Over the past several decades there has been a growing recognition of the role that covalent drug candidates have played in the drug development process. With this recognition, compounds that are capable of selectively and irreversibly inactivating their targets through covalent bond formation are now being specifically designed rather than being serendipitously identified. Until recently, vinyl sulfones comprised only a small fraction of the warheads under development as covalent drug candidates, but an increasing number of compounds containing this versatile functional group are now under development and consideration as drug candidates. Vinyl sulfones are generally more reactive than structurally-related acrylamides and vinyl sulfonamides, presenting a challenge for producing target-specific inactivators. The most progress in overcoming this challenge has been made in designing vinyl sulfones as selective inactivators of microbial and human cysteine proteases, incorporating these reactive warheads into peptide and peptide mimetic structures that utilize the substrate recognition motifs of these proteases. However, effective vinyl sulfones have also been produced against a growing range of phosphoryl-utilizing enzymes including kinases, phosphatases and metabolic enzymes. Here, target selection takes advantage of the capability of the sulfonyl group to act as a phosphoryl mimic. An example of this approach is presented for the targeting of a metabolic enzyme, fungal aspartate semialdehyde dehydrogenase, an essential microbial enzyme in amino acid metabolism. The studies conducted to date demonstrate the potential utility of designing vinyl sulfone drug candidates to achieve selectivity against challenging and new drug-resistant targets.
Zahra Lorigooini, Fatemeh Heibati, Seyyed Matin Ahmadi
et al.
Abstract Drug addiction is one of the most important global problems. Medicinal herbs have been traditionally used in the management and treatment of opioid withdrawal syndrome and pain. The aim of this study was to determine the effect of A. dracunculus essential oil in reducing the symptoms of morphine withdrawal in mice. Male mice (25-30 g) were randomly assigned into 4 groups (n=10). Morphine-dependent groups received morphine (50 and 75 mg/kg ip; three times/day, 3 days) and a single injection of morphine (50 mg/kg) and then naloxone on the fourth day via IP injection. The control group received saline. The post-treated group received morphine for 3 days; on the fourth day, ten minutes before receiving naloxone, A. dracunculus essential oil with a dose of 75 mg/kg was injected. All groups received naloxone 2 hours after receiving the last dose of morphine; then, the morphine withdrawal symptoms were measured for 30 minutes. In the post-treated and co-treated groups, the body stretching and shaking the claw were significantly less than morphine-dependent groups (p<0/05). Also, in the post-treated and co-treated groups, the blinking, itching, and the number of standing on two legs significantly decreased compared to the morphine group. Hence, it might be concluded that A. dracunculus essential oil can significantly reduce morphine withdrawal symptoms.
Catalyst- and additive-free reactions for synthesizing valuable organic compounds have garnered significant attention in the context of sustainable development. As crucial structural motifs, allylic sulfones find extensive applications in pharmaceutical development and organic synthesis. Despite remarkable advances in allylic sulfone construction, catalyst-free and additive-free methodologies remain an underexplored frontier. Herein, we present an environmentally benign and atom-economical approach for synthesizing allylic sulfones by reacting electron-rich aryl-1,3-dienes with sulfinic acids, achieving yields of 10–94%. This transformation proceeds under ambient air at room temperature, eliminating the need for catalysts or additives. The protocol demonstrates exceptional regio- and chemo-selectivity, streamlined operational simplicity, and excellent scalability potential. This methodology establishes a sustainable and cost-effective paradigm for allylic sulfone synthesis, aligning with green chemistry principles.
Mohsen Adib, Mohammad Hossein Jarrahzadeh, Tayebeh Toliyat
et al.
Background and objectives: Ajuga genus is used as wound healing in traditional Persian medicine. This study aimed to evaluate the effectiveness of Ajuga chamaecistus ssp. tomentella ointment on healing pressure ulcers in patients admitted to the intensive care unit. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 131 patients with grade 1 or 2 pressure ulcers were randomly assigned into one of two groups through simple randomization. The study group received 3% Ajuga ointment, containing 17.26 µg/mL of 20-hydroxyecdysone (ecdysterone) as the main compound, while the control group received placebo twice a day for 14 days in addition to the standard care for pressure ulcers Changes in the degree and size of wounds were considered as the primary outcomes of the study based on the 2-digit Stirling scale. Results: Forty patients in each group completed the research. Mean (95% confidence interval) difference values, for wound degree, between two groups on day 7 vs. day 0 was -0.88 (-1.01 to -0.76, p<0.001), and on day 14 vs. day 0 was -1.57 (-1.78 to -1.36, p<0.001). Mean (95% confidence interval) difference values, for wound area, between two groups on day 7 vs. day 0 was -1.730(-1.979 to -1.48, p<0.001), and on day 14 vs. day 0 was -3.142(-3.563 to -2.72, p<0.001).Conclusion: Topical application of Ajuga ointment significantly improved pressure ulcers on days 7 and 14 compared to placebo. Evaluation of the effects of this plant on a larger sample size, for a longer period of time and in different medical centers is recommended.
Background:
Surgical site infections (SSIs) are a serious concern in cesarean sections, leading to research on improved preventive measures, to evaluate the effectiveness of standard antibiotic prophylaxis alone versus an extended regimen that includes azithromycin in reducing SSIs in nonelective cesarean sections.
Methods:
In this randomized controlled trial, 288 women who were undergoing nonelective cesarean sections at a tertiary care hospital in South India were involved. Participants were divided into two groups: one receiving standard prophylaxis with cefazolin and the other receiving an extended regimen with azithromycin. The main focus was on the occurrence of SSIs within six weeks after the surgery.
Results:
The extended regimen group had a slightly lower incidence of SSIs (1.42%) compared to the standard regimen group (6.12%), but this difference did not reach statistical significance (P = 0.112).
Conclusion:
Although the inclusion of azithromycin alongside standard prophylactic antibiotics demonstrated a slight decrease in SSIs, the results did not reach statistical significance. These findings indicate potential advantages in certain patient groups, which should be explored in more detail.
Background Fraud in pharmaceutical tenders is a severe form of corruption that poses a significant threat to public health, patients, and the community. Due to the substantial financial volume in the pharmaceutical sector, vulnerable points in decision-making for market entry and purchase are at risk. As a result, the objective of this study was to measure the level of transparency and risk of corruption in pharmaceuticals’ procurement practices in South Wollo, North-East Ethiopia.Methodology From October 1 to December 15, 2023, a multi-facility, cross-sectional study was conducted. The participants were pharmaceutical procurement committee (PPC) members. The World Health Organization's (WHO’s) standardised interviewer-administered questionnaire was used to collect the data. The collected data was entered, cleaned, processed, and analyzed using Statistical Package for Social Sciences (SPSS) version 27. Both descriptive and inferential statistics (univariate and linear regression analyses) were computed. The relationship between the independent (health facility level) and dependent (level of transparency) variables was determined using beta with a p-value of less than 0.05 and a 95% CI.Results One hundred eighty-seven respondents, from 47 health centres (low, medium, and high volume) and 14 hospitals (primary, secondary, and tertiary), participated. The aggregate result showed that pharmaceutical procurement practice was very vulnerable to corruption, with a transparency level of only 33.0% (3.3 out of 10). The univariate analysis demonstrated a significant disparity in the mean transparency scores between health centres and hospitals. The linear regression also showed that for every one standard deviation increase in the facility level, there was an associated 0.39 increase in the transparency level of pharmaceutical procurement (β = 0.39, 95% CI: 0.02-0.04).Conclusion The pharmaceutical procurement practice at the health facilities was generally found to be very vulnerable to corruption, which slightly increased with a decrease in facility levels and vice versa.
Therapeutics. Pharmacology, Pharmacy and materia medica
Natanim Degefu, Abera Jambo, Lemma Demissie Regassa
et al.
Background: Acute cardiogenic pulmonary oedema is highly associated with poor in-hospital outcomes. This study aimed to determine the in-hospital outcome and its predictors among patients with acute cardiogenic pulmonary oedema at a tertiary hospital in Harar, Eastern Ethiopia, from May 1 to 20, 2023.Methods: A retrospective cohort study was employed among 204 patients with acute cardiogenic pulmonary oedema who were admitted between 1st May 2018 and 30th April 2023. The collected data were entered into Excel, and analysed using theSTATA software version 17. The hazard ratio with its 95% confidence interval was used and a P-value < 0.05 was considered a statistically significant association.Results: The overall mortality rate was 17.60 (95% CI: 11.59–26.72) per 1000 person-day observation with mean (±SD) time to death was 2.88 (±2.06) days. Age (AHR: 1.35; 95% CI: 1.04–1.74 for every 10 years), being smoker (AHR: 3.26; 95% CI: 1.05–10.10), having respiratory rate of ≥40 breaths per minute (AHR: 5.46; 95% CI: 1.71–17.45), and having anaemia (AHR: 4.35; 95% CI: 1.23–15.33) were significant predictors of in-hospital mortality.Conclusion: More than one in ten patients in this study died in the hospital. Therefore, special attention needs to be considered for patients with those predictors of in-hospital mortality.
Therapeutics. Pharmacology, Pharmacy and materia medica
Periodic changes in the environmental conditions affect significantly on the biosynthesis of bioactive compounds and the therapeutic potential in medicinal plants. Although Berberis lycium is being extensively used against various ailments, specifically infectious diseases, impact of seasonal variations on its polyphenolic contents and antibacterial activities has rarely been explored yet. Consequently, present study was focused on the determination of phenolics and flavonoids content and antibacterial activities in the root and stem bark of B. lycium harvested throughout the year from same location (Abbottabad) using standard analytical approaches. Relatively, stem bark had high concentration of total phenolics than root bark, but in the case of total flavonoids there was no significant difference. In root bark, the highest concentration of TPC was in the month of December (373.5±0.58 mg GAE/100 g DW), while stem bark exhibited highest concentration of TPC (476.1±13.7 mg GAE/100 g DW) in the month of January. In root bark, TFC ranged from 32.00±7.62 to 124.5±5.58 mg QE/100 g DW with highest concentration in April. Whereas, in stem bark, TFC varied from 19.51±4.94 to 135.50±7.11 mg QE/100 g DW, with highest concentration in the month of April. Likewise, in January, November and December inhibition potential was maximum against Escherichia coli and Staphylococcus aureus both in root and stem bark samples. Although, significant associations were observed between total phenolics and antibacterial activities. However total phenolics, total flavonoids, and antibacterial activities depicted negative correlations with growing conditions viz. temperature, rain fall and humidity. Our findings confirm the impact of seasonal variations on the phytochemical composition and bioactive potential in medicinal plants. Specifically, to get maximum health benefits from B. lycium, winter season could be more appropriate in the Himalayan region.
Pharmacy and materia medica, Therapeutics. Pharmacology
Olaia Martínez-Iglesias, Vinogran Naidoo, Iván Carrera
et al.
Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.
Gabriel Nóbrega da Costa, Letícia Yoshitome Queiroz, Isaque Nilton dos Santos
et al.
Abstract Acai (Euterpe oleracea Mart.) and guarana (Paullinia cupana Kunth) are native species from the Amazon Forest that in folk medicine are used to treat several diseases due to their anti-inflammatory and antioxidant properties. This review brings together findings from different studies on the potential neuroprotective effects of acai and guarana, highlighting the importance of the conservation and sustainable exploitation of the Amazon Forest. A bibliographic survey in the PubMed database retrieved indexed articles written in English that focused on the effects of acai and guarana in in vitro and in vivo models of neurodegenerative diseases. In general, treatment with either acai or guarana decreased neuroinflammation, increased antioxidant responses, ameliorated depression, and protected cells from neurotoxicity mediated by aggregated proteins. The results from these studies suggest that flavonoids, anthocyanins, and carotenoids found in both acai and guarana have therapeutic potential not only for neurodegenerative diseases, but also for depressive disorders. In addition, acai and guarana show beneficial effects in slowing down the physiological aging process. However, toxicity and efficacy studies are still needed to guide the formulation of herbal medicines from acai and guarana.
Fernanda Padoin dos Reis, Graziela Vargas Rigo, Cristina Wayne Nogueira
et al.
Trichomoniasis is the most common nonviral sexually transmitted infection in the world, but its available therapies present low efficacy and high toxicity. Diphenyl diselenide (PhSe<sub>2</sub>) is a pharmacologically active organic selenium compound; however, its clinical use is hindered by its lipophilicity and toxicity. Nanocarriers are an interesting approach to overcome the limitations associated with this compound. This study designed and evaluated a vaginal hydrogel containing PhSe<sub>2</sub>-loaded Eudragit<sup>®</sup> RS100 and coconut oil nanocapsules for the treatment of trichomoniasis. Nanocapsules presented particle sizes in the nanometric range, positive zeta potential, a compound content close to the theoretical value, and high encapsulation efficiency. The nanoencapsulation maintained the anti-<i>Trichomonas vaginalis</i> action of the compound while improving the scavenger action in a DPPH assay. The hydrogels were prepared by thickening nanocapsule suspensions with locust bean gum (3%). The semisolids maintained the nanometric size of the particles and the PhSe<sub>2</sub> content at around the initial concentration (1.0 mg/g). They also displayed non-Newtonian pseudo-plastic behavior and a highly mucoadhesive property. The chorioallantoic membrane method indicated the absence of hemorrhage, coagulation, or lysis. The compound, from both non-encapsulated and nano-based hydrogel delivery systems, remained on the surface of the bovine vaginal mucosa. Therefore, the formulations displayed the intended properties and could be a promising alternative for the treatment of trichomoniasis.
Olha Mykhailenko, Liudas Ivanauskas, Ivan Bezruk
et al.
The application of the Quality by Design (QbD) concept to extracts obtained from <i>Crocus sativus</i> perianth with potential anticancer activity will ensure the safety, efficiency, and quality control of the entire technological process, as well as determine the critical factors affecting the quality of extracts. Potentially critical points of the production of the plant extracts, including the cultivation and processing of the plant materials, the extraction process, and the choice of solvents, were identified using the Ishikawa diagram and FMEA risk assessment methods as well as the corrective actions proposed. The Herbal Chemical Marker Ranking System (HerbMars) approach was used to justify the Q-markers choice of <i>Crocus</i>, which takes into account bioavailability, pharmacological activity, and the presence of the selected standard. An experimental design (DoE) was used to assess the influence of potentially critical factors on the efficiency of the compound extraction from raw materials with water or ethanol. The presence of 16 compounds in <i>Crocus</i> perianth was determined by HPLC and their quantitative assessment was established. Selected compounds (ferulic acid, mangiferin, crocin, rutin, isoquercitrin) can be used for the quality control of <i>Crocus</i> perianth. In addition, the stigmas from the Volyn region met the requirements of ISO 3632 for saffron as a spice (category I). The cytotoxic activity against melanoma (IGR39) and triple-negative breast cancer (MDA-MB-231) cell lines of the hydroethanolic extract of <i>C. sativus</i> perianth was significantly more pronounced than the water extract, probably due to the chemical composition of the constituent components. The results show that the QbD approach is a powerful tool for process development for the production of quality herbal drugs.
Haseeb Ahsan, Salman Ul Islam, Muhammad Bilal Ahmed
et al.
Cancer is a complex and multistage disease that affects various intracellular pathways, leading to rapid cell proliferation, angiogenesis, cell motility, and migration, supported by antiapoptotic mechanisms. Chemoprevention is a new strategy to counteract cancer; to either prevent its incidence or suppress its progression. In this strategy, chemopreventive agents target molecules involved in multiple pathways of cancer initiation and progression. Nrf2, STAT3, and Src are promising molecular candidates that could be targeted for chemoprevention. Nrf2 is involved in the expression of antioxidant and phase II metabolizing enzymes, which have direct antiproliferative action as well as indirect activities of reducing oxidative stress and eliminating carcinogens. Similarly, its cross-talk with NF-κB has great anti-inflammatory potential, which can be utilized in inflammation-induced/associated cancers. STAT3, on the other hand, is involved in multiple pathways of cancer initiation and progression. Activation, phosphorylation, dimerization, and nuclear translocation are associated with tumor cell proliferation and angiogenesis. Src, being the first oncogene to be discovered, is important due to its convergence with many upstream stimuli, its cross-talk with other potential molecular targets, such as STAT3, and its ability to modify the cell cytoskeleton, making it important in cancer invasion and metastasis. Therefore, the development of natural/synthetic molecules and/or design of a regimen that can reduce oxidative stress and inflammation in the tumor microenvironment and stop multiple cellular targets in cancer to stop its initiation or retard its progression can form newer chemopreventive agents.
Background Pharmaceuticals are produced and consumed in increasing volume every year. Unfortunately, not all medications that go in to the hand of the consumers get consumed; large quantities remain unused or expire. The accumulation of medication at household and unsafe disposal of unwanted medicines could lead to inappropriate medicine sharing, accidental childhood poisonings and diversion of medicines to illicit use. Methods A descriptive cross-sectional study was conducted among 695 residents in kebele(ward) 16 of Jinela woreda(district), Harar city from February 27–April 27. A multi-stage sampling technique was used to select individual households. Face-to-face interview using structured questionnaires were conducted to collect data from each study subject. The cleaned data was entered in to epidata analyzed using SPSS version 20 software. Descriptive statistics on sample characteristics was computed including frequencies and percentage and presented using tables and figures. Results Most participants displayed correct understanding toward medication waste (72.9%) and its effect on environmental if disposed improperly (86%). A large portion of the respondents did not know about drug-take-back system 464 (66.9%). In order to minimize the entry of pharmaceuticals into environment, 68.6% of the participants suggested the need for proper guidance to the consumer. Majority of the respondents believed risk related to the presence of unwanted drug in home, potential harm to children, lack of adequate information on safe disposal practice and need for take-back program. Approximately 66% of the respondents had unused medicine stored at home and the common types of medicines kept in households were analgesics (62.7%) and antibiotics (24%). Preferred ways of disposal of both unused and expired medicine was throwing away in household garbage (53.2%) and two third of them disposed the pharmaceuticals in its original package and dosage form. Conclusion In present study, there was high practice of keeping medication at home and most disposal approach indicated by the participants was not recommended methods. Awareness about proper disposal of unused and expired medicines among the public should be created. Guidelines on safe disposal are required and an organized method of collecting unused and expired pharmaceuticals needs to be introduced.
Therapeutics. Pharmacology, Pharmacy and materia medica
E. A. Mardganieva, V. A. Ryabchenko, E. V. Malysheva
et al.
LLC Novartis Pharma, Moscow, Russian Federation Abstract. The problem of off-label use is still unsolved during the pharmacotherapy in children. In connection with the above, the need to stimulate the conduct of specially organized clinical studies, the purpose of which will be to evaluate the efficacy and safety of using drugs in children in different age groups, becomes evident. However the complexity of the organization of clinical studies in pediatrics is associated not only with regulatory aspects but also with lack of understanding of the importance of these studies by pediatricians and parents. The authors conducted a study aimed at finding out the frequency of off-label prescriptions in the Russian Federation in pediatric practice and doctors’ and parents’ attitude to this kind of use of medications. The study has shown the evidence that the off-label prescription practice is widely-used in healthcare in Russia and is routine for most respondents. The highest frequency of off-label prescriptions is observed in the group of children from 0 to 5 years. The majority of physicians and parents don’t consider themselves responsible for popularization of clinical trials which indicates that this problem should be widely discussed in the society. Parents trust physicians in terms of therapy choices or their recommendations regarding participation in clinical trials. A portrait of a typical “staunch opponent” of clinical trials among parents.
Eremostachys laciniata, having rich flavonoid content, is expected to have a considerable antioxidant effect. In this study We used ACMS (Accelerated cytotoxic or protective mechanism screening technique) to evaluate the possible antioxidant effect of E. laciniata rhizome against oxidative cell damages induced by different types of oxidative stress such as iron-8-hydroxyquinolin (IQ) complex and copper in freshly isolated liver cells. The extracts were prepared with n-hexane, dichloromethane and methanol. Hepatocytes were isolated from male Sprague-Dawley rats by a two-step collagenase perfusion. Cell viability was measured by trypan blue exclusion method. DPPH (2, 2-diphenyl-1-picrylhydrazyl) assay was used to evaluate the antioxidant activity. ROS formation was measured by using DCFDA (2, 7-dichlorofluorescin diacetate) probe, mitochondrial membrane potential (MMP) was assessed by rhodamine 123 fluorescence and lipid peroxidation was determined by thiobarbituric acid reactive substances (TBARS) assay. The MET extract was demonstrated to possess a significant radical scavenging activity (RC50%=0.212). Unlike MET extract, the n-hexane and dichloromethane extracts showed toxic effects in cell suspensions. The MET extract significantly decreased cell death and ROS formation induced by IQ complex and copper and demonstrated protective effects against copper-induced mitochondrial membrane potential collapse and lipid peroxidation. The protection induced by MET extract can be attributed to antioxidant characteristics of the phenylethanoids content.