DOI: 10.3897/folmed.68.e165953

Authors: Sabreen S. Salman Al Anei, Ahmed R. Abu Raghif, Hala A. Almoayed

Abstract: Aim: This study evaluated Glycyrrhiza glabra (licorice) supplementation’s therapeutic efficacy in polycystic ovarian syndrome (PCOS) by assessing its impact on clinical and biochemical parameters, including metabolic and inflammatory markers. Materials and methods: This randomized clinical trial evaluated Diane-35 plus crude licorice extract for improving symptoms in PCOS. Seventy five participants were randomly assigned to three groups: Diane-35 monotherapy (n=25), Diane-35-plus-licorice (450 mg twice daily; n=25), and health controls (n=25). Treatment lasted three months, with biochemical and clinical parameters assessed before and after therapy to determine therapeutic efficacy. Results: Before treatment, PCOS patients showed higher body mass index (BMI; p=0.004), insulin resistance (p<0.001), fasting insulin, glucose, total cholesterol, and LDL (all p<0.001), with lower HDL. Furthermore, HbA1c was slightly reduced (p=0.012). IL-1β and TNF-α were elevated (p<0.001), while total antioxidant capacity (TAC) was unchanged. In the post-treatment, BMI was similar between the Diane-35 and Diane-35-plus-licorice group (p=0.07). The Diane-35-plus-licorice group showed greater reductions in insulin resistance, fasting insulin, total cholesterol, and IL-1β, with increased HDL and TAC, while TNF-α and LDL showed minimal change. Conclusion: Licorice improved metabolic and inflammatory markers in PCOS, reducing insulin, HOMA-IR, glucose, lipids, IL-1β, and TNF-α, supporting its potential as adjunctive PCOS therapy.

HTML

XML

PDF

DOI: 10.3897/folmed.67.e149527

Authors: Tatiana A. Zhiganova, Evgenia A. Radkova

Abstract: Aim: The study objective was to assess the frequency of gene alleles responsible for the metabolism and elimination of drugs in treatment-resistant patients to antipsychotics and/or antidepressants. Materials and methods: The frequency of CYP2D6, CYP2C19, and CYP1A2 gene alleles was studied in 133 patients aged 18–70 years in comparison with a healthy population. Results: Patients with treatment resistance to antipsychotics and/or antidepressants demonstrated the increased allele frequency of CYP2D6 *3 (4.5% vs. 1.0%, OR 4.5, p=0.003), CYP2C19 *17 (24.4% vs. 15.4%, OR 1.78, p=0.027), CYP1A2 *1A (68.5% vs. 41.4%, OR 3.03, p<0.001), decreased allele frequency of CYP2C19 *1 (61.3% vs. 88.3%, OR 0.21, p<0.001) and CYP1A2 *1F (30.4% vs. 58.6%, p<0.001). The frequency of CYP2D6 *5 allele was higher in females (3.8% vs. 0% in males, OR 11.6, p=0.029). No age difference was found in CYP2D6, CYP2C19, and CYP1A2 alleles frequencies in the subgroups of patients aged 18–30 years versus 31–70 years. Conclusion: The observed difference in the genotype prevalence of CYP2D6, CYP2C19, and CYP1A2 in patients with antipsychotic and/or antidepressant resistance allows us to recommend pharmacogenetic testing for routine clinical practice in order to select the most effective and safe treatment for patients with antipsychotic and antidepressant resistance.

HTML

XML

PDF

DOI: 10.3897/folmed.67.e151128

Authors: Radiana Staynova, Desislava Andonova

Abstract: Introduction: In 2010, the European Union (EU) introduced new pharmacovigilance legislation that established an additional monitoring (AM) measure for certain medicines following their marketing authorization. Since 2013, a black inverted triangle (▼), accompanied by a brief explanatory sentence, has been displayed on their leaflet and in the summary of product characteristics. This symbol is uniformly used across all EU member states to indicate medicines subject to AM. Aim: To analyze the medicines under AM listed by the European Medicines Agency (EMA) and compare them with those available on the pharmaceutical market in Bulgaria. Material and methods: A descriptive analysis was performed on the EMA’s list of medicines under AM as of February 23, 2024 (EMA/245297/2013 Rev. 119). Additionally, the study assessed the market access and affordability of these medicines in Bulgaria by examining their inclusion in the Positive Drug List (PDL). Public electronic registers of the National Council on Prices and Reimbursement of Medicinal Products in Bulgaria were used for this analysis. Results: The EMA’s list comprised a total of 358 medicines, of which 90 were available on the Bulgarian pharmaceutical market as of February 2024. The analysis revealed that the majority of these medicines were new active substances (n=27, 30%), new biologicals (n=12, 13.3%), and medicines requiring post-authorization safety studies, PASS (n=21, 23.3%). Conclusion: Notably, only 25% of medicines under AM authorized in the EU were marketed in Bulgaria, with a significant proportion of these being new active substances, particularly in therapeutic areas such as oncology, hematology, and neurology.

HTML

XML

PDF

DOI: 10.3897/folmed.66.e115800

Authors: Natalia Vilmosh, Maria Georgieva-Kotetarova, Ilin Kandilarov, Hristina Zlatanova-Tenisheva, Mariana Murdjeva, Veselina Kirina, Stela Dimitrova, Mariana Katsarova, Petko Denev, Ivanka Kostadinova

Abstract: Introduction: Many chronic somatic and psychiatric diseases are associated with oxidative stress and inflammation, both of which have detrimental effects on human health. Aim: To investigate the in vitro antioxidant and in vivo immunomodulatory activities of Satureja montana dry extract. Material and methods: The in vitro antioxidant activity of Satureja montana dry extract was assessed using ORAC, HORAC, and electrochemical methods. Immunomodulatory activity was evaluated in acute and chronic stress models by measuring the serum levels of cytokines TNF-α, IL-6, and IL-1β in a cohort of 112 male 8-week-old Wistar rats. The rats were randomly divided into 7 groups for each of both stress models and then subjected to ELISA analysis (14 groups with 8 rats in each group). The rodents were gavaged with a dry extract of Satureja montana (250 mg/kg and 500 mg/kg), rosmarinic acid (15 mg/kg), and carvacrol (500 mg/kg) for 14 days and 60 days, respectively. Results: We demonstrated that, for all employed in vitro methods, the dried extract of Satureja montana exhibited considerable antioxidant activity. Satureja montana did not significantly lower serum concentrations of TNF-α, IL-6, or IL-1β in either stress model as compared to the positive saline control group. On the other hand, in the acute stress model, a dose of 250 mg/kg of Satureja montana significantly decreased IL-6 in comparison to carvacrol and significantly reduced TNF-α and IL-6 in comparison to rosmarinic acid. Conclusion: Although Satureja montana dry extract has significant antioxidant activity in vitro, its influence on systemic inflammation is still unknown. Future research will look into how it affects serum levels of pro-inflammatory cytokines.

HTML

XML

PDF

DOI: 10.3897/folmed.65.e107259

Authors: Maria Georgieva-Kotetarova, Ilin Kandilarov, Natalia Vilmosh, Hristina Zlatanova, Nikolay Yanchev, Delian Delev, Tihomir Dermendzhiev, Marianna Murdjeva, Ivanka Kostadinova, Ilia Kostadinov

Abstract: Aim: Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation. Materials and methods: Male Wistar rats were randomly divided into 4 groups: control, LPS control, LPS + CBD 5 mg/kg bw, and LPS + CBD 10 mg/kg bw. Animals were treated with CBD 14 days before LPS administration and throughout the experiment. Step-through passive avoidance task, Y-maze, and novel object recognition test (NORT) were used to assess the memory functions. The following parameters were recorded: latency time, spontaneous alternations percentage (SA%) and recognition index (RI). IL-10, IL-6, TNF-α, and IL-1β serum levels were measured to evaluate the immunomodulatory properties of CBD. Results: LPS led to significant decrease of the recorded parameters in all memory tasks. This demonstrated the memory-impairing effect of LPS-induced inflammation. In the Y-maze and NORT tests, both doses of CBD increased SA% and RI, respectively. Significant difference was found in comparison with the LPS controls. Rats from the CBD treated groups showed increased latency in the step-through passive avoidance task. In the short-term memory test, both CBD doses significantly increased this parameter when compared with both control groups (p<0.05 and p<0.001, respectively), whereas in the long-term memory test, statistical significance was reached only in comparison with the LPS controls (p<0.01). CBD treatment failed to reduce TNF-α and IL-6 serum levels. The lower studied dose significantly decreased IL-10 and IL-1β concentrations compared to LPS controls (p<0.01 and p<0.05, respectively). Conclusions: CBD improved spatial working and recognition memory in rats with LPS-induced inflammation. Suppression of IL-1β production could be attributed to the observed effect.

HTML

XML

PDF

DOI: 10.3897/folmed.65.e97410

Authors: Boyana Parvanova, Bilyana Tacheva, Ivan Ivanov

Abstract: Introduction: Chlorpromazine, thioridazine, and trifluoperazine are phenothiazine drugs that cause colloid-osmotic hemolysis of human erythrocytes by unknown mechanism. To clarify this mechanism, the impact of these drugs on the βsp (1.4 MHz) and γ1sp (9 MHz) dielectric relaxations was investigated. Each relaxation was shown to reduce its strength on the severing specific bridge that connects the spectrin network with the lipid membrane. For βsp relaxation, this is the spectrin-actin-glycophorin C bridge while for γ1sp relaxation this is the spectrin-ankyrin-band 3 bridge. Aim: To elucidate the mechanisms of the effects of phenothiazine drugs in prehemolytic concentrations on the red blood cell plasma membrane using scanning temperature-dependent (thermal) differential dielectric spectroscopy. Materials and methods: Erythrocytes were isolated from freshly drawn blood and 100 μl of them were suspended in 1 ml isotonic solution of 10 mM NaCl and mannitol (working medium) containing the indicated concentration of the drug for 10 min at 23°C. The treated erythrocytes were isolated, suspended in working medium, hematocrit 0.55, and heated (heating rate 1.5°C/min) above the denaturation temperature of spectrin (TA≈49.5°C) in order to obtain the differential dielectric spectroscopy data. The complex admittance, Y* = Y’+j.Y”, of the tested suspensions was continuously measured and separated into its real (Y’) and imaginary (Y”) parts using Solartron 1260 Impedance Frequency Analyzer. Results: At pre-hemolytic concentrations, each drug inhibited these two relaxations, predominantly the γ1sp relaxation. The results could be interpreted in terms of a sigmoid effect of the drugs on the spectrin-ankyrin-band 3 bridge severing it at concentration just prior to the start of massive hemolysis. Conclusions: The study points at the possible mechanism of erythrocyte damage after treatment with phenothiazine drugs at prehemolytic concentrations. This is probably due to the disruption of the bridges between the phospholipid bilayer and the submembrane spectrin network.

HTML

XML

PDF

DOI: 10.3897/folmed.65.e86540

Authors: Nikolay B. Yanchev, Delian P. Delev, Natalia B. Vilmosh, Pepa K. Atanassova, Petar I. Hrischev

Abstract: Introduction: Sideritis scardica, Lamiaceae, is a plant with anti-inflammatory, antirheumatic, digestive, and antimicrobial properties that is widely used in folk medicine throughout the Balkan Peninsula. The name derives from the Greek word ‘sideros’, meaning iron, and it is believed that the plant was also used by soldiers to heal wounds caused by cutting weapons. Aim: The study aimed to assess the subchronic toxicity of a dry hydromethanolic extract from Sideritis scardica, Lamiaceae. Materials and methods: To investigate the subchronic toxicity, male Wistar rats were given orally a solution of dry hydromethanolic extract daily for 12-weeks at doses of 100, 200, and 400 mg/kg bw. Blood and blood serum were collected at the end of the experiment, and different organs were prepared for histopathological examination. Statistical analysis was performed with One-Way ANOVA test, using IBM SPSS 19.0. Results: All hematological and biochemical results remained within the normal reference ranges described for the species. The histological examination showed no abnormalities in the morphology of the examined organs (brain, stomach, liver, and kidney). Conclusions: The study contributes to a better understanding of the possible pharmacological effects, while documenting the absence of toxicity and safe use of the herb for future new indications.

HTML

XML

PDF

DOI: 10.3897/folmed.65.e83722

Authors: Natalia Vilmosh, Maria Georgieva-Kotetarova, Stela Dimitrova, Maria Zgureva, Pepa K. Atanassova, Petar I. Hrischev, Ivanka Kostadinova

Abstract: Introduction: Satureja montana is a wild growing medicinal plant, part of the Lamiaceae family. This herb is well known as a source of phenolic compounds, which can vary in a broad range depending on different factors and exert many pharmacological activities. Aim: The aim of the study was to investigate the composition and chronic toxicity of dry extract of Satureja montana. Material and methods: The composition was investigated by high-performance liquid chromatographic system with diode-array detector. To establish the chronic toxicity of dry extract of Satureja montana we used 40 eight-week-old male Wistar rats, treated orally with saline, olive oil (control groups), Satureja montana at a dose of 500 mg/kg bw, carvacrol – 500 mg/kg bw, and rosmarinic acid – 15 mg/kg bw. The animals were sacrificed at the end of the experiment and blood samples and organs for histological examination were obtained. Statistical analysis was performed with one-way analysis of variance (ANOVA) using IBM SPSS 19.0. Results: Rosmarinic acid and small quantities of carvacrol were found in the dry extract of Satureja montana. Full blood count and the biochemical parameters ASAT, ALAT, uric acid, cholesterol, triglycerides, glucose and ionized Ca were in the reference values for 17+ weeks old male Wistar rats. The histological samples showed no signs of organ toxicity. Conclusions: The main ingredient in the dry extract of Satureja montana is rosmarinic acid. The extract is not toxic after 90-days oral administration.

HTML

XML

PDF

DOI: 10.3897/folmed.65.e71854

Authors: Vesela Borisova-Nenova, Miroslav Eftimov, Stefka Valcheva-Kuzmanova

Abstract: Introduction: Impaired circadian rhythm (ICR) is a commonly used model of mild stress. The fruit juice of Chaenomeles japonica var. maulei (Mast.) Lavall‚e (CMFJ) is rich in polyphenols known for their anti-inflammatory, antioxidant, and neuroprotective properties. Aim: The aim of this study was to investigate the effects of CMFJ on the behavior of rats subjected to ICR. Materials and methods: Male Wistar rats were divided into five groups of 10 animals each: control group (without ICR), the ICR, ICR+CMFJ2.5, ICR+CMFJ5, and ICR+CMFJ10 groups. ICR was induced by exposing rats to 14 days of constant light. Over these days, oral treatment was administered with distilled water (the control and ICR groups) and CMFJ at doses 2.5, 5, and 10 ml/kg for the respective groups. Then we performed the open field test, the social interaction test (SIT), and the forced swim test (FST) to assess rats’ locomotion, anxiety, and the depressive-like behavior, respectively. Results: The ICR animals increased their horizontal and vertical locomotion when compared to the controls. The ICR rats did not change significantly the social interaction time in the SIT test and immobility time in the FST. The horizontal and vertical activity of the ICR+CMFJ10 rats was reduced in comparison with ICR animals. Compared to ICR rats, the animals treated with CMFJ at doses of 2.5 and 10 ml/kg demonstrated an improved social interaction and decreased immobility time in the FST. Conclusions: CMFJ prevented the development of ICR-induced hyperactivity and showed an anxiolytic-like and antidepressant-like effect, probably due to its high polyphenol content.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e68824

Authors: Antoaneta Georgieva, Milena Todorova, Miroslav Eftimov, Krasimir Kuzmanov, Stefka Valcheva-Kuzmanova

Abstract: Introduction: The ovariectomized rat is a model used to mimic the changes in female organism during menopause. Aronia melanocarpa fruit juice (AMFJ) is extremely rich in phenolic substances (procyanidins, flavonoids and phenolic acids). Aim: The present study aimed to evaluate the effects of AMFJ on rat behavior in a model of ovariectomy-induced estrogen deficit. Materials and methods: Four groups of female Wistar rats were used, each consisting of 14 animals – sham operated (SO), ovariectomized (OVX), OVX+AMFJ5, and OVX+AMFJ10. After two-week recovery from the operation, three-month oral treatment was performed with distilled water for the SO and OVX groups, and AMFJ at doses of 5 ml/kg and 10 ml/kg for the OVX+AMFJ5 and OVX+AMFJ10 groups, respectively. Then, behavioral tests were conducted. Locomotor activity was assessed using the open field test (OFT). Anxiety was evaluated in the OFT, elevated plus-maze test and social interaction test. Depressive behavior was assessed in the forced swim test. Thermal pain sensitivity was measured in the hot plate test. Results: OVX rats showed increased anxiety, depressive behavior and pain sensitivity in comparison with SO animals. Compared to OVX rats, anxiety, depressive behavior, and pain sensitivity of AMFJ-treated animals were decreased. Locomotor activity of AMFJ-treated rats was reduced in comparison with both SO and OVX animals, probably due to the sedative effect of the juice. Conclusions: AMFJ was able to antagonize the negative impact of the estrogen deficit on rat behavior (anxiety, depression, pain sensitivity), probably due to the biological activity of its polyphenolic ingredients.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e67739

Authors: Nina Doncheva, Anita Mihaylova, Hristina Zlatanova, Mariya Ivanovska, Delian Delev, Marianna Murdjeva, Ilia Kostadinov

Abstract: Introduction: Vitamin D is a fat-soluble secosteroid, its primary function being regulation of calcium-phosphate homeostasis and maintenance of bone integrity and mineralization. Recently, pleotropic effects of this vitamin have been recognized, including an immunomodulatory role and involvement in normal brain development and functioning. Aim: The aim of the present study was to investigate the influence of cholecalciferol on serum inflammatory markers and memory functions in lipopolysaccharide (LPS) model of inflammation. Materials and methods: Male Wistar rats were randomly divided into 4 groups (n=8): control group, LPS control group, LPS + cholecalciferol (vitamin D3) 500 UI group, and 1000 IU/kg bw group. Step-down passive avoidance test, novel object recognition test (NORT), Y- and T-maze were performed to assess the memory functions. Latency, recognition index (RI), % spontaneous alteration (SA), and working memory index were registered. Tumor necrosis factor-alpha (TNF-α), IL-1β, transforming growth factor-β1 (TGF-β1), and brain derived neurotrophic factor (BDNF) serum levels were measured by ELISA. Results: LPS administration caused significant impairment in memory functions in all memory tasks. Cholecalciferol treatment caused significant increase in % SA, RI, and working memory index. In the step-down passive avoidance test, cholecalciferol-treated groups showed statistically significant increase in latency in the long-term memory test. Vitamin D3-treated rats showed decreased TNF-α and IL-1β serum levels whereas the concentration of TGF-β1 and BDNF increased. Conclusions: Cholecalciferol improves spatial working and episodic memory, which can at least partially be explained with its effect on systemic inflammatory response that is closely related with the development of neuroinflammation.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e68987

Authors: Neli Vilhelmova, Ivanka Nikolova, Kaloyan D. Georgiev, Iliya J. Slavov

Abstract: Introduction: Based on traditional medicine, many countries use various plant products (fruits, leaves and other plant parts) as food supplements or in the form of tea. The use of these plant sources has been established through the years of use and the proven benefits of their ingredients to improve human health. Aim: In the present study, we have focused on the effect of Lycium barbarum fruit extract and methylxanthines isolated from Pu-erh (MXP) and Bancha (MXB) tea leaves on Herpes simplex virus type 1 (HSV-1), poliovirus 1 (PV1) and coxsackievirus B1 (CVB1) virus in vitro. Materials and methods: We used in vitro antiviral and virus attachment assays to determine the effects of the three extracts we studied. Results: None of the extracts showed significant inhibition of replication of the three treated viruses but a remarkable inhibitory effect on extracellular virions of HSV-1 was exhibited 30 minutes after exposure, especially by the Lycium barbarum extract. The inhibitory effect of the three extracts on the level of adsorption of the HSV-1 to sensitive cells (MDBK) was also significant, with the most pronounced effect of the MXP. The protective effect of the extracts against herpes infection on healthy cells was also determined, the MXP showing the most notable effect. Conclusions: The three studied extracts can be used effectively in the treatment of herpes infections, as well as in infections with other enveloped viruses.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e66784

Authors: Sajedeh Daei, Roghayeh Abbasalipourkabir, Korosh Khanaki, Fatemeh Bahreini, Nasrin Ziamajidi

Abstract: Introduction: Nanomedicine has recently been known as an emerging research area with promising applications in cancer diagnosis and treatment. Aside from this, gold nanoparticles (AuNPs), as one of the important components of nanomedicine, have attracted considerable attention due to their special physicochemical properties and lower toxicity than other nanoparticles. Despite the impressive advantages of AuNPs, it has not been yet determined whether oxidative stress contributes to the toxicity of AuNPs on bladder cancer. Aim: The aim of this study was to address this issue by conducting experiments in order to investigate the effects of 20 nm AuNPs on human bladder cancer 5637 cells. Materials and methods: The viability of 5637 cells was evaluated upon 24 hour exposure to different concentrations of AuNPs (0-50 µg/ml) by 3-(4, 5-dimethylthiazol, 2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. In order to evaluate oxidative stress status, total antioxidant capacity (TAC), total oxidant status (TOS), malondialdehyde (MDA) and also activities of antioxidant enzymes including glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) were all determined by colorimetric assay kits. Results: The results from our experiment showed that the cytotoxicity caused by AuNPs was dose-dependent and the IC50 value was found to be 43.14 µg/ml after 24-hour exposure. Furthermore, MDA and TOS levels were significantly increased in treated cells compared to untreated cells (p<0.05). In contrast, TAC level and the activities of SOD, GPx, CAT were significantly decreased in AuNPs-treated groups as compared with the untreated cells (p<0.05). Conclusions: Overall, AuNPs decrease the cell viability and increase oxidative stress in bladder cancer 5637 cells.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e68365

Authors: Ashish Shah, Chhagan Patel

Abstract: Inflammation is considered a general protective reaction of localized tissue against injury, irritation, or swelling. Inflammation may be acute, which is part of the defensive response; or chronic, which may lead to the development of various diseases including cancer. Several pro-inflammatory genes play important role in the various cellular processes like cell proliferation, angiogenesis, metastasis, and suppression of apoptosis. These pro-inflammatory genes include TNF-α, interleukins, chemokines, MMPs, cyclooxygenase, lipoxygenase, iNOS, Jak/STAT pathway, etc. All these genes are mainly regulated by the transcription factor NF-κB, which is found active in many types of neoplastic cells. Therefore, developing molecules that target pro-inflammatory genes or transcription factor is believed to be one of the good strategies for development of anti-cancer agents. Literature data suggest that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, corticosteroids, statins, metformin, embelin, and some natural products, can interfere with the tumor microenvironment by inhibiting pro-inflammatory genes or transcription factors and increasing cell apoptosis. This review describes the link between inflammation and cancer, the role of pro-inflammatory genes and transcription factors in the development of tumor cells, and the use of anti-inflammatory agents in cancer.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e58086

Authors: Mitayani Purwoko, Harijono Kario Sentono, Bambang Purwanto, Dono Indarto

Abstract: Introduction: Plumbago zeylanica grows widely in many tropical countries. In Indonesia, this plant, known as Daun Encok, has some beneficial effects on human health. Aim: This exploration study aimed to identify the plumbagin compound in P. zeylanica roots from Indonesia. Materials and methods: Dried roots of P. zeylanica were manually ground and then the powder was macerated using ethanol and chloroform for 24 hours at room temperature. All extracts of P. zeylanica were then analyzed using gas chromatography-mass spectrometry (GC-MS). Plumbagin concentration was measured by comparing the extract with pure plumbagin. Results: GC-MS analysis of ethanol extract and chloroform extract of P. zeylanica roots showed the presence of plumbagin as the highest peak. Plumbagin concentration in ethanol extract was 13%, while in chloroform extract it was 81%. Conclusions: The chloroform extract of P. zeylanica root from Indonesia demonstrates a higher concentration of plumbagin compared to ethanol extract.

HTML

XML

PDF

DOI: 10.3897/folmed.64.e59492

Authors: Sachin Parmar, Rakesh Prajapati, Manisha Kalarias

Abstract: Introduction: Lagenaria siceraria (Molina) Standley (Cucurbitaceae) is a traditional vegetable plant, popularly known as bottle gourd (English) and lauki (Hindi). It is a climbing herb characterized with a number of therapeutic properties. Traditionally Lagenaria siceraria (LS) fruits were used for their cardioprotective, hepatoprotective, diuretic, and purgative effects, but there is very little scientific data available on its neuroprotective potential. Aims: The present study aimed to assess the neuropharmacological profile of the sterol-enriched chloroform fraction of methanolic extract of Lagenaria siceraria fruits in animal experimental models. Materials and methods: Neuropharmacological screening was conducted in specific reported animal models. Adult Wistar albino rats were subjected to behaviour despair test and elevated plus maze test. Thiopental-induced sedation, locomotor activity, and rota rod test were conducted on Swiss albino mice. Similarly, pentylenetetrazole-induced convulsions and maximal electroshock-induced seizures in Swiss albino mice were performed to evaluate the anti-epileptic potential. Results: The results of the study demonstrated that the anxiolytic activity of phytocompound-enriched chloroform fraction of methanolic extract of Lagenaria siceraria fruits (100, 200, and 400 mg/kg per os) was characterized by increased time spent in and increased number of entries into the open arms of the elevated plus maze prototype as compared to the control group (p<0.001). Chloroform fraction (100-400 mg/kg, p.o.) showed the dose-dependent significant reduction in duration of immobility (p<0.001) in the behaviour despair test. Similarly, the chloroform fraction was found to exert a significant reduction in motor co-ordination (p<0.001) and prolongation of thiopental-induced sleeping time (p<0.001) during the animal studies. Moreover, the test fraction significantly increased (p<0.001) the onset of myoclonic seizures in pentylenetetrazole-induced convulsions model as well as in the maximal electroshock-induced seizures model at all three dose levels selected. Interestingly, the chloroform fraction neither produced any overt motor dysfunction nor any kind of extra pyramidal symptoms in any of the animal models during pharmacological screening. Preliminary phytochemical screening of the fraction showed presence of saponins, phytosterols, terpenoids, fats, and trace amount of polyphenolic compounds. HPTLC fingerprinting analysis was also carried out. Conclusions: This is the first study exploring the neuroprotective potential of Lagenaria siceraria fruits by showing the anxiolytic, anti-depressant, sedative, and anti-epileptic-like activities, confirming the traditional claims. Future prospectus and investigations will give emphasis on isolation of the bioactive phytocompounds and their precise mechanisms involved in the neuroprotective activities.

HTML

XML

PDF

DOI: 10.3897/folmed.63.e59216

Authors: Gabriela Kehayova, Snezha Zlateva, Petko Marinov

Abstract: Introduction: Lipid emulsions are increasingly used as an antidote to lipophilic drug intoxications. The dose recommended by the American Society of Regional Anesthesia is used primarily for the treatment of local anesthetic systemic toxicity. There is insufficient information about what the dose of lipid emulsions (LE) should be in other intoxications depending on their severity.Aim: To determine the LE dose in a shock or haemodynamic instability in patients with acute exogenous intoxications treated with LE.Materials and methods: Forty-nine patients with acute lipophilic drug intoxications were treated with LE in the Clinic of Toxicology at the Naval Hospital in Varna.Statistical analysis was performed using the statistical functions of Excel 2016 and the Statistica 7.0 software package.Results: The percentage of patients receiving a low dose of LE of 0.3 ml/kg (93.87%) was significantly higher than the percentage of patients treated with a medium (2.04%) and a high dose (4.08%) of LF. The high dose of LE of 1.5 ml/kg recommended by the American Society of Regional Anesthesia was administered to two patients (4.08%). In severe intoxications with exotoxic shock, the rate of LE administration varies from 20 ml/h to 40 ml/h.Conclusions: In severe intoxications with cardiotoxic syndrome and haemodynamic instability, LE should be used in the dose as suggested by the American Society of Regional Anesthesia. It is possible to use lower doses of LE in the range of 0.3–0.6 ml/kg in all moderate poisonings administered by continuous intravenous infusion for 12-24-48 hours. No side effects were observed at these doses.

HTML

PDF

DOI: 10.3897/folmed.63.e57713

Authors: Devaraja Sannaningaiah, Ashwini Shivaiah, Jayanna Kengaiah, Chandramma Srinivasa, Sharath Kumar M. Nandish, Chethana Ramachandraiah, Sujatha Hanumegowda, Bhagyalakshmi Manjappa, Sebastin Santosh Martin, Ramesh Komalapura Laxmaiah, Manohar Shinde

Abstract: Introduction: Oxidative stress plays a critical role in the progression of diabetes, arthritis, cancer, eryptosis, cardiovascular disease, and thrombosis. Currently, antioxidants from natural sources are in high demand due to their beneficial role in the management of said diseases.Aim: The purpose of the study was to evaluate the protective effect of sorghum protein buffer extract (SBE) on sodium nitrite-induced oxidative stress and thrombosis.Materials and methods: Protein characterization of SBE was done using SDS-PAGE. Oxidative stress in RBC was induced using sodium nitrite (NaNO2) and the key stress markers such as lipid peroxidation (LPO), protein carbonyl content (PCC), and the level of antioxidant enzymes (SOD and CAT) were measured. The anticoagulant effect of SBE was identified by employing in-vitro plasma recalcification time, activated partial thromboplastin time (APTT), prothrombin time (PT), and in-vivo mouse tail bleeding time. SBE antiplatelet activity was examined using agonist adenosine diphosphate (ADP) and epinephrine-induced platelet aggregation. Non-toxic property of SBE was identified using in-vitro direct haemolytic, haemorrhagic, and edema forming activities using experimental mice.Results: SBE revealed similar protein banding pattern under both reduced and non-reduced conditions on SDS-PAGE. Interestingly, SBE normalized the level of LPO, PCC, SOD, and CAT in stress-induced RBCs. Furthermore, SBE showed anticoagulant effect in platelet rich plasma by enhancing the clotting time from the control 250 s to 610 s and bleeding time from the control 200 s to more than 500 s (p<0.01) in a dose dependent manner. In addition, SBE prolonged the clot formation process of only APTT but not PT. SBE inhibited the agonists ADP and epinephrine induced platelet aggregation. SBE did not hydrolyze RBC cells, devoid of edema and haemorrhage properties.Conclusions: This study demonstrates for the first time the anticoagulant, antiplatelet, and antioxidant properties of SBE. Thus, the observed results validate consumption of sorghum as good for health and well-being.

HTML

PDF

DOI: 10.3897/folmed.63.e57265

Authors: Mikaela Kolaci, Leonard Deda, Alma Idrizi, Myftar Barbullushi, Dariel Thereska

Abstract: Introduction: Mycophenolate mofetil and its active metabolite mycophenolic acid are routinely used as immunosuppressant drugs in solid organ transplantation in a fixed daily dose regimen in association with cyclosporine, tacrolimus and steroids. Therapeutic drug monitoring for mycophenolic acid concentration has been suggested to optimize outcomes by reducing rejection and drug related toxicities in clinical renal transplantation.Aim: To determine the predose concentration of mycophenolic acid in renal transplanted patients by a validated proposed high-performance liquid chromatography (HPLC) method and to estimate the interindividual variability based on the therapeutic target.Materials and methods: An HPLC method combined with protein precipitation has been validated for mycophenolic acid determination in the human plasma obtained from 21 renal transplant recipients. HPLC analysis was carried out using the chromatographic system Agilent Technologies 1200 DAD. Samples were injected manually, and the compounds were separated on a LiChrosphere® select B C18 analytical column. The mobile phase was 45:55 (v/v) acetonitrile-buffer phosphate, pH 2.5, flow rate of 1.0 mL/min and column temperature of 30°C. Detection was performed at 215 nm. Whole blood samples were collected into vacutainers containing EDTA and separated at 6000 g for 10 minutes. A 200-μL aliquot of patient plasma was transferred to a tube, followed by addition of 10 μL of naproxen as internal standard and 400 μL of acetonitrile (v/v) as a protein precipitating agent. Each tube was vortex-mixed for 30 sec and then centrifuged for 10 min at 10000 rpm. 20 μL of the supernatant was injected into the HPLC system for analysis.Results: The method showed appropriate linearity for MPA with correlation coefficient greater than 0.999. High inter-patient variability is observed with 18% of patients within the target trough concentration range, 27% of patients below the target trough concentration range and 54% over the range with risk of toxicity.Conclusions: Therapeutic monitoring of MPA might contribute to a better management of renal transplant recipient with the goal of optimizing therapeutic regimens in order to reduce the risk of rejection and MPA‐related toxicity.

HTML

PDF

DOI: 10.3897/folmed.63.e56786

Authors: Chaitali Lad, Ishan Panchal, Ashish Patel, Afzal Nagani, Vruti Parikh, Harnisha Patel, Bhargav Bhimani

Abstract: Introduction: Malaria is one of the varieties of fatal diseases caused by a protozoan parasite that is now considered to be the greatest global health challenge. A parasite of Plasmodium species triggers it transmitting the disease to humans by the bites of female Anopheles mosquitoes.Aim: To screen out designed molecules by molecular docking analysis and assess their pharmacokinetic properties using SwissADME. To synthesize the designed compounds. To characterize the synthesized compounds by TLC, melting point, IR spectroscopy, mass spectrometry, 1H NMR, and 13C NMR. To evaluate the synthesized compounds for antimalarial activity.Materials and methods: In silico analysis was performed with SWISSADME, and molecular docking was performed by AutoDock Vina version 4.2. In vitro antimalarial activity study was performed.Results: In-vitro studies of synthesized molecules showed that compounds C2 (IC50 1.23), C6 (IC50 0.48), C10 (IC50 0.79), and C14 (IC50 0.19) possess good antimalarial activity.Conclusions: 7-chloroquinoline-piperazine derivatives exhibited potential antimalarial compounds for pf-DHFR inhibitors.

HTML

PDF

DOI: 10.3897/folmed.63.e58995

Authors: Sandip N. Badeliya, Pankaj P. Kapupara, Navneet F. Chauhan, Ishan I. Panchal

Abstract: Malaria, a life-threatening disease, is caused by parasitic single-celled microorganisms. It is specifically transmitted by the anopheles female mosquito of the Plasmodium family. There are a lot of drugs available in the market to treat this life-challenging disease. Chloroquine, a cheaper molecule that is available worldwide, is one of them. Drug resistance has been observed with chloroquine as well as with some other quinine derivatives and with artemisinin derivatives in the southeast region of Asia in countries like Cambodia, Thailand, Myanmar, and Vietnam country since 1957. After 1970, the drug resistance has been further increased and it has been expanded in several localities of India. Also, antimalarial agents, particularly chloroquine, have so many side effects such as nausea, vomiting, blurred vision, abdominal cramps, diarrhea, headache, appetite loss, deprivation of hearing, skin color change, baldness, reduced body weight, and seizures. Furthermore, this drug cannot be given to pregnant women. Hence, it is the right time to design and develop newer antimalarial agents so that this kind of drug resistance, as well as side effects of the drugs, can be overcome.

HTML

PDF

DOI: 10.3897/folmed.63.e55938

Authors: Margarita Y. Zhelyazkova, Nadya G. Hristova-Avakumova, Georgi Tsv. Momekov

Abstract: Aim: We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to influence iron-induced oxidative damage of biologically relevant molecules.Materials and methods: MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose.Results: Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation.Conclusions: This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors.

HTML

PDF

DOI: 10.3897/folmed.63.e55267

Authors: Antoaneta Georgieva, Miroslav Eftimov, Milena Todorova, Vasilena Kuzmanova, Atanas Kuzmanov, Krasimir Kuzmanov, Mila Vlaskovska, Stefka Valcheva-Kuzmanova

Abstract: Aim: The objective of the present study was to make a complex evaluation of behaviour, lipid metabolism, inflammation, and bone turnover in an ovariectomized rat model used to simulate postmenopausal clinical findings.Materials and methods: Female Wistar rats were divided into 2 groups of 16 animals each: sham operated (SO) animals and ovariectomized (OVX) animals. Three months after the operation, a battery of behavioural tests was performed including an open field test (OFT), elevated pus-maze test (EPM), the social interaction test (SIT), the forced swim test (FST), and a hot plate test (HPT). At termination of experiment, weight gain and fat deposits (total and retroperitoneal) were measured. Serum concentrations of blood lipids were determined. Tumor necrosis factor alpha (TNF-alpha) and alkaline phosphatase (ALP) serum concentrations were used for evaluation of the inflammation and bone turnover, respectively. Femur bone mineral density (BMD) was evaluated using dual energy X-ray absorptiometry.Results: OVX rats did not demonstrate any significant behavioural changes in OFT and EPM tests but showed a decreased interaction time in SIT and an increased immobility time in FST test which indicated anxiety and depression. The OVX rats had a significantly lower pain sensitivity threshold. They had greater weight gain, increased total and retroperitoneal fat deposits, as well as elevated total fat/body weight and retroperitoneal fat/body weight ratios. Blood cholesterol, ALP and TNF-alpha of the OVX group were also significantly higher. Femur BMD of OVX rats was slightly but not significantly reduced.Conclusions: Estrogen deficiency in OVX rats caused depression, anxiety, hyperalgesia, obesity, dyslipidemia, and inflammation before the reduction in bone mineral density was prominent.

HTML

PDF

DOI: 10.3897/folmed.63.e55136

Authors: Anita Mihaylova, Ilia Kostadinov, Nina Doncheva, Delian Delev, Hristina Zlatanova

Abstract: Introduction: Parkinson’s disease (PD) is а neurodegenerative disorder characterized mainly by its motor symptoms. The non-motor symptoms including pain are increasingly recognized in the last few decades. Existing evidence suggests that the dopaminergic neurotransmission has an essential role in pain control.Aim: The aim of the present study was to investigate the antinociceptive effect of dopaminergic drugs pramipexole and tolcapone against chemical and thermal stimuli in naive rats.Materials and methods: Male Wistar rats divided into 8 groups (n=8): saline; diclofenac 25 mg/kg body weight (bw) (positive control); pramipexole 0.5; 1 and 3 mg/kg bw; tolacapone 5; 15 and 30 mg/kg bw. Paw pressure and plantar tests were performed. Paw withdrawal pressure and latent time were measured. Statistical analysis was done by SPSS 19.Results: In the paw pressure test, pramipexole, in a dose of 1 and 3 mg/kg bw and tolcapone in a dose of 30 mg/kg bw, increased significantly the latency at 1, 2, and 3 hours compared to saline (p<0.05). In the plantar test, only the highest dose of pramipexole reached significance at 3 hours compared to the control rats (p<0.05). In contrast to pramipexole the three experimental groups with tolcapone markedly increased the latent time at 1 and 3 hours compared to saline (p<0.05).Conclusions: Pramipexole and tolcapone reduce mechanical and thermal nociception in naïve rats by enhancing dopaminergic neurotransmission at both spinal and supraspinal levels. In addition, tolcapone stimulates noradrenergic mediation which may contribute to its antinociceptive effect.

HTML

PDF

DOI: 10.3897/folmed.63.e61484

Authors: Hristo Y. Ivanov, Branimir Velinov, Gergana Kyosovksa, Denitsa Grigorova, Peter Shopov

Abstract: Introduction: Pharmacogenetics in psychiatry is currently gaining momentum. The efficiency of antipsychotic therapy is often limited by the lack of response and the presence of side effects. Pharmacogenetic variation is probably one of the causative factors for the observed interindividual differences in the response to and the side effects of antipsychotics, which could be addressed and whose negative effects could be avoided or mitigated.Aim: The present study aimed to conduct a comprehensive analysis of the frequency of DRD2 rs1799732, COMT rs4680, MC4R rs489693, and HTR2C rs3813929 in Bulgarian psychiatric patients.Materials and methods: The frequency of genotypes and the alleles of variants DRD2 rs1799732, COMT rs4680, MC4R rs489693, and HTR2C rs3813929 were studied in a cohort of 515 Bulgarian psychiatric patients using the polymerase chain reaction (PCR) method.Results: We found no significant difference between our cohort and the dataset of the 1000 Genomes Project. Moreover, we found that 433 out of 515 patients carried at least one, and 191 out of 515 carried at least two variants which, based on multiple scientific sources with consistent findings, could potentially alter the expected response rate, time to respond and/or risk of side effects to antipsychotic medications.Conclusions: Considering the consistent data about the frequency of these pharmacogenetic variants, testing these genetic variants may prove useful in clinical practice. Further studies regarding the clinical interpretation and frequency distribution in larger cohorts and different populations are warranted.

HTML

PDF

DOI: 10.3897/folmed.63.e53060

Authors: Teodora Tomova, Nina Doncheva, Anita Mihaylova, Ilia Kostadinov, Lyudmil Peychev, Mariana Argirova

Abstract: Introduction: The Ginkgo biloba L. tree is considered as one of the oldest species on Earth. It is known as a “living fossil” dating back approximately 200 million years. Both the leaves and seeds of this tree have been used for millennia in traditional Chinese medicine.Aim: To study the phytochemical profile of Gingko biloba seed extract (GBSE) and its memory enhancing effects.Materials and methods: Liquid chromatography with mass detection (LC-MS) was performed for phytochemical analyses of the extracts. For the in vivo experiments, male Wistar rats were divided randomly into 5 groups (n=8): saline; piracetam; GBSE 50; 100, and 200 mg/kg b.w. Y-maze, T-maze, step-down passive avoidance and novel object recognition test (NORT) were performed. The observed parameters were: percentage of spontaneous alternations (% SA), working memory index, latency of reaction and recognition index, respectively. Statistical analysis was done using SPSS 19.Results: LC-MS analysis showed the presence of the flavonoids quercetin, kaempferol and isorhamnetin (as aglycones), the ginkgolides A, B, C, J, and bilobalide. In Y-maze task, the groups treated with 50 and 100 mg/kg of GBSE significantly increased the % SA during the memory test compared to saline (p<0.05). In T-maze test, the three experimental groups with GBSE significantly increased the working memory index in comparison with that of the control group (p<0.05). In step-down test, the animals receiving 100 mg/kg b.w. GBSE, notably increased the latency during both retention tests (p<0.05 and p<0.01, respectively). In NORT, only the animals with the middle dose of GBSE ameliorated the recognition index when compared to saline (p<0.05).Conclusions: GBSE enhances spatial working memory, recognition memory, and short- and long-term recall in naïve rats due to the synergic effects of detected flavonoids and terpene lactones on brain functions. The brain structures involved are probably the hippocampus and prefrontal cortex.

HTML

PDF

DOI: 10.3897/folmed.63.e53479

Authors: Roohollah Fateh, Ali Javadi, Jalil Kardan-Yamch, Hossein Ali Rahdar, Masumeh Amini, Fatemeh Ghasemi, Akram Azimi, Masoumeh Davarpanah, Razieh Mohammadzadeh

Abstract: Introduction: Helicobacter pylori is considered a major agent causing gastritis and peptic ulcer disease. Unfortunately, the occurrence of increasing drug resistance to this bacterium would result in some difficulties in its treatment. Therefore, the application of nanotechnology has been suggested to resolve such problems. Nanoparticles usage in medical research has been expanded in recent years. Among nanometals, gold nanoparticles have exclusive features that can be used in such applications. Using nanotechnology in medical science could help mankind to solve this problem in the future.Aim: Our aim in this research was to investigate the antimicrobial effect of gold nanoparticles on H. pylori strains.Materials and methods: Gold nanoparticles were synthesized by the Turkevich method. Then, their size and dispersion were investigated using spectrophotometry, DLS, and TEM microscopy. Subsequently, the combination of metronidazole and gold nanoparticles was obtained by mixing method, and then the anti-helicobacter effects of the two were evaluated according to CLSI.Results: The highest size of gold nanoparticles was between 12 and 9 nm, and the maximum absorbance was 522 nm; however, in conjugated state, the maximum absorbance was 540 nm, which indicated the accumulation of drug-conjugated nanoparticles in the conjugate state. Some changes indicated the binding of metronidazole to gold nanoparticles. Antimicrobial testing of gold nanoparticles and metronidazole did not affect the Helicobacter pylori. Therefore, the combination of gold nanoparticles and metronidazole had a 17-mm growth inhibition zone.Conclusions: The anti-helicobacter effects of metronidazole significantly increased in conjugation with gold nanoparticles.

HTML

PDF

DOI: 10.3897/folmed.63.e53912

Authors: Hristina Angelova, Ekaterina Krumova, Elena Dzhambazova, Daniela Pechlivanova

Abstract: Introduction: The endogenous dipeptide L-tyrosine-L-arginine (kyotorphin, KTP) is found in brain structures related to the processing of information for nociception, the control of emotions, and memory formation. Besides the antinociceptive effect of KTP, it has a mild protective activity against the deleterious influence of the brain hypoperfusion and streptozotocin on the behavior and memory. Aim: We aimed to study the effects of the intracerebroventricular injection of effective antinociceptive doses of KTP on the motivational behavior, memory, and blood and hippocampal levels of the carbonylated proteins in healthy male adult Wistar rats.Materials and methods: We used a paw-pressure test for assessment of acute nociception, an open field test for assessment of exploration and habituation to a new environment, elevated plus maze test for the evaluation of anxiety-like behavior, and novel object recognition test for working memory. Carbonylated protein assay was used for the assessment of the oxidative impairment of the proteins. The results were analyzed by ANOVA.Results: The present data showed that all single doses of KTP exerted an antinociceptive effect, but this effect was not observed after chronic administration. Only the highest dose of 100 µg was able to induce anxiolytic and motor inhibiting effects. None of the doses used showed effects on the recognition memory or the level of the carbonylated protein. Conclusion: Our results showed that KTP exerted its antinociceptive effect without affecting negatively the blood and brain carbonylated protein or basic behavioral parameters related to the exploration, motivation, and memory formation in healthy rats.

HTML

PDF

DOI: 10.3897/folmed.63.e49167

Authors: Girish Sailor, Komal Hirani, Ghanshyam Parmar, Rajesh Maheshwari, Rupa Singh, Avinash Kumar Seth

Abstract: Introduction: Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes, also known as platelets, in the blood. Several medicinal plants possess curative and protective effect against thrombocytopenia associated with diseases or drugs.Aim: In the present study, we have investigated the platelet augmentation activity of polyherbal formulation (VITA PLAT Capsule) in cyclophosphamide-induced thrombocytopenic rat model. Materials and methods: Twenty-four albino Wistar rats were divided into four groups. Thrombocytopenia was induced in the rats by administering cyclophosphamide (25 mg/kg, i.p.) for three days to all the groups except normal controls. The test groups were given orally a polyherbal formulation suspended in normal saline for 14 days. Blood was withdrawn from the retro-orbital plexus of the rats on days 1, 7, and 14 of study to determine platelet counts in all groups. Clotting time and bleeding time were determined on the last day of study. Data were collected and analyzed using GraphPad Prism 8. Results: The results showed that the polyherbal formulation treatment could significantly ameliorate platelet count in thrombocyto-penic rats in the initial as well as in the later phase. The total WBC count was also improved during later phase in test groups. However, there is no significant difference between clotting time and bleeding time in all groups. Conclusions: Our study suggests a potential role of this formulation in the augmentation of platelet counts in various thrombocyto-penic disorders including a role in ameliorating the haemorrhagic complications of dengue fever.

HTML

PDF

DOI: 10.3897/folmed.63.e51944

Authors: Nurina Tyagita, Endang Mahati, Azizah Hikma Safitri

Abstract: Introduction: Antidiabetic medicinal plants are increasingly used in the treatment of diabetes as they are generally assumed to pro-duce minimal side effects. Okra is a quercetin-containing plant which can induce pancreas regeneration and has antidiabetic effect. There has been a lot of research that demonstrate that purple okra contains more quercetin than green okra.Aim: To demonstrate the advantages of purple okra over green okra on the diabetic markers improvement in diabetic rats.Materials and methods: Fifteen male 2-month-old Wistar rats were injected intraperitoneally with 65 mg streptozotocin and 110 mg niacinamide. Their blood glucose levels were measured three days after the injection. The induction of diabetes was deemed successful if the glucose level of the rats got higher than 250 mg/dL, and then such rats were considered diabetic. The diabetic rats were divided into three groups: an acarbose group, a purple okra powder group, and a green okra powder group. The latter two were given, respectively, purple and green okra powder for 28 days. Blood serum was taken to examine the fasting blood glucose, insulin, HOMA-B and GLUT-4 levels. Pancreas was examined histologically for damage using hematoxylin eosin staining. Results: Fasting blood glucose, insulin, HOMA-B, and GLUT-4 levels of diabetic rats that received purple okra powder (p<0.05) were better than those of the rats that received green okra powder. The least damage (p<0.05) to pancreatic beta cells was found in the purple okra powder group.Conclusions: Purple okra is superior to green okra in terms of improving the diabetic markers of rats.

HTML

PDF

DOI: 10.3897/folmed.63.e52791

Authors: Ishan Panchal, Archana Navale, Ashish Shah, Sandip Badeliya, Rati Tripathi

Abstract: Cancer refers to the group of diseases characterized by uncontrolled growth of abnormal cells. It spreads throughout the body which makes this disease one of the huge global threats to mankind. Intensive research over the years has established deregulation of mam-malian target of rapamycin pathway in cancer. This has led to the development of mammalian target of rapamycin inhibitors. Several inhibitors of the mammalian target of rapamycin are under preclinical and early clinical trials. Researchers have investigated a series of furoquinoline, phenyl sulphonylureas, 4-acrylamido-quinoline, pyrazolochalcones, imidazole [4,5-b] pyridine, thienopyrimidine, aminopyrimidin scaffolds in the last three years. This review provides comprehensive information and critical discussions on designing of novel selective inhibitors of mammalian target of rapamycin with superior activity in the treatment of cancer.

HTML

PDF

DOI: 10.3897/folmed.62.e51473

Authors: Michaela Shishmanova-Doseva, Jana Tchekalarova, Zlatina Nenchovska, Natasha Ivanova, Katerina Georgieva, Lyudmil Peychev

Abstract: Introduction: Epilepsy and antiepileptic drugs can affect negatively the cognitive abilities of patients.Aim: The present study aimed to evaluate the effect of topiramate (TPM) and lacosamide (LCM) on the emotional and cognitive re-sponses in naive animals and in animals with pilocarpine-induced status epilepticus. Materials and methods: Male Wistar rats were randomly divided into 6 groups and status epilepticus was evoked in half of them by a single i.p. administration of pilocarpine (Pilo) (320 mg/kg): Pilo-veh, Pilo-TPM (80 mg/kg) and Pilo-LCM (30 mg/kg). Matched naive rats were treated with the same doses as follows: C-veh, C-TPM, and C-LCM. In a step-down passive avoidance test, the learning session was held for one day, the early retention test was conducted on day 2, and the long-term memory test - on day 7. Motor activity and anxiety were evaluated in an open field test. Results: The Pilo-TPM and Pilo-LCM groups increased the time spent on the platform compared to Pilo-veh animals while the C-LCM animals decreased the time compared to C-veh animals during short- and long-term memory retention tests. TPM and LCM exerted an anxiolytic effect in naive rats. The two antiepileptic drugs were unable to alleviate the hyperactivity, but they alleviated the impulsivity associated with decreased anxiety level in epileptic rats.Conclusions: Our findings suggest that LCM and TPM have a beneficial effect on cognition both in naive and epileptic rats. While the two antiepileptic drugs can produce an anxiolytic effect in naive rats, they alleviate the impulsivity after pilocarpine treatment.

HTML

PDF

DOI: 10.3897/folmed.62.e53742

Authors: Nigyar Dzhafer, Jannis V. Papathanasiou

Abstract: Introduction: Despite clinical trials, there are still no approved specific therapies or any vaccine against COVID-19. The only option available is using investigational drugs for compassionate use. The update of the existing regulation regarding compassionate use is to ensure the effective and sustainable development of health policies and technologies over the COVID-19 pandemic and beyond.Aim: The present short communication aimed to highlight the need for early and expanded access to investigational drugs for compassionate use as well as a call for an update of the existing regulation in Bulgaria concerning compassionate use in the era of COVID-19.Materials and Methods: In EU and Bulgaria as well, the legal framework for compassionate use was introduced by Article 83 (1) of Regulation (EC) No 726/2004 of the European Parliament and of the Council; in principle, Regulations of the European Parliament and of the Council are mandatory for all Member States. Remdesivir appears to have a favorable clinical and safety profile, as reported in a case involving patients with severe COVID-19 through a compassionate use programme.Results: The overall probability of clinical improvement observed in 36 of 53 COVID-19 patients received intravenous remdesivir as part of a compassionate use programme was 68% (95% CI 40% to 80%). Thirty two patients (60%) demonstrated at least one adverse event, twelve 12 patients (23%) experienced serious adverse events and seven patients (13%) died.Conclusion: The global pandemic mandates Bulgarian Drug Agency for a reasonable update of the existing national regulation concerning compassionate use and off-label therapies. In the era of COVID-19, it is important for Bulgarian patients to have early and expanded access to investigational drugs for compassionate use.

HTML

PDF

DOI: 10.3897/folmed.62.e47844

Authors: Vera N. Gledacheva, Iliyana D. Stefanova, Valeri I. Slavchev, Rayna G. Ardasheva, Atanas D. Kristev, Stoyanka A. Nikolova, Kremena E. Saracheva, Darinka S. Dimitrova

Abstract: Introduction: Examination of the potential possibilities of 2-chloro-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylacetamide (IQP) to affect bioelectrogenesis and the contractile activity of isolated smooth muscles (SM) from stomach.Aim: Having in mind the structural similarities between the molecules of papaverine and IQP, the aim of the present study was to examine such features of the newly synthesized molecule that may potentially affect the muscle tonus, spontaneous bioelectrical and contractile activities of smooth muscles isolated from the stomach, basing on specific mechanisms of papaverine.Materials and methods: The synthesis of IQP is based on the initially formed aziridine ring by principles of Gilbert’s reaction. Impact of IQP on the bioelectrogenesis and the contractile activity of isolated smooth muscles from male Wistar rats was measured by the single sucrose-gap method and isometrically recorded.Results: IQP (1×10-5 – 2.5×10-4 mol/l) causes muscle relaxation, producing changes in two processes that have influence on the mechanical activity of smooth muscles:1. Blocked Ca2+ influx through the potential-dependent membrane Ca2+ channels, followed in turn by lowering the Ca2+ intracellular levels. This effect is proved by the changes in the frequency and amplitude of spike-potentials in sucrose-bridge experiments when IQP is applied.2. Activation of a cAMP-dependent signal cascade. The relaxing effect of IQP was significantly reduced in the presence of KT5720(5×10-6 mol/l), an inhibitor of protein kinase A.Conclusion: We assume that there might be interconnections between these two IQP-dependent processes, because PKA-dependent phosphorylation of the L-type Ca2+ channels in smooth muscles provokes a reaction of inactivation.

HTML

PDF

DOI: 10.3897/folmed.62.e48742

Authors: Dionysia D. Fermeli, Theodoros D. Marantos, Alexandros-Leonidas D. Liarakos, George D. Panayiotakopoulos, Vasileios K. Dedes, Georgios I. Panoutsopoulos

Abstract: Tuberculosis is a severe, infectious disease caused by Mycobacterium tuberculosis. The aim of this review was to present the efficacy of linezolid as an agent against multidrug and extensively drug-resistant tuberculosis as gathered from many recent research studies. Linezolid seems to have strongly the potential of being used as an anti-tuberculosis agent because it blocks bacterial ribosomal protein synthesis. Nevertheless caution is required because of the adverse effects it causes, especially when the linezolid daily dosage exceeds 600 mg. The most severe adverse effects include anemia, peripheral neuropathy, optic neuropathy and thrombocytopenia. Still, more trials and research need to be done in order to gather more information and value the cost-benefit dosage of the treatment.

HTML

PDF

DOI: 10.3897/folmed.62.e47510

Authors: Silvia Gancheva, Martina Kitanova, Peter Ghenev, Maria Zhelyazkova-Savova

Abstract: Introduction: Vitamin K (VK) is a co-factor in the post-translational gamma glutamic carboxylation of Gla-proteins. VK-dependent coagulation factors are carboxylated in the liver by VK1. Osteocalcin and Matrix-Gla protein (MGP) are carboxylated in extrahepatic tissues by VK2. A model of VK deficiency would be suitable for studying extrahepatic Gla-proteins provided that severe bleeding is prevented.Aim: The aim of this work was to adapt an established protocol of vascular calcification by warfarin-induced inactivation of MGP as a calcification inhibitor, in an attempt to create a broader state of subclinical VK deficiency and to verify its safety.Materials and methods: Two consecutive experiments, each lasting 4 weeks, were required to modify the dosing schedule of warfa­rin and VK1 and to adapt it to the Wistar rats used. The original high doses of warfarin used initially had to be halved and the protective dose of VK1 to be doubled, in order to avoid treatment-induced hemorrhagic deaths. The second experiment aimed to confirm the efficacy and safety of the modified doses.To verify the VK deficiency, blood vessels were examined histologically for calcium deposits and serum osteocalcin levels were mea­sured.Results: The original dosing schedule induced VK deficiency, manifested by arterial calcifications and dramatic changes in carboxyl­ated and uncarboxylated osteocalcin. The modified dosing regimen caused similar vascular calcification and no bleeding.Conclusion: The modified protocol of carefully balanced warfarin and VK1 doses is an effective and safe way to induce subclinical VK deficiency that can be implemented to investigate VK-dependent proteins like osteocalcin.

HTML

PDF

DOI: 10.3897/folmed.62.e46759

Authors: Mahsa Kamali, Habibolah Johari, Javad Hami

Abstract: The objective of this study was to assess the effects of the hydroalcoholic extract of flax seed on the teratogenic activity of lamotrigine in the brain of fetuses of rats who had received the drug. In this experimental study, 40 female rats were assigned randomly into four groups and after mating and confirming the vaginal plug, the control animals (group 1) were kept with no intervention, and the other three experimental groups were intraperitoneally injected with respective lamotrigine (75 mg/kg), and 100 and 200 mg/kg of flax seed hydroalcoholic extract. The drug was administered during the organogenesis period. Rats were sacrificed at the 20th day of gestation (one day before term) and fetuses were macroscopically examined, weighed and crown-rump length measured. Fetal brain specimens were processed for H&E and for histological study, using the ImageJ software. Results showed that fetuses of the experimental groups that received lamotrigine had reduced body weight, prefrontal cortical and hippocampal thickness, and pyramidal neurons in the hip­pocampus; Nevertheless, these factors were improved by high-dose administration of flax seed in the experimental group 3 and 4. Our research concludes that lamotrigine negatively influences the development of brain in rats and flax seed has a protective impact on these complications.

HTML

PDF

DOI: 10.3897/folmed.62.e47647

Authors: Jayesh Dhalani, Gaurang Dubal, Chirag Rathod, Pankaj Nariya

Abstract: Background: Plumbago zeylanica plant belongs to Plumbaginaceae. The plant is reported for many pharmacological activities.Aim: The objective of the study was to identify fatty acids and non-polar chemical compounds in Plumbago zeylanica leaves. Materials and methods: Petroleum ether extract was prepared using soxhlet apparatus. Saponifiable and unsaponifiable matter was separated with saponification process. To identify fatty acids in saponifiable matter further esterification was performed. Gas chromatography and mass spectrometry analysis was performed of both saponifiable and unsaponifiable fractions. All the fatty acid methyl esters and non-polar chemical compounds were identified using NIST library data.Results: A total of 14 compounds were identified with comparison of NIST data. From that, 8 fatty acid methyl esters and 6 non-polar chemical compounds were identified. Here we have analyzed fatty acids and non-polar chemical compounds by the same GC-MS method.Conclusions: The present analysis showed that Plumbago Zeylanica leaves contain 8 fatty acids and 6 non-polar chemical compounds. Principal determination of the research was development of efficient method to identify non-polar compound from plant by single injection using chromatographic technique.

HTML

PDF

DOI: 10.3897/folmed.62.e47735

Authors: Velid Unsal, Ergül Belge Kurutaş

Abstract: Introduction: 2-AAF and DEN are well-known liver toxicants commonly used to stimulate tumors in laboratory animals. Aim: The aim of this study was to investigate the effect of octreotide on DEN-induced and 2-AAF-supplemented hepatocarcinogenesis in Wistar albino rats. Materials and methods: In this study, 64 Wistar albino rats were divided into 8 groups. DEN (175 mg/kg) initiated and 2-AAF (20 mg/kg) promoted liver carcinogenesis in rats. The tumor growth inhibitor octreotide (300 μg/kg) was used. Rats were sacrificed at the end of experiment and their liver tissues were taken for the study. SOD, GSH-Px, CAT activities, NO and MDA levels were measured spectrophotometrically. Also, Hsp70 and 8-OHdG was measured by the ELISA method. Results: In group 7, MDA, 8-OHdG, and Hsp70 levels were significantly increased. In addition, SOD, GSH-Px activity was significantly reduced in this group. MDA, 8-OHdG and Hsp70 levels were significantly reduced in Group 8, which received octreotide for treatment. Conclusion: DEN and 2-AAF cause very serious liver damage. Octreotide protects the liver from carcinogenesis, increases the activity of cellular antioxidant enzymes and helps reduce DNA damage. Therefore, octreotide may be an inhibitor in tumor cells and may reduce oxidative stress.

HTML

PDF

DOI: 10.3897/folmed.62.e47737

Authors: Laura Andrini, Gustavo H. Marin, Ana Maria Inda, Heriberto Bruzzoni-Giovanelli, Marcela Garcia, Jorge Errecalde, Angelita Rebollo

Abstract: Objective: To test cell penetrating and interfering peptide Mut3DPT-PP2A/SET in interaction between serine threonine phosphatase PP2A and its physiological inhibitor, the oncoprotein SET. Materials and methods: Adult male C3H/S-strain mice, 60 days old, were given a graft of breast adenocarcinoma cells (TN60) into subcutaneous tissue. Mut3DPT-PP2A/SET peptide was used to block PP2A and SET oncoprotein interaction. The graft-bearing animals were divided into a control group (injected with saline buffer), and an intervention group injected intraperitoneally with Mut3DPT-PP2A/SET peptide (5 mg/kg) every day from day 5 to day 37. The variables we used to compare the outcome in both groups were tumor size in mm (length×width) and histological changes. In the statistical analysis we used ANOVA and Student-Keuls multiple comparisons test and Tuckey for the post-test analysis. Results: 48 mice were grafted at day 0 with breast UNLP-C3H/S tumor cells, and after randomization, they were assigned to one of the two study groups. At day 5 all mice were injected either with placebo or with the peptide. The treated group showed significant tumor reduction (p<0.07). Histological changes showed presence of apoptosis and necrosis of tumor in treated group. Conclusion: The peptide Mut3DPT-PP2A/SET has demonstrated anti-tumor activity by reduction in vivo of tumor growth becoming a promising future in anticancer therapy.

HTML

PDF

DOI: 10.3897/folmed.62.e49370

Authors: Neli Vilhelmova, Lora Simeonova, Nadya Nikolova, Elitsa Pavlova, Zlatina Gospodinova, Georgi Antov, Angel Galabov, Ivanka Nikolova

Abstract: Introduction: Due to the high prevalence of viral infections having no specific treatment and the constant emergence of resistant viral strains, searching for effective antiviral compounds is crucial. The present study explores in vitro the antiviral activity of ethanolic extract from aerial parts of Tanacetum vulgare L. against viral strains of three taxonomic groups, including agents that cause socially significant diseases in humans for which antiviral chemotherapy is indicated, namely coxsackievirus B1 (family Picornaviridae), herpes simplex virus type 1 (family Herpesviridae) and influenza A virus (family Orthomyxoviridae). Aim: The aim of the current study was to evaluate antiviral activity of ethanolic extract from herbaceous plant Tanacetum vulgare L. against some important human viruses for which antiviral chemotherapy is needed and to characterize extract for its antioxidant activity in vitro. Materials and methods: The crude aqueous ethanolic extract from aerial parts of Tanacetum vulgare L. contained flavonoids determined as apigenin, coumarins determined as aesculin, tannic compounds determined as tannin, and others. Antiviral activity of ethanolic extract from herbaceous plant Tanacetum vulgare L. against coxsackievirus B1, influenza A and herpes simplex virus type 1 was evaluated by viral yield reduction technique. The total antioxidant activity was determined by measuring the capacity of the sample to inhibit the generation of thiobarbituric acid reactive substances (TBARS). Results: The results show that the extract has the lowest toxicity on the MDBK cell line and similar cytotoxicity in Hep-2, whereas in the MDCK cells it has more than twice the highest toxicity. Testing the antiviral activity of Tanacetum vulgare L. extract revealed a slight inhibition of replication of HSV-1 with a selective index of 7.07 and IAV/H3N2 (SI = 3.69) but no specific antiviral effect against CVB1 replication was found. The evaluation of the antioxidant activity showed great antioxidant activity of the ethanolic extract from T. vulgare – 26 mmol/l for the applied 20 mg/ml extract. Conclusion: The crude extract from aerial parts of the medicinal plant Tanacetum vulgare L. demonstrated low cytotoxicity in Hep-2, MDBK and moderate cytotoxic effects in MDCK cells. It exerted significant antiviral activity against HSV-1 as determined by the recorded inhibition of viral replication, the blockage of virus entry - absorption stage and direct virucidal effects on extracellular virions. The observed effect when testing Tanacetum’s extract on influenza A H3N2 virus infection in vitro was milder, which probably resulted from the interference with the cellular pathways involved in the replication cycle. The presence of virucidal and adsorption-suppressing activity but the absence of viral replication inhibitory effects against CBV-1 suggests a possible interaction of the extract’s components with viral capsid proteins or related cell receptors.

HTML

PDF

DOI: 10.3897/folmed.61.e47965

Authors: Ashish P. Shah, Ghanshyam R. Parmar, Girish U. Sailor, Avinash K. Seth

Abstract: Background: Aspartic protease found in plasmodium parasites such as plasmepsin I, II and IV plays an important role in the degradation of hemoglobin. The studies have shown that effective drug must be able to inhibit more than one type of plasmepsin to avoid further growth of parasites and to prevent resistance of drug. Therefore, plasmepsins are believed to be excellent drug target for malarial disease. Extract of the plant Euphorbia hirta has been proved to exert antimalarial activity. However, molecular mechanism of this activity was not described.Aim: The aim of present investigation is to identify antimalarial phytochemicals of Euphorbia hirta as plasmepsin protease inhibitors using an in silico approach.Materials and methods: Docking studies were performed on three different protein targets plasmepsin I, II, and IV using iGEMDOCK. ADME and bioactivity predictions were done using molinspiration online tool. Toxicity studies were performed using ProTox-II online tool.Results: In the docking studies seven compounds showed significant inhibitory activity with low docking score as compared to standard drug artemisinin. Six compounds showed no violations as per Lipinski rule. Bioactivity prediction states that all the compounds may act through enzyme inhibition. The results of in silico studies suggest that out of the eleven selected phytochemicals isorhamnetin and pinocembrin have more drug likeliness properties and lesser in silico toxicity with more binding affinity than artemisinin on all receptors. Conclusion: These findings indicate that isorhamnetin and pinocembrin have promising potential for development of antimalarial drug as plasmepsin inhibitors.

HTML

PDF

DOI: 10.3897/folmed.61.e47810

Authors: Vesela A. Borisova, Miroslav Tz. Eftimov, Stefka V. Valcheva-Kuzmanova

Abstract: Background: The fruit juice from Chaenomeles japonica var. maulei (Mast.) Lavall,e is very rich in polyphenolic compounds.Aim: The aim of the current study was to investigate the effects of Chaenomeles maulei fruit juice (CMFJ) on reserpine-induced beha-vioral changes in rats.Materials and methods: The experimental design included a total of 50 animals, divided in the following groups: control, R, R+CMFJ2.5, R+CMFJ5, and R+CMFJ10. All groups except the control received a single intraperitoneal injection of reserpine while the Control group was injected with the vehicle. CMFJ was applied through an orogastric cannula at 0, 19, and 23 hours after reserpine injection at doses of 2.5 ml/kg, 5 ml/kg, and 10 ml/kg to groups R+CMFJ2.5, R+CMFJ5, and R+CMFJ10, respectively. The groups control and R received distilled water (10 ml/kg) at the same time points. The open field test (OFT) and the forced swim test (FST) were carried out. In the OFT, crossings and rearings were recorded as a measure of locomotor activity. In the FST, the immobility time served as a measure of depressive-like behavior.Results: In the OFT, the number of crossings of rats were significantly reduced (p<0.05) by reserpine. CMFJ antagonized the effects of reserpine on rat locomotor activity. In the FST, reserpine caused an insignificant reduction of the immobility time while CMFJ reversed this effect probably by increasing the locomotor activity.Conclusion: CMFJ reversed reserpine-induced hypokinesia in rats. This effect of CMFJ might be attributed to the polyphenols found in very high concentrations in the juice.

HTML

PDF

DOI: 10.3897/folmed.61.e47955

Authors: Chintan Pandit, Khushal M. Kapadiya

Abstract: Background: In chemistry, the derivatives of benzofuran which are substituted on five-membered ring constitute one of the salient moieties in medicinal field and a survey of literature revealed that a good number of reports have shown that tetrahydrobenzofuran derivatives are of valuable biological activities.Aim: On the basis of previous survey, we aimed to generate a series of 2-(4-azidobenzoyl)-3-substitutedaryl-6,6-dimethyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one bearing azide group which were identified by anti-cancer screening against sixteen cell-lines of NCI (National Cancer Institute) using nine different cancer cell panels.Materials and methods: The tetrahydrobenzofuran derivatives were synthesized by multi-component reactions. It was achieved by coupling of dimedone (3.57 mmole), 4-azido phenacyl bromide (3.92 mmole) and various aromatic aldehydes (3.57 mmole) using two different bases i.e. pyridine and N,N- diethylethanamine under reflux condition. Anti-cancer activity was carried out by NCI-60 cell-lines using standard protocol by National Institute of Health.Results: The results from anti-cancer study shows that the compound 4a exhibited diverse cytotoxic activity against renal cancer panel (UO-31) with significant selectivity and had inhibitory effect on the generation of UO-31 (growth percent= 69.36%) and the compound 4e showed comparable activity in the same cell-line (UO-31: growth percent= 80.86%).Conclusions: In summary, a series of azide group containing tetrahydrobenzofuran derivatives have been synthesized and were evaluated for their anticancer activity. It was concluded that the derivatives 4a and 4e exhibited promising anticancer activity. Nature of substituent on phenyl ring seems to be the crucial factor affecting the activity in both the compounds.

HTML

PDF

DOI: 10.3897/folmed.61.e47957

Authors: Roman E. Tashev, Galya Tz. Stavreva, Margarita St. Velikova

Abstract: Introduction: Endocannabinoid system is involved in neuropsychiatric disorders such as major depression. The bilaterally olfactory bulbectomized rat is widely used as an animal model of depression. The removal of the olfactory bulbs produces behavioural, physiological, and neurochemical alterations resembling clinical depression. There is increasing evidence that highlights the important role of cannabinoid signalling in depression and nociception.Aim: To investigate the effect of CB1 receptor agonist HU 210 and CB1 receptor antagonist SR 141716A administered icv subchronically (for 7 days) on nociception of rats with model of depression - bilateral olfactory bulbectomy (OBX).Material and methods: Experimental model of depression - bilateral olfactory bulbectomy (OBX). Bilaterally olfactory bulbectomized rats were used as an experimental model of depression. HU 210 (5 µg) or SR 141716A (3 µg) were infused icv for 7 consecutive days, starting 15 days after the olfactory bulbectomy. Nociception was examined by applying paw pressure test (analgesy-meter) evaluating the rat pain threshold. On day 7, five minutes after the last microinjection, the rats were tested in an analgesy-meter and their mechanically evoked pain responses were measured in arbitrary units (AU).Results: Microinjections of HU 210 (5 µg) significantly decreased the pain threshold in olfactory bulbectomized rats, while SR 141716A (3 µg) exerted antinociceptive effect by increasing the pain threshold.Conclusions: Data point to an involvement of CB1 receptors in depression-like behaviour and nociception in olfactory bulbectomized rats and support the data for the association between depressive disorder and pain pathways.

HTML

PDF