy, cardiac arrhythmia, cardiomegaly, cardiomyopathy, focal band necrosis in the myocardium, and myocarditis. Given the available data, we deduced that all cardiac eventualities reported in the literature could have been compounded by polysubstance use and unresolved underlying medical illnesses. Conclusion: Although kratom use has been associated with death and cardiotoxicity, especially at higher doses and when associated with other psychoactive drugs, the dearth of data and methodological limitations reported in existing studies do not allow a definitive conclusion, and further studies are still necessary to address this issue.
Fulltext Cost-Effectiveness of Testing for NS5A Resistance to Optimize Treatment of Elbasvir/Grazoprevir for Chronic Hepatitis C in China

Liu J, Zhang Y, Wu B, Wang S, Bin-Chia Wu D, You R

Front Pharmacol, 2021;12:717504.
PMID: 34721016 DOI: 10.3389/fphar.2021.717504

Objectives: Baseline presence of nonstructural protein 5A (NS5A) resistance-associated variants can attenuate the efficacy of new direct-acting antivirals. A potential method to attain the higher efficacy would be to screen for NS5A polymorphisms prior to the initiation of therapy and to adjust the treatment length based on the test results. However, baseline testing adds additional costs and it is unclear whether this would represent a high value strategy for chronic hepatitis C in China. Methods: A hybrid model compared 1) standard 12-weeks treatment (no testing), 2) shortened 8-weeks treatment (no testing), and 3) baseline testing with 12-/8-weeks treatment for those with/without NS5A polymorphisms from a lifetime Chinese health care payer perspective. All model inputs were retrieved from clinical trials and publically available literature. And sensitivity analyses were also conducted to assess the impact of uncertainty. Results: Baseline testing was associated with overall increase in total health care cost of USD 13.50 and in QALYs of 0.002 compared with standard 12-weeks treatment (no testing), yielded in an ICER of USD 6750/QALY gained. Scenario analyses suggested that shortened 8-weeks treatment (no testing) was found to be lower costs and great QALYs compared with other two strategies when the sustained virologic response (SVR) rate increased to 95%. Sensitivity analyses indicated that the results were robust. Conclusions: Our results suggest prior assessment of NS5A sensitivity followed by optimizing treatment duration was an economic strategy. In addition, shortened 8-weeks treatment (no testing) was shown to be dominant with the SVR rate increased to 95%.
Fulltext An In Vitro Anticancer Activity Evaluation of Neolamarckia cadamba (Roxb.) Bosser Leaves' Extract and its Metabolite Profile

Razali S, Firus Khan AY, Khatib A, Ahmed QU, Abdul Wahab R, Zakaria ZA

Front Pharmacol, 2021;12:741683.
PMID: 34721030 DOI: 10.3389/fphar.2021.741683

The leaves of Neolamarckia cadamba (NC) (Roxb.) Bosser (family: Rubiaceae) are traditionally used to treat breast cancer in Malaysia; however, this traditional claim is yet to be scientifically verified. Hence, this study was aimed to evaluate the anticancer effect of NC leaves' ethanol extract against breast cancer cell line (MCF-7 cells) using an in vitro cell viability, cytotoxicity, and gene expression assays followed by the gas chromatography analysis to further confirm active principles. Results revealed 0.2 mg/ml as the half maximal inhibitory concentration (IC50) against MCF-7. The extract exerted anticancer effect against MCF-7 cells in a dose- and time-dependent manner. The cell cycle assay showed that the extract arrested MCF-7 cells in the G0/G1 phase, and apoptosis was observed after 72 h by the Annexin-V assay. The gene expression assay revealed that the cell cycle arrest was associated with the downregulation of CDK2 and subsequent upregulation of p21 and cyclin E. The extract induced apoptosis via the mediation of the mitochondrial cell death pathways. A chromatography analysis revealed the contribution of D-pinitol and myo-inositol as the two major bioactive compounds to the activity observed. Overall, the study demonstrated that NC leaves' ethanol extract exerts anticancer effect against MCF-7 human breast cancer cells through the induction of apoptosis and cell cycle arrest, thereby justifying its traditional use for the treatment of breast cancer in Malaysia.
Fulltext Parkia speciosa Hassk. Empty Pod Extract Alleviates Angiotensin II-Induced Cardiomyocyte Hypertrophy in H9c2 Cells by Modulating the Ang II/ROS/NO Axis and MAPK Pathway

Siti HN, Jalil J, Asmadi AY, Kamisah Y

Front Pharmacol, 2021;12:741623.
PMID: 34721028 DOI: 10.3389/fphar.2021.741623

Cardiac hypertrophy is characteristic of heart failure in patients who have experienced cardiac remodeling. Many medicinal plants, including Parkia speciosa Hassk., have documented cardioprotective effects against such pathologies. This study investigated the activity of P. speciosa empty pod extract against cardiomyocyte hypertrophy in H9c2 cardiomyocytes exposed to angiotensin II (Ang II). In particular, its role in modulating the Ang II/reactive oxygen species/nitric oxide (Ang II/ROS/NO) axis and mitogen-activated protein kinase (MAPK) pathway was examined. Treatment with the extract (12.5, 25, and 50 μg/ml) prevented Ang II-induced increases in cell size, NADPH oxidase activity, B-type natriuretic peptide levels, and reactive oxygen species and reductions in superoxide dismutase activity. These were comparable to the effects of the valsartan positive control. However, the extract did not significantly ameliorate the effects of Ang II on inducible nitric oxide synthase activity and nitric oxide levels, while valsartan did confer such protection. Although the extract decreased the levels of phosphorylated extracellular signal-related kinase, p38, and c-Jun N-terminal kinase, valsartan only decreased phosphorylated c-Jun N-terminal kinase expression. Phytochemical screening identified the flavonoids rutin (1) and quercetin (2) in the extract. These findings suggest that P. speciosa empty pod extract protects against Ang II-induced cardiomyocyte hypertrophy, possibly by modulating the Ang II/ROS/NO axis and MAPK signaling pathway via a mechanism distinct from valsartan.
Fulltext Kaempferia galanga L.: Progresses in Phytochemistry, Pharmacology, Toxicology and Ethnomedicinal Uses

Wang SY, Zhao H, Xu HT, Han XD, Wu YS, Xu FF, et al.

Front Pharmacol, 2021;12:675350.
PMID: 34737693 DOI: 10.3389/fphar.2021.675350

K. galanga is an aromatic medicinal herb. It is locally to India and distributed in China, Myanmar, Indonesia, Malaysia, and Thailand. K. galanga is a Traditional Chinese Herb Medicine (TCHM), which has been applied to treat cold, dry cough, toothaches, rheumatism, hypertension and so on. In addition, it has been used widely as spices since its highly aromas. The aim of this review is to compile and update the current progresses of ethnomedicinal uses, phytochemistry, pharmacology and toxicology of K. galanga. All the data on K. galanga were based on different classical literary works, multiple electronic databases including SciFinder, Web of Science, PubMed, etc. The results showed that ninety-seven compounds have been identified from rhizome of K. galanga, including terpenoids, phenolics, cyclic dipeptides, flavonoids, diarylheptanoids, fatty acids and esters. Modern pharmacology studies revealed that extracts or secondary metabolites of the herb possessed anti-inflammatory, anti-oxidant, anti-tumorous, anti-bacterial, and anti-angiogenesis effects, which were closely related to its abundant ethnomedicinal uses. In conclusion, although previous research works have provided various information of K. galanga, more in-depth studies are still necessary to systemically evaluate phytochemistry, pharmacological activities, toxicity and quality control of this herb.
Fulltext Editorial: Edible Bird's Nest-Chemical Composition and Potential Health Efficacy and Risks

Li G, Lee TH, Chan G, Tsim KWK

Front Pharmacol, 2021;12:819461.
PMID: 35153768 DOI: 10.3389/fphar.2021.819461
Fulltext Anti-Allergic Properties of Propolis: Evidence From Preclinical and Clinical Studies

Liew KY, Kamise NI, Ong HM, Aw Yong PY, Islam F, Tan JW, et al.

Front Pharmacol, 2021;12:785371.
PMID: 35126124 DOI: 10.3389/fphar.2021.785371

Allergic diseases are a global health burden with increasing prevalence. Side effects of available medications (antihistamines and steroids), lack of patients' perceived effectiveness and high cost of biologic therapies (omalizumab) are challenges to the clinical management of allergic diseases. As allergy symptoms persist for a long time, complementary and alternative medicine (CAM) such as propolis may be considered a potential prophylactic or therapeutic option to avoid long-term medication use. Propolis is a natural resinous substance produced by bees. Although propolis is well known to possess antioxidant, antimicrobial, and anticancer properties, its anti-allergic potential is not fully explored. Several preclinical studies demonstrated the therapeutic effects of propolis extracts against allergic inflammation, asthma, allergic rhinitis, atopic dermatitis, and food allergy, which may be partly attributed to their inhibitory effects on the activation of mast cells and basophils. Clinically, the consumption of propolis as a supplement or an adjunct therapy is safe and attenuates various pathological conditions in asthma. Such an approach may be adopted for atopic dermatitis and allergic rhinitis. Although flavonoids (chrysin, kaempferol, galangin, and pinocembrin) and cinnamic acid derivatives (artepillin C and caffeic acid phenethyl ester) can contribute to the anti-allergic activities, they may not be present in all propolis samples due to variations in the chemical composition. Future studies should relate the anti-allergic activity of propolis with its chemical contents. This mini-review summarizes and discusses existing preclinical and clinical studies reporting the anti-allergic activities of propolis to provide insights into its potential applications in allergic diseases.
Fulltext Genistein: A Review on its Anti-Inflammatory Properties

Goh YX, Jalil J, Lam KW, Husain K, Premakumar CM

Front Pharmacol, 2022;13:820969.
PMID: 35140617 DOI: 10.3389/fphar.2022.820969

Nowadays, non-resolving inflammation is becoming a major trigger in various diseases as it plays a significant role in the pathogenesis of atherosclerosis, asthma, cancer, obesity, inflammatory bowel disease, chronic obstructive pulmonary disease, neurodegenerative disease, multiple sclerosis, and rheumatoid arthritis. However, prolonged use of anti-inflammatory drugs is usually accompanied with undesirable effects and hence more patients tend to seek for natural compounds as alternative medicine. Considering the fact above, there is an urgency to discover and develop potential novel, safe and efficacious natural compounds as drug candidates for future anti-inflammatory therapy. Genistein belongs to the flavonoid family, in the subgroup of isoflavones. It is a phytoestrogen that is mainly derived from legumes. It is a naturally occurring chemical constituent with a similar chemical structure to mammalian estrogens. It is claimed to exert many beneficial effects on health, such as protection against osteoporosis, reduction in the risk of cardiovascular disease, alleviation of postmenopausal symptoms and anticancer properties. In the past, numerous in vitro and in vivo studies have been conducted to investigate the anti-inflammatory potential of genistein. Henceforth, this review aims to summarize the anti-inflammatory properties of genistein linking with the signaling pathways and mediators that are involved in the inflammatory response as well as its toxicity profile. The current outcomes are analysed to highlight the prospect as a lead compound for drug discovery. Data was collected using PubMed, ScienceDirect, SpringerLink and Scopus databases. Results showed that genistein possessed strong anti-inflammatory activities through inhibition of various signaling pathways such as nuclear factor kappa-B (NF-κB), prostaglandins (PGs), inducible nitric oxide synthase (iNOS), proinflammatory cytokines and reactive oxygen species (ROS). A comprehensive assessment of the mechanism of action in anti-inflammatory effects of genistein is included. However, evidence for the pharmacological effects is still lacking. Further studies using various animal models to assess pharmacological effects such as toxicity, pharmacokinetics, pharmacodynamics, and bioavailability studies are required before clinical studies can be conducted. This review will highlight the potential use of genistein as a lead compound for future drug development as an anti-inflammatory agent.
Fulltext Barriers and Enablers for Adherence to Antiretroviral Therapy Among People Living With HIV/AIDS in the Era of COVID-19: A Qualitative Study From Pakistan

Ahmed A, Dujaili JA, Jabeen M, Umair MM, Chuah LH, Hashmi FK, et al.

Front Pharmacol, 2021;12:807446.
PMID: 35153763 DOI: 10.3389/fphar.2021.807446

Background: With the increased availability of safe antiretroviral therapy (ART) in recent years, achieving optimal adherence and patient retention is becoming the biggest challenge for people living with HIV (PLWH). Care retention is influenced by several socioeconomic, socio-cultural, and government policies during the COVID-19 pandemic. Therefore, we aim to explore barriers and facilitators to adherence to ART among PLWH in Pakistan in general and COVID-19 pandemic related in particular. Methods: Semi-structured interviews were conducted among 25 PLWH from December 2020 to April 2021 in the local language (Urdu) at the ART centre of Pakistan Institute of Medical Sciences, Islamabad, Pakistan. Interviews were audio-recorded in the local Urdu language, and bilingual expert (English, Urdu) transcribed verbatim, coded for themes and sub-themes, and analyzed using a phenomenological approach for thematic content analysis. Results: Stigma and discrimination, fear of HIV disclosure, economic constraints, forgetfulness, religion (Ramadan, spiritual healing), adverse drug reactions, lack of social support, alternative therapies, and COVID-19-related lock-down and fear of lesser COVID-19 care due to HIV associated stigma were identified as barriers affecting the retention in HIV care. At the same time, positive social support, family responsibilities, use of reminders, the beneficial impact of ART, and initiation of telephone consultations, courier delivery, and long-term delivery of antiretrovirals during COVID-19 were identified as facilitators of HIV retention. Conclusion: Improving adherence and retention is even more challenging due to COVID-19; therefore, it requires the integration of enhanced access to treatment with improved employment and social support. HIV care providers must understand these reported factors comprehensively and treat patients accordingly to ensure the continuum of HIV care. A coordinated approach including different stakeholders is required to facilitate patient retention in HIV care and consequently improve the clinical outcomes of PLWH.
Fulltext Effect of drying methods on yield, physicochemical properties, and total polyphenol content of chamomile extract powder

Lee SY, Ferdinand V, Siow LF

Front Pharmacol, 2022;13:1003209.
PMID: 36408266 DOI: 10.3389/fphar.2022.1003209

Chamomile (Matricaria chamomilla L.) is a traditional medicinal plant used to treat hay fever, inflammation, muscle spasms, menstrual disorders, insomnia ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Dried chamomile flowers have a longer shelf life and the dried extract in form of powder offers much flexibility for new therapeutic formulations as it could be used as a replacement for liquid extract and serve as a shelf-stable ingredient in new applications. This study aims to determine the effect of drying methods, i.e., convection oven-drying at 45 °C, freeze-drying at -50°C, and spray-drying at 140°C at 10.5 and 12 ml/min, respectively) on powder yield, physicochemical properties (moisture content, water activity, and color attributes), and total polyphenol content of chamomile extract powder. Our findings showed that spray-drying conducted at 140°C, 12 ml/min resulted in the lowest yield of powder (16.67%) compared to convection oven-drying (90.17%) and freeze-drying (83.24%). Decreasing the feed flow rate to 10.5 ml/min during spraying caused an increase in powder yield to 26.99%. The moisture content of spray-dried chamomile extract powder obtained at 140°C, 10.5 ml/min was higher (11.00%) compared to that of convection oven-dried (8.50%) and freeze-dried (7.50%). Both convection oven-dried and freeze-dried chamomile extract powder displayed no significant difference (p > 0.05) in moisture content. The higher feed flow rate (12 ml/min) in spray-drying also led to an increase in the moisture content of chamomile extract powder to 12.00%. The higher residual moisture found in the spray-dried samples resulted in partial agglomeration of particles. In terms of water activity, freeze-dried chamomile extract powder was found to have the highest water activity (0.63) compared to that of convection oven-dried (0.52), spray-dried at 140°C, 10.5 ml/min (0.57), and spray-dried at 140°C, 12 ml/min (0.58). Spray-dried and freeze-dried chamomile extract powder with high moisture content and water activity could be highly susceptible to microbial growth. In terms of color attributes, higher drying temperature in spray-drying led to darker, redder, and more yellowish chamomile extract powder that could be caused by heat-induced Maillard reaction and caramelization. Since lower drying temperature was used in both convection oven-drying and freeze-drying, both convection oven-dried (56.94 mg GAE/g powder) and freeze-dried chamomile extract powder (55.98 mg GAE/g powder) were found to have higher total polyphenol content compared to those of spray-dried (42.79-46.79 mg GAE/g powder). The present findings allow us to understand the effect of drying methods on the properties of chamomile extract powder and provide a better drying option to dry chamomile extract. Due to higher powder yield with ideal powder properties such as low moisture content and water activity, desirable color, and high total polyphenol content obtained from convection oven-drying, convection oven-drying was a better option than freeze-drying and spray-drying for drying chamomile extract.
Fulltext Baicalein prevents stress-induced anxiety behaviors in zebrafish model

Selvaraj LK, Jeyabalan S, Wong LS, Sekar M, Logeshwari B, Umamaheswari S, et al.

Front Pharmacol, 2022;13:990799.
PMID: 36386131 DOI: 10.3389/fphar.2022.990799

Baicalein is a flavonoid mainly obtained from plants with wide range of biological activities, including neuroprotection. An acute and unexpected chronic stress (UCS) protocol has recently been adapted to zebrafish, a popular vertebrate model in brain research. The present study was aimed to evaluate baicalein's anti-anxiety potential in a zebrafish model by induction, which included neuropharmacological evaluation to determine behavioural parameters in the novel tank diving test (NTDT) and light-dark preference test (LDPT). The toxicity was also assessed using the brine shrimp lethality assay, and the 50% lethal concentration (LC50) was determined. The animals were then stressed for 7 days before being treated with different doses of baicalein (1 and 2 mg/L) for another 7 days in UCS condition. Due to acute stress and UCS, the frequency of entries and time spent in the 1) top region and 2) light area of the novel tank reduced significantly, indicating the existence of elevated anxiety levels. The biological activity of baicalein was demonstrated by its high LC50 values (1,000 μg/ml). Additionally, baicalein administration increased the frequency of entries and duration spent in the light region, indicating a significant decrease in anxiety levels. Overall, the present results showed that baicalein has a therapeutic advantage in reversing the detrimental consequences of UCS and acute stress, making it is a promising lead molecule for new drug design, development, and therapy for stress.
Fulltext Sensitization effect of kaempferol from persimmon leaves on HepG2 hepatoma cells with ABT-199 resistance and its molecular mechanisms

Chen L, Jiang X, Gao S, Liu X, Gao Y, Kow ASF, et al.

Front Pharmacol, 2022;13:1032069.
PMID: 36386146 DOI: 10.3389/fphar.2022.1032069

ABT-199 (venetoclax) is the first-in-class selective B-cell lymphoma 2 (BCL2) inhibitor, which is known to be ineffective towards liver cancer cells. Here, we investigated the efficacy and the underlying molecular processes of the sensitization effect of kaempferol isolated from persimmon leaves (KPL) on the ABT-199-resistant HepG2 cells. The effects of various doses of KPL coupled with ABT-199 on the proliferation of HepG2 cells and on the H22 liver tumor-bearing mouse model were examined, as well as the underlying mechanisms. Our findings showed that ABT-199 alone, in contrast to KPL, had no significant impact on hepatoma cell growth, both in vitro and in vivo. Interestingly, the combination therapy showed significantly higher anti-hepatoma efficacy. Mechanistic studies revealed that combining KPL and ABT-199 may promote both early and late apoptosis, as well as decrease the mitochondrial membrane potential in HepG2 cells. Western blot analysis showed that combination of KPL and ABT-199 significantly reduced the expression of the anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, raised the expression of Bax and cleaved caspase 3, and enhanced cytochrome C release and Bax translocation. Therefore, KPL combined with ABT-199 has a potential application prospect in the treatment of hepatocellular carcinoma.
Fulltext Exploring Undergraduate Pharmacy Students Perspectives Towards Antibiotics Use, Antibiotic Resistance, and Antibiotic Stewardship Programs Along With the Pharmacy Teachers' Perspectives: A Mixed-Methods Study From Pakistan

Khan FU, Khan A, Shah S, Hayat K, Usman A, Khan FU, et al.

Front Pharmacol, 2021;12:754000.
PMID: 34819859 DOI: 10.3389/fphar.2021.754000

Background: Antibiotic resistance (ABR) is one of the major issues around the globe. Timely education and awareness of pharmacy students regarding the appropriate use of antibiotics, ABR, and antimicrobial stewardships are required. Methods: The present study was first conducted in 12 (public and private sector) universities among undergraduate pharmacy students (UGPS) (n = 414) irrespective of their study year through a validated questionnaire, and the insights of pharmacy teachers were taken through in-depth semi-structured interviews in the second phase. For the quantitative data, different statistical methods were used, and data were presented in tabulated form, whereas inductive thematic interpretation was used to categorize themes and derive conclusions from qualitative evidence. Results: The majority of the students were males (n = 223, 54%) with the mean age group 19-23 years, and 20 faculty members were interviewed with a mean duration of 15 min. Students have good knowledge about antibiotics use and the majority purchased antibiotics through prescription (n = 277, 66.9%) during the last month and strongly agreed to stop unnecessary household storage (n = 183 44.2%). Most of the students have heard the terminologies related to antimicrobial resistance through social media while unaware (n = 104, 25.1%) of a Pakistan national action plan against AMR (antimicrobial resistance). Overall, respondents have a somewhat good understanding of the ABR. Regular use of antibiotics without consultation of a physician can lead to ABR and some wrong answers were observed (162, 39.1%; p > 0.05). The majority of the students (n = 198, 47.8%) and teachers believe that the current pharmacy syllabus must be swiftly updated with the new subjects related to ABR and AMS (antimicrobial stewardship) in Pakistan. The UGPS have emphasized (n = 220, 53.1%; Median = 1, IQR = 2) establishing a link between academia and hospitals. The ABR issue has been highlighted by pharmacy faculty members, who have urged students to take practical efforts toward ABR and AMS knowledge. Conclusion: The UGPS knowledge related to ABR and AMS must be updated. Students at the undergraduate level must get training in order to encourage the sensible use of antibiotics. Courses on ABR and AMS should be included in present pharmacy curricula.
Fulltext Breaking Barriers Amid the Pandemic: The Status of Telehealth in Southeast Asia and its Potential as a Mode of Healthcare Delivery in the Philippines

Macariola AD, Santarin TMC, Villaflor FJM, Villaluna LMG, Yonzon RSL, Fermin JL, et al.

Front Pharmacol, 2021;12:754011.
PMID: 34819860 DOI: 10.3389/fphar.2021.754011
Fulltext Centella asiatica (L.) Urb. Prevents Hypertension and Protects the Heart in Chronic Nitric Oxide Deficiency Rat Model

Bunaim MK, Kamisah Y, Mohd Mustazil MN, Fadhlullah Zuhair JS, Juliana AH, Muhammad N

Front Pharmacol, 2021;12:742562.
PMID: 34925007 DOI: 10.3389/fphar.2021.742562

Background: Hypertension is a major risk factor for cardiovascular disease (CVD), which is the number one cause of global mortality. The potential use of natural products to alleviate high blood pressure has been demonstrated to exert a cardioprotective effect. Centella asiatica (L.) Urb. belongs to the plant family Apiaceae (Umbelliferae). It contains a high amount of triterpenoid and flavonoid that have antioxidant properties and are involved in the renin-angiotensin-aldosterone system which is an important hormonal system for blood pressure regulation. Objective: This study aimed to investigate the effects of C. asiatica ethanolic extract on blood pressure and heart in a hypertensive rat model, which was induced using oral N(G)-nitro-l-arginine methyl ester (l-NAME). Methods: Male Sprague-Dawley rats were divided into five groups and were given different treatments for 8 weeks. Group 1 only received deionized water. Groups 2, 4, and 5 were given l-NAME (40 mg/kg, orally). Groups 4 and 5 concurrently received C. asiatica extract (500 mg/kg, orally) and captopril (5 mg/kg, orally), respectively. Group 3 only received C. asiatica extract (500 mg/kg body weight, orally). Systolic blood pressure (SBP) was measured at weeks 0, 4, and 8, while serum nitric oxide (NO) was measured at weeks 0 and 8. At necropsy, cardiac and aortic malondialdehyde (MDA) contents, cardiac angiotensin-converting enzyme (ACE) activity, and serum level of brain natriuretic peptide (BNP) were measured. Results: After 8 weeks, the administrations of C. asiatica extract and captopril showed significant (p < 0.05) effects on preventing the elevation of SBP, reducing the serum nitric oxide level, as well as increasing the cardiac and aortic MDA content, cardiac ACE activity, and serum brain natriuretic peptide level. Conclusion: C. asiatica extract can prevent the development of hypertension and cardiac damage induced by l-NAME, and these effects were comparable to captopril.
Fulltext Editorial: Targeting Human Inflammatory Skin Diseases With Natural Products: Exploring Potential Mechanisms and Regulatory Pathways

Goh BH, Mocan A, Xiao J, Mah SH, Yap WH

Front Pharmacol, 2021;12:791151.
PMID: 34867426 DOI: 10.3389/fphar.2021.791151
Fulltext Osteoprotective Effects in Postmenopausal Osteoporosis Rat Model: Oral Tocotrienol vs. Intraosseous Injection of Tocotrienol-Poly Lactic-Co-Glycolic Acid Combination

Ibrahim N', Mohd Noor H', Shuid AN, Mohamad S, Abdul Malik MM, Jayusman PA, et al.

Front Pharmacol, 2021;12:706747.
PMID: 34867320 DOI: 10.3389/fphar.2021.706747

Osteoporosis, the most common bone disease, is associated with compromised bone strength and increased risk of fracture. Previous studies have shown that oxidative stress contributes to the progression of osteoporosis. Specifically, for postmenopausal osteoporosis, the reduction in estrogen levels leads to increased oxidative stress in bone remodeling. Tocotrienol, a member of vitamin E that exhibits antioxidant activities, has shown potential as an agent for the treatment of osteoporosis. Most studies on the osteoprotective effects of tocotrienols had used the oral form of tocotrienols, despite their low bioavailability due the lack of transfer proteins and high metabolism in the liver. Several bone studies have utilized tocotrienol combined with a nanocarrier to produce a controlled release of tocotrienol particles into the system. However, the potential of delivering tocotrienol-nanocarrier combination through the intraosseous route has never been explored. In this study, tocotrienol was combined with a nanocarrier, poly lactic-co-glycolic acid (PLGA), and injected intraosseously into the bones of ovariectomized rats to produce targeted and controlled delivery of tocotrienol into the bone microenvironment. This new form of tocotrienol delivery was compared with the conventional oral delivery in terms of their effects on bone parameters. Forty Sprague-Dawley rats were divided into five groups. The first group was sham operated, while other groups were ovariectomized (OVX). Following 2 months, the right tibiae of all the rats were drilled at the metaphysis region to provide access for intraosseous injection. The estrogen group (OVX + ESTO) and tocotrienol group (OVX + TTO) were given daily oral gavages of Premarin (64.5 mg/kg) and annatto-tocotrienol (60 mg/kg), respectively. The locally administered tocotrienol group (OVX + TTL) was given a single intraosseous injection of tocotrienol-PLGA combination. After 8 weeks of treatment, both OVX + TTO and OVX + TTL groups have significantly lower bone markers and higher bone mineral content than the OVX group. In terms of bone microarchitecture, both groups demonstrated significantly higher trabecular separation and connectivity density than the OVX group (p < 0.05). Both groups also showed improvement in bone strength by the significantly higher stress, strain, stiffness, and Young's modulus parameters. In conclusion, daily oral tocotrienol and one-time intraosseous injection of tocotrienol-PLGA combination were equally effective in offering protection against ovariectomy-induced bone changes.
Fulltext Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Sudhesh Dev S, Zainal Abidin SA, Farghadani R, Othman I, Naidu R

Front Pharmacol, 2021;12:772510.
PMID: 34867402 DOI: 10.3389/fphar.2021.772510

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.
Fulltext Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

Hanapi NA, Chear NJ, Azizi J, Yusof SR

Front Pharmacol, 2021;12:751656.
PMID: 34867362 DOI: 10.3389/fphar.2021.751656

Parallel to the growing use of kratom, there is a wealth of evidence from self-report, preclinical, and early clinical studies on therapeutic benefits of its alkaloids in particular for treating pain, managing substance use disorder, and coping with emotional or mental health conditions. On the other hand, there are also reports on potential health risks concerning kratom use. These two aspects are often discussed in reviews on kratom. Here, we aim to highlight specific areas that are of importance to give insights into the mechanistic of kratom alkaloids pharmacological actions. This includes their interactions with drug-metabolizing enzymes and predictions of clinical drug-drug interactions, receptor-binding properties, interactions with cellular barriers in regards to barrier permeability, involvement of membrane transporters, and alteration of barrier function when exposed to the alkaloids.

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