The Antiangiogenic Activity of Flaxseed Oil Alone and Combination with Mefenamic Acid in Vivo and in Vitro Assay.

BACKGROUND: Antiangiogenic agents are commonly used for the management of many types of cancers. Flaxseed oil is a wealthy source of omega-3,omega-6, and lignans, and possesses anticancerous and antioxidant activities. OBJECTIVE: To investigate the antiangiogenic activity of flaxseed oil alone and in combination with mefenamic acid in a dose-response study. METHODS: Oil was extracted from flaxseeds. The ex vivo rat aorta ring assay was used to screen the flaxseed oil alone and in combination with mefenamic acid for possible antiangiogenic activity. Also, the assay was used to determine the dose-response effect.An in vivo chick chorioallantoic membrane (CAM) assay was used to quantify the zone of inhibition of blood vessel by flaxseed oil. RESULTS: The 200,100,50,25,12.5, and 6.25µg/ml of the flaxseed oil inhibited blood vessel growth with values of 91±0.42, 84±2.06,36±2.71, 21±2.15,23±1.56, and 5±0.93%, respectively, withan IC50 value of 45.695 µg/ml. These concentrations showed a dose-dependent inhibition of angiogenesis. At 200, 100, and 50 µg/ml of flaxseed oil in combination with 50 µg/ml of mefenamic acid inhibited blood vessel growth with inhibition percentages of 81.48±0.82,79.63±0.75, and 77.78±1.26, respectively, with an IC50 of 2.27 µg/ml. Also, these concentrations indicated a dose-dependent inhibition of angiogenesis.  Flaxseed oil produced a significant inhibition zone of blood vessels in the CAM assay. The LD50 for flaxseed oil was 5.656g/kg. CONCLUSION: Flaxseed oil alone and in combination with mefenamic acid exhibited antiangiogenic activity both in ex vivo and in vivo assays. At doses of 2.5, 1.25, 0.625, and 0.312 g/kg of flaxseed oil intraperitoneally injected into mice, no symptoms of toxicity or death of mice due to acute toxicity were observed. However, doses of 5 and 10 g/kg of oil resulted in the death of the majority of mice.

Analgesic Efficacy of Curcuma longa (Curcumin) after Surgical Periodontal Therapy.

PURPOSE: To compare the analgesic efficacy of orally administered Curcuma longa (curcumin) and mefenamic acid (MA) after surgical periodontal therapy (SPT). MATERIALS AND METHODS: Seventy-six periodontitis patients were randomly divided into two groups. In the test group, patients received curcumin capsules (200 mg), and in the control group, patients received MA (500 mg). All patients underwent post-operative antibiotic therapy using 500 mg amoxicillin and 400 mg metronidazole for 7 days. Post-operative pain and discomfort were evaluated using the numerical rating scale (NRS) and verbal rating scale (VRS), respectively. Evaluation were performed after 24 (T1), 48 (T2), and 72 h (T3). Group comparisons were done using Student's t-test and the Mann-Whitney U-test. The level of statistical significance was established at p < 0.05. RESULTS: All patients had stage 3/grade C periodontitis. The mean age of individuals in the test and control groups were 58.4 ± 7.3 and 57.2 ± 5.2 years, respectively. A family history of periodontal diseases was reported by 37.5% and 47.4% individuals in the test and control groups, respectively. In the test and control groups, the total mean duration of periodontal surgery was 168.2 ± 12.2 and 173.4 ± 10.7 min, respectively. There was no statistically significant difference in the mean NRS and VRS scores among patients in the test and control groups. In both groups, there was no statistically significant difference in the change in NRS scores at any time point. CONCLUSIONS: Compared with MA, curcumin is ineffective for pain and discomfort management after SPT. The possibility of the results being biased due to lack of operator blinding cannot be overlooked.

Comparison of effect of auriculotherapy and mefenamic acid on the severity and systemic symptoms of primary dysmenorrhea: a randomized clinical trial.

BACKGROUND: Primary dysmenorrhea (PD) is the most common complaint in young women and adolescents. Side effects of non-steroidal anti-inflammatory drugs can limit their use. Therefore, non-pharmacological pain relief methods such as auriculotherapy may play an important role in PD management. This study was conducted to compare the effect of auriculotherapy and mefenamic acid on the severity and systemic symptoms of PD. METHODS: In a randomized clinical trial, 83 students were randomized into two groups. In the auriculotherapy group, electrical stimulation of the ear was conducted once a week for two menstrual cycles. In each cycle close to menstruation, ear seeds were inserted on pressure points to be pressed in times of pain. In the mefenamic acid group, subjects took mefenamic acid capsules upon seeing the initial symptoms of menstruation until the pain reduces. The primary outcomes were mean pain intensity and systemic symptoms associated with it. Pain intensity was measured through the visual analog scale (VAS) and the verbal multidimensional scoring system (VMS). Systemic symptoms were assessed using VMS, as well as the yes/no question form. RESULTS: Mean pain intensity with the VAS was significantly lower in the auriculotherapy group than the mefenamic acid group in the first and second cycles of intervention. There was a significant difference in VMS grade between both groups during the second cycle of intervention. In terms of the systemic symptoms in the second cycle of intervention, no subjects had dysmenorrhea grade 3 (common systemic symptoms) in the auriculotherapy group. Whereas in the mefenamic acid group, 16.7% of the subjects still had dysmenorrhea grade 3. There was no significant difference between the two groups in the frequency of systemic symptoms of PD. There was a significant decrease in the frequency of fatigue and diarrhea in both groups. However, there was a significant reduction in the frequency of nausea, headache, and anger in the auriculotherapy group. CONCLUSION: Mean pain intensity with the VAS was lower with the auriculotherapy. Also, 65.9% of auriculotherapy group subjects were in the dysmenorrhea grades 0 and 1. Therefore, auriculotherapy is recommended because of its fewer complications and more effect on PD. TRIAL REGISTRATION: ClinicalTrials.gov IRCT20181207041873N1. Registered on February 24, 2019. https://en.irct.ir/user/trial/35967/view.

Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors.

BACKGROUND: Mefenamic acid (MFA), a commonly prescribed non-steroidal anti-inflammatory drug (NSAID), possesses a greater risk of dose-related central nervous system (CNS) toxicity than other NSAIDs. In this study, α-tocopherol and α-tocopherol acetate were selected as prodrug moieties for MFA in an attempt to reduce the CNS toxicity and enhance the therapeutic efficacy. METHOD: α-tocopherol monoester of MFA (TMMA) and α-tocopherol di-ester of MFA (TDMA) were synthesized by esterification reaction and were subjected to various in vivo characterizations. RESULTS: Masking of the carboxylate group of MFA with the proposed pro-moieties significantly (p<0.05) delayed the onset of tonic-clonic seizure in mice. Besides, the intraperitoneal administration of TMMA and TDMA in mice produced significantly (p<0.05) stronger anti-inflammatory effects in the carrageenan-induced paw edema test and greater anti-nociceptive effect in the acetic acid-induced writhing test than MFA at an equimolar dose of 20 mg/kg. Treatment with TMMA and TDMA caused a significant (p<0.05) inhibition of pain at 1st and 2nd phases of formalin-induced licking test in mice, whereas treatment with MFA inhibited the 2nd phase only. Pretreatment with naloxone and flumazenil significantly (p<0.05) reversed the anti-nociceptive effect of MFA, TMMA and TDMA in the acetic acid-induced writhing test. In addition, treatment with TMMA and TDMA caused significantly (p<0.05) a higher inhibition of pain in the glutamate-induced licking response in mice than MFA. CONCLUSION: Masking the carboxylate moiety of MFA by α-tocopherol and α-tocopherol acetate has a great potential for reducing CNS toxicity, enhancing the therapeutic efficacy and altering the mode of anti-nociceptive action.

Randomized, double-blind, placebo-controlled clinical trial studying the effects of Turmeric in combination with mefenamic acid in patients with primary dysmenorrhoea.

Primary dysmenorrhea (PDM) is one of the common complaints in women. This study aimed to assess the effects of turmeric and mefenamic acid and a combination compared with placebo on PDM. This clinical trial was conducted on dormitory students with PDM. Subjects completed the visual analog scale (VAS) before randomization. One hundred twenty-eight patients, randomly assigned to one of following groups: Turmeric group (n=32), mefenamic acid group (n=32), turmeric and mefenamic acid group (n=32), and placebo group (n=32). Turmeric and mefenamic acid were administrated in 500mg and 250mg, respectively. Pain severity was assessed in the baseline and the end line by VAS. Statistical analysis was performed using SPSS software. The combination of turmeric and mefenamic acid, dramatically, alleviated pain in comparison to other groups. Our results illustrated that combination of turmeric and mefenamic acid would be better in pain alleviation in PDM.

Supportive therapy for dysmenorrhea: Time to look beyond mefenamic acid in primary care.

Dysmenorrhea is a recurrent and chronic primary health care issue. Mefenamic acid and NSAID based therapy regimens have unwanted side effects on its long-term usage. NSAIDs reduce pain, albeit they do not address the enhanced pain sensitivity and other neuronal symptoms of dysmenorrhea. Hence, there is a need for supportive therapy which can target both pelvic pain and the neuronal symptoms. Historically, European medicinal plants and their extracts such as, valeriana officinalis, humulus lupulus, and passiflora incarnata have been used in menstrual disorders for centuries. The current review is focused on the available evidence for its use as monotherapy or as supportive therapy in combination with other conventional medications.

Investigating the Effect of Melissa Officinalis on After-Pains: A Randomized Single-Blind Clinical Trial.

Introduction: Regarding high prevalence of postpartum pain and side-effects of pharmaceutical analgesics on maternal and neonatal health, the present study aimed to explore the effect of Melissa officinalis on after-pain among mothers hospitalized in Asgariyeh Hospital, Isfahan, 2016. Methods: In this single-blind clinical trial, 110 women with moderate to severe after-pain were divided into two M.officinalis and mefenamic acid groups by random allocation. Samples in the first group received 250mg of mefenamic acid and the second group received 395mg of M.officinalis oral capsules every 6hours for 24hours following childbirth. The primary outcome (After-pain) was assessed using a numeric 10-point scale before intervention, 1,2 and 3hours after the first intervention and every 6hours to 24hours after delivery for each of second, third and fourth interventions. Data were analyzed, using SPSS by independent t-test, Mann-Whitney and chi-square test. Results: The demographic and obstetric variables and after-pain severity before the intervention in both groups were homogenous. Pain intensity wasn't significantly different between the two groups during first and second hours after the first intervention, but there was a significant difference in the third hour, The severity of pain was significantly different between the two groups in different assessments including: an hour after the second, third and fourth intervention (P<0.05). A significant difference was found between mefenamic acid and M.officinalis in pain relief. Conclusion: M.officinalis can reduce the severity of after-pain, because it eliminates the need for pharmaceutical analgesics and works much better than mefenamic acid.

A double-blind controlled crossover study to investigate the efficacy of salix extract on primary dysmenorrhea.

OBJECTIVES: Primary dysmenorrhea in the absence of pelvic pathology is a common gynecologic disorder affecting the quality of life of women of reproductive age. This study evaluates the effect of salix extract on primary dysmenorrhea. DESIGN: This study was a randomized crossover clinical trial. SETTING: The study population included 96 female students with level two or three of primary dysmenorrhea: 48 students in the treatment group (sequence I) followed by control (sequence II) and 48 students in control group (sequence I) followed by treatment (sequence II). INTERVENTIONS: The intervention was salix capsule (400 mg daily) and the active control was mefenamic acid capsule (750 mg daily) as. MAIN OUTCOMES: Pain intensity, measured by the visual analog scale (VAS), amount of bleeding, and severity of dysmenorrhea symptoms were outcomes. Generalized estimating equations were used for data analysis. RESULTS: The demographic and menstrual characteristics of the students were homogenous between the groups. The results showed that the students in mefenamic acid group had a significantly higher level of VAS than the students in the salix group over time (1.61 ± 0.06, P < 0.001). The estimated odds of the bleeding level in the salix and mefenamic acid group were not significantly different (P = 0.31). In average, 77.39%±16.18 of the students in salix group showed no symptoms followed by 22.18%±14.08 of the students who experienced mild symptoms. Averagely, 44.58%±20.16 of the students in the mefenamic acid group had mild symptoms followed by moderate symptoms (28.12%±15.29). CONCLUSIONS: Salix extract significantly decreased dysmenorrhea in comparison to mefenamic acid, as the standard treatment of dysmenorrhea.

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis.

BACKGROUND: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties. METHODS: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly. FINDINGS: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly. INTERPRETATION: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

Effect of alpha-lipoic acid at the combination with mefenamic acid in girls with primary dysmenorrhea: randomized, double-blind, placebo-controlled clinical trial.

Primary dysmenorrhea is a common gynecologic disorder and is one of the main causes for referral to the gynecology clinic. This study aimed to determine the effects of alpha-lipoic acid (ALA) and mefenamic acid and a combination compared with placebo on the girls with primary dysmenorrhea. This double-blind, placebo-controlled clinical trial done on population consisted of female students living in dormitories of Qazvin University of Medical Sciences who had moderate to severe dysmenorrhea using the Visual Analog Scale (VAS) questionnaire. Participants were randomly divided into four groups (n = 100): ALA, mefenamic acid, ALA + mefenamic acid and placebo groups. ALA and mefenamic acid were administrated in 600 mg and 250 mg, respectively. The severity of the pain was measured in the beginning and the end of the study. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL). Our final results suggested that, although mefenamic acid significantly decreased the menstrual pain, ALA supplementation, 600 mg, would be more efficient than mefenamic acid in 250 mg. Also, the combination of ALA and mefenamic acid significantly has been far. Considering the ALA supplementation effect on pain relief in patients with primary dysmenorrhea, this antioxidant can be recommended for the healing of symptoms of these patients.

Effect of Hydroalcoholic Extracts of Capsella Bursa-Pastoris on Heavy Menstrual Bleeding: A Randomized Clinical Trial.

OBJECTIVES: Heavy menstrual bleeding (HMB) is one of the leading causes of low quality of life and iron deficiency anemia in women. This study aimed to determine the effect of hydroalcoholic extracts of Capsella bursa-pastoris on HMB. DESIGN: This study is a triple-blinded, randomized clinical trial. SETTING: The study was conducted in gynecology clinics affiliated to Shahid Beheshti University of Medical Sciences, Tehran, Iran. SUBJECTS: Our patients affected to a complaint of HMB. After obtaining a complete medical history of the women and filling out the demographic forms, the participants were assigned randomly into the experimental (n = 42) and control groups (n = 42). INTERVENTION: The eligible participants were given a pictorial blood loss assessment chart (PBLAC) to confirm HMB during the menstrual cycle. The experimental group received two capsules of mefenamic acid (500 mg) every 8 h and two Capsella bursa-pastoris capsules every 12 h. The intervention started from the first day of menstruation to the end of this period up to 7 days for two consecutive cycles. In the control group, the patients received mefenamic acid and placebo instead of Capsella bursa-pastoris capsules. OUTCOME MEASUREMENTS: The PBLAC score and number of bleeding days, incidence of any possible problems, as well as participant satisfaction were measured. The data were analyzed using t-test, Chi-square, repeated-measures ANOVA, and ANCOVA tests in PASW Statistics ver. 18. RESULTS: After the intervention, there was observed significant decrease in the amount of menstrual bleeding in both groups. However, the mean decrease in the amount of bleeding was significantly more in the Capsella bursa-pastoris group (p < 0/001). CONCLUSION: Compared with control group, hydroalcoholic extracts of Capsella bursa-pastoris capsule appeared to be effective in reducing menstrual bleeding in this study. Further research regarding the efficacy and safety of Capsella bursa-pastoris is required.

Comparison of the effect of honey and mefenamic acid on the severity of pain in women with primary dysmenorrhea.

BACKGROUND AND OBJECTIVE: Primary dysmenorrhea starts simultaneously with menstruation or before it and usually continues for 48-72 h. As a prevalence disorder, it affects about 80-97% of women in the reproductive age. The conventional treatment modalities of primary dysmenorrhea are associated with complications and side effects. In addition, there is a lack of knowledge of the effect of honey on the treatment of primary dysmenorrhea. The objective of this study is to investigate the effect of honey on the severity of pain in women with dysmenorrhea. METHODS: A randomized crossover clinical trial was conducted on 56 female students. Subjects were randomly assigned to two groups. Groups I and II received honey and mefenamic acid in the 'first treatment period', respectively. In the 'second treatment period', the intervention methods were reversed between the groups. Samples recorded the severity of pain during the first 3 days of menstruation. RESULTS: There were no significant differences in the most severe level of pain in the first and second months of the first treatment period, and the first and second months of the second treatment period between the groups. CONCLUSIONS: Honey and the mefenamic acid capsules led to the same amount of pain relief in women with primary dysmenorrhea. Honey is suggested to be used for pain relief due to its lower side effects and pharmacological complications.

In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

Evaluation of mint efficacy regarding dysmenorrhea in comparison with mefenamic acid: A double blinded randomized crossover study.

BACKGROUND: Menthol is the most important active material in mint and different mechanisms have been suggested for the way mint functions, most of which emphasize its analgesic effect owing to the presence of a group of temporary protein receptors. This study investigates the efficacy of peppermint capsule in the treatment of primary dysmenorrhea, in comparison with Mefenamic Acid and placebo. MATERIALS AND METHODS: This was a prospective, double-blinded, crossover study and was conducted on 127 girl students studying in Hamadan University of Medical Sciences who had experienced primary dysmenorrhea. Each participant was asked to take one of the drugs including Mefenamic Acid and Mint, starting from the first menstruation for 3 days. At the end of each period, a questionnaire was used to gather information; through the volunteer herself, pain intensity was recorded according to visual analog scale (VAS), duration of pain according to COX questionnaire, and bleeding amount according to pictorial blood loss assessment chart (PBAC) chart (Hygham). RESULTS: Average pain intensity and duration of pain were significantly lower after intake of Mefenamic Acid and Mint (P < 0.05). Average bleeding was significantly lower in those taking Mefenamic Acid capsule than in those taking peppermint extract (P < 0.05). Nausea and diarrhea were lower in the mint group than in Mefenamic Acid group. But analgesic usage was lower in Mefenamic Acid group than in peppermint group (P < 0.05). CONCLUSIONS: While the bleeding amount did not significantly change, pain and its severity and all the clinical signs and symptoms decreased after taking peppermint extract. Because the side effect of herbal drugs is lower than other medicinal drugs, using mint is advised for treating dysmenorrhea symptoms.

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid.

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.

Comparison the effect of mefenamic acid and Teucrium polium on the severity and systemic symptoms of dysmenorrhea.

BACKGROUND: Primary dysmenorrhea is a prevalent problem and its effects decrease the quality of life in many women across the world. The aim of this study was to research the effect of Teucrium polium compared to mefenamic acid on primary dysmenorrhea. MATERIALS AND METHODS: This triple-blind, randomized, clinical trial study was performed on 70 single female students between 20 and 30 years old educating in Shahid Beheshti University (Tehran, Iran) from October 2014 to February 2014.They were allocated randomly into two groups: In T. polium group (n = 35) who took 250 mg of T. polium powder q6h for the first 3 days of menstruation for two cycles. The second group (n = 35) received 250 mg mefenamic acid,. Dysmenorrhea severity was determined by visual analog scale (VAS). RESULTS: There were no differences between two groups for demographic or descriptive variables. Comprising the VAS showed that the participants in T. polium and mefenamic acid groups had lower significant pain in the 1st and the 2nd months after the treatment (P < 0.05). No side effects were reported in the T. polium and Mefenamic Acid groups. CONCLUSION: T. polium was as effective as mefenamic acid in decreasing the pain severity in primary dysmenorrhea.

Herb-drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariae Radix (SR), the dried root of Scutellariae baicalensis Georgi, has a lot in common with non-steroidal anti-inflammatory drugs (NSAIDs). Their similarities in therapeutic action (anti-inflammation) and metabolic pathways (phase II metabolisms) may lead to co-administration by patients with the potential of pharmacokinetic and/or pharmacodynamic interactions. The current study aims to investigate the potential interactions between SR and an NSAID, mefenamic acid (MEF), on the overall pharmacokinetic dispositions, anti-inflammatory effects and adverse effects in rats. MATERIALS AND METHODS: The current study simultaneously monitored the pharmacokinetic and pharmacodynamic interactions in a single animal. Four groups of Sprague-Dawley rats (n=7 each) received oral doses of a standardized SR extract (300mg/kg, twice daily), MEF (40mg/kg, daily), combination of SR extract and MEF, and vehicle control, respectively, for 5 days. On Day 5, blood samples were collected after first dose over 24h for the determination of (1) plasma concentrations of SR bioactive components, MEF and its metabolites by LC-MS/MS, and (2) prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) gene expression by ex vivo analyses using LPS-stimulated RAW264.7 macrophage cells, ELISA and real time-PCR. After the rats were sacrificed, stomachs were isolated to assess their gross mucosal damage. Statistical comparisons were conducted using ANOVA and t-test. RESULTS: Minimal pharmacokinetic interaction between SR extract and MEF was observed. Co-administration of SR extract and MEF did not significantly alter the plasma concentration-time profile or the pharmacokinetic parameters such as Cmax, AUC0→24, Tmax or clearance. Pharmacodynamic interaction via the COX-2 pathway was observed. The PGE2 level in LPS-stimulated RAW264.7 cells treated with plasma collected from control group over the 24h sampling (AUC0→24[PGE2]) was 191981±8789pg/mlhr, which was significantly reduced to 174,780±6531 and 46,225±1915pg/mlhr by plasma collected from rats administered with SR extract and MEF, respectively. Co-administration of SR extract and MEF further potentiated the PGE2 inhibition, with an AUC0→24[PGE2] of 37013±2354pg/mlhr (p<0.05, compared to SR or MEF group). By analyzing the COX-2 gene expression, SR extract significantly prolonged the COX-2 inhibitory effect of MEF over the 24h (p<0.05). Furthermore, the MEF-induced stomach ulcer after the 5-day treatment, as evidenced by the increased gross ulcer index and sum of lesion length (p<0.05, compared to control), could be alleviated by co-administration with SR extract (p<0.05). CONCLUSIONS: Co-administration of SR extract and MEF potentiated the anti-inflammatory effects, alleviated the MEF-induced stomach adverse effect while having minimal pharmacokinetic interactions. Our findings provide insight for combination therapy of SR extract and MEF against inflammatory diseases.

Effect of Dill (Anethum graveolens) on the severity of primary dysmenorrhea in compared with mefenamic acid: A randomized, double-blind trial.

BACKGROUND: Dysmenorrhea has negative effects on women's life. Due to side-effects of chemical drugs, there is growing trend toward herbal medicine. The aim of this study was to assess the effect of Dill compared to mefenamic acid on primary dysmenorrhea. MATERIALS AND METHODS: This double-blind, randomized, clinical trial study was conducted on 75 single female students between 18 and 28 years old educating in Nursing and Midwifery School and Paramedical Faculty of Qom University of Medical Sciences of Iran in 2011. They were allocated randomly into one of the three groups: In Dill group, they took 1000 mg of Dill powder q12h for 5 days from 2 days before the beginning of menstruation for two cycles. Other groups received 250 mg mefenamic acid or 500 mg starch capsule as placebo, respectively. Dysmenorrhea severity was determined by a verbal multidimensional scoring system and a visual analog scale (VAS). Students with mild dysmenorrhea were excluded. Data were analyzed by SPSS using the descriptive statistic, paired-samples t-test, Wilcoxon signed-rank test, Mann-Whitney test, and Kruskal-Wallis test. RESULTS: There were no significant differences between three groups for demographic or descriptive variables. Comprising the VAS showed that the participants of Dill and mefenamic acid groups had lower significant pain in the 1(st) and the 2(nd) months after treatment, whereas in the placebo group this was only significant in the 2(nd) month (P < 0.05). CONCLUSION: Dill was as effective as mefenamic acid in reducing the pain severity in primary dysmenorrhea. Further studies regarding side-effects of Dill and its interactivity are recommended.

Comparison of the effects of Matricaria chamomila (Chamomile) extract and mefenamic acid on the intensity of premenstrual syndrome.

The study aimed to compare the effects of Chamomile Extract and Mefenamic acid (MA) on the intensity of Premenstrual syndrome (PMS) symptoms. This study was a clinical randomized double blind trial, carried out with 90 students living in the dorms of Iran. The participants filled the daily forms about the intensity of PMS for two consecutive months. Once the definitive diagnosis of PMS was made, the participants were divided into two groups, each receiving either Chamomile capsule 100 mg or MA 250 mg three times a day. Intensity reduction of emotional symptoms was significantly higher among Chamomile Extract-users (30.1 ± 26.6 and 33.4 ± 25.3 percent) than that among MA-users (11.6 ± 25.7 and 10.7 ± 26.8 percent) after two cycles intervention (p < 0.001). Intensity reduction of physical symptoms was not significantly different (p > 0.05) among groups. Consumption of Chamomile seems to be more effective than MA in relieving the intensity of PMS associated symptomatic psychological pains.