Phenolic profile, safety assessment, and anti-inflammatory activity of Salvia verbenaca L.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia species are known to have anti-inflammatory properties, and are traditionally used for healing purposes. Salvia verbenaca is an Algerian plant used for healing wounds and ulcers. AIM OF THE STUDY: This work aims to assess the acute and subacute safety of S. verbenaca and its possible anti-inflammatory activity as a mechanism contributing to its traditional applications. MATERIALS AND METHODS: Lethal toxicity of S. verbenaca hydromethanolic extract was evaluated against Artemia salina larvae, while acute and subacute toxicity were orally tested on mice. The anti-inflammatory activity was screened ex vivo using membrane stabilization and in vivo using xylene induced ear edema as an acute inflammation model. The antiradical, reducing power and iron chelating activities of S. verbenaca were also investigated in vitro, and phenolic compounds were determined using UHPLC-DAD-ESI-MSn. RESULTS: Salvia verbenaca extract contained high amounts of phenolic compounds (206 µg GAE/mg extract). The in vitro antioxidant activity showed promising radical scavenging ability, iron chelating (IC50: 189 µg/mL), reducing power and strong anti-lipid-peroxidation effect (IC50: 111 µg/mL). The extract had potential cytotoxic effect against Artemia salina larvae (LC50: 30 µg/mL), but did not exhibit any acute/subacute toxicity effect on mice. Salvia verbenaca inhibited hypotonic and heat induced hemolysis and also reduced 50% of xylene induced ear edema at 600 mg/kg bw. Rosmarinic acid and caffeoylmalic acid were identified as the major compounds. CONCLUSION: Salvia verbenaca hydromethanolic extract was found to be safe at acute and subacute levels. Its in vitro/in vivo antioxidant activity, membrane stabilizing properties and anti-inflammatory activity may be an important aspect of its wound healing and anti-ulcer traditional use.

In-vivo anti-inflammatory activity and safety assessment of the aqueous extract of Algerian Erica arborea L. (Ericaceae) aerial parts.

ETHNOPHARMACOLOGICAL RELEVANCE: Erica arborea known as Khlenj in Algeria is a small shrub belonging to Ericaceae family. E. arborea Aqueous extract (EAAE) is used in traditional medicine for anti-inflammatory, diuretic, antimicrobial, and antiulcer purposes. AIM OF THE STUDY: To our knowledge, no data reveal the combination between in-vivo anti-inflammatory and toxicological studies of EAAE. For this purpose, the aim of this study is to evaluate the biological activity cited above and assess its safety. MATERIAL AND METHODS: Anti-inflammatory activity was undergone using carrageenan-induced paw edema and croton oil-induced ear edema. The acute and sub-acute toxicity were conducted following the OECD guidelines 423 and 407, respectively. Phytochemical identification was carried out using HPLC-DAD-MS. Quantitative evaluation of polyphenols; flavonoids and antioxidant activity of EAAE were also determined. RESULTS: Oral administration of EAAE (250 and 500 mg/kg) significantly (p < 0.05) reduced the edema induced by carrageenan. Administration of EAAE dosed at 250 and 500 mg/kg exhibited efficacy in reducing edema induced by croton oil. The acute administration of EAAE at doses of 2000 and 5000 mg/kg did not cause any mortality or adverse effects indicating that the LD50 is above 5000 mg/kg. The prolonged administration of EAAE (500 and 1000 mg/kg) showed a significant reduction in triglycerides levels in male and female rats whereas no significant changes in other biochemical and hematological parameters were observed. Histopathological damages were recorded in both liver and kidney animal's tissues of both sexes treated with medium and maximum doses of EAAE. Phytochemical characterization of EAAE revealed a high amount of phenolic compounds, HPLC-DAD-MS analysis led to the identification of chlorogenic acid and five flavonol glycosides: myricetin pentoside, quercetin-3-O-glucoside, myricetin-3-O-rhamnoside, quercetin-3-O-pentoside, and quercetin-3-O-rhamnoside. CONCLUSION: In the light of the results obtained in this study, EAAE corroborates the popular use to treat the anti-inflammatory impairments. EAAE can be considered as non-toxic in acute administration and exhibited a moderate toxicity in sub-acute administration. High phenolic content and in-vitro antioxidant activity observed indicate that EAAE may reduce oxidative stress markers in-vivo.

Assessment of in vivo estrogenic and anti-inflammatory activities of the hydro-ethanolic extract and polyphenolic fraction of parsley (Petroselinum sativum Hoffm.).

ETHNOPHARMACOLOGICAL RELEVANCE: Since the dawn of time, medicinal and aromatic plants (AMPs) represent a precious heritage for humanity, especially in developing countries, who exploit their virtues in traditional pharmacopoeia to cope with health problems such as diabetes, kidney stones, ulcer, and digestive disorders. Petroselinum sativum Hoffm. belongs to Apiaceae family. It is traditionally used to treat arterial hypertension, diabetes, cardiac disease, renal disease, and recently reported as a plant endowed with a female anti-infertility effect. AIM OF THE STUDY: This study aims to evaluate the in vivo effect of hydro-ethanolic extract and polyphenols of Petroselinum sativum Hoffm. on cholesterol, protein and estrogen levels, and characterize the chemical composition of polyphenolic fraction. In addition, acute toxicity and anti-inflammatory activity of tested extract was also investigated. MATERIALS AND METHODS: Chemical composition of polyphenolic fraction was determined using High-Performance Liquid Chromatography with Diode-Array Detection (HPLC-DAD). First, toxicological investigations including sub-acute toxicity were performed by measuring animals' weights daily for four weeks. Afterwards, histopathological examination of livers and kidneys, and serum assay of ASAT and ALAT were also checked. Next, the acute in vivo anti-inflammatory study of the hydro-ethanolic extract and polyphenols of Petroselinum sativum Hoffm. versus Indomethacin was conducted. Furthermore, we evaluated the estrogenic effect of its hydro-ethanolic extract and the polyphenolic fraction following biochemical assays for the determination of proteins, cholesterol and estrogen levels. RESULTS: The results revealed the presence of some phenolic compounds mainly ferulic acid, gallic acid and quercetin. Petroselinum sativum Hoffm. extracts also showed no evidence of hepatotoxicity nor nephrotoxicity, with remarkable anti-inflammatory activity, as well as a significant estrogenic effect compared to negative control. CONCLUSION: This study provides a scope of the potential use of Petroselinum sativum Hoffm. extracts in counteracting female infertility issues.

Comprehensive Characterization of Secondary Metabolites from Colebrookea oppositifolia (Smith) Leaves from Nepal and Assessment of Cytotoxic Effect and Anti-Nf-κB and AP-1 Activities In Vitro.

Here we report the comprehensive characterization of the secondary metabolites from the leaves of Colebrookea oppositifolia Smith, a species used as medicinal plant in the traditional medicine of Nepal. Phytochemical screening of bioactives was performed using an integrated LC-MSn and high resolution MS (Mass Spectrometry) approach. Forty-three compounds were tentatively identified, mainly aglyconic and glycosilated flavonoids and phenolic acids, as well as other bioactives such as coumarins and terpenes were detected. Furthermore, the NF-κB and AP-1 inhibitory activity of C. oppositifolia extract were evaluated, as well as its cytotoxicity against THP-1 cells, in order to assess the potential use of this herb as a source of anti-inflammatory and cytotoxic compounds. The results so far obtained indicate that C. oppositifolia leaves extract could significantly reduce the viability of THP-1 cells (IC50 = 6.2 ± 1.2 µg/mL), as well as the activation of both NF-κB and AP-1 at the concentration of 2 µg/mL. Our results indicate that Nepalese C. oppositifolia is a valuable source of anti-inflammatory and cytotoxic compounds. The phytochemical composition reported here can partially justify the traditional uses of C. oppositifolia in Nepal, especially in the treatment of inflammatory diseases, although further research will be needed to assess the full potential of this species.

Metabolomic analysis of Cyrtopodium glutiniferum extract by UHPLC-MS/MS and in vitro antiproliferative and genotoxicity assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of orchids have been traditionally used as human phytotherapeutics. Cyrtopodium flavum, for example, due to the analgesic and anti-inflammatory properties, beside the capacity of heal skin lesions has been focus of research. Also Cyrtopodium glutiniferum, an orchid found in the Brazilian southeastern rainforest, is known to synthesize anti-inflammatory glucomannans in the pseudobulbs, as other potentially therapeutic compounds. AIM OF THE STUDY: We have reported the first metabolomic analysis focused on the phenols expression of the neotropical orchid Cyrtopodium glutiniferum Raddi, besides free radical scavenging, anti-inflammatory and antiproliferative activities, and the genotoxicity properties of the aqueous extract. MATERIAL AND METHODS: The metabolomics of C. glutiniferum aqueous extract was performed through UHPLC-MSn acquisition. We have detected the scavenging potential of the extract using DPPH assay. The genotoxic potential was performed by Ames Test (0-5000 µg mL-1) and micronucleous assay (0-5000 µg mL-1) in RAW264.7 cells. The cytotoxic potential of the extract against RAW264.7 was tested by WST-1 assay (0-500 µg mL-1). And after all, the RAW264.7 cells were treated with non-cytotoxic concentrations of C. glutiniferum (0-50 µg mL-1) to evaluate the antiproliferative and anti-inflammatory potential, besides the mitochondrial activity. RESULTS: From the 55 molecules identified, 45.5% belonged to the phenolic compounds database from Phenol Explorer, 29% to an in-house Orchidaceae molecules database, and 25.5% to both. Among the identified phenolic compounds, 18 subclasses were discriminated, being phenanthrenes the most abundant. Doses-dependent of C. glutiniferum extracts were able to induce DPPH free radicals scavenging and also to increase TA100 His+ revertants, in metabolic environment, showing mutagenicity just in the highest concentration, of 5 mg/plate. On Eukaryotic cell models, the extract also has induced dose-response and time-response cytotoxicity against RAW264.7 macrophages, mainly after 48 h and 72 h, even though the extract has not been able to induce the increase of micronucleated cells and mitotic index alteration on Micronucleus assay. The activation and proliferation of macrophages cultures were downregulated after 24 h and 48 h by the non-cytotoxic concentrations of the extract in a dose-dependent manner. CONCLUSIONS: The Cyrtopodium glutiniferum metabolomics, anti-inflammatory and anti-proliferative properties observed in this study suggest a therapeutic efficacy of the orchid extract applied in folk medicine.

Investigations on acute oral toxicity studies of purpurin by application of OECD guideline 423 in rodents.

The anticancer, anti-inflammatory and antioxidant properties of Purpurin were generated from in vitro studies, and no scientific reports were found on its safety and efficacy, related to their in vivo studies; thus, the present study was focused on acute oral toxicity of purpurin in female Wistar rats as per the OECD 423 guidelines. In this study, purpurin was administered at starting dosage of 300 mg/kg followed by 2000 mg/kg, p.o, and animals were observed for toxic signs at 24 h and for the next 14 days to different animal groups. Animals were observed for mortality, behavioral changes, biochemistry, hematological parameters, and histopathological examination after a follow up on the 14th day. The oral lethal dose for mice was greater than 2000 mg/kg, b.wt. in female rats and classified under category 5 as per the acute oral toxicity study. It was found that there were no significant differences in body weight changes, food/water intake, hematology, and clinical biochemistry. The histopathological study directly depicted that there were no pathological changes observed in the vital organs of rats treated with the different dose of Purpurin. The present work advocates that an acute oral administration of Purpurin was found to be a non-toxic and safe drug in the tested experimental conditions.

Genotoxic Assessment of the Dry Decoction of Myracrodruon urundeuva Allemão (Anacardiaceae) Leaves in Somatic Cells of Drosophila melanogaster by the Comet and SMART Assays.

Medicinal plants are worldwide used as an efficient treatment of many diseases. Myracrodruon urundeuva Allemão (Anacardiaceae) is widely used Brazilian folk medicine to treat inflammations and infections of the female genital tract, conditions of the stomach and throat, and to heal wounds on the skin and mucous membranes. Several pharmacological properties of extracts and compounds isolated from M. urundeuva are found in the literature, corroborating its uses as antiulcer and gastroprotective, anti-inflammatory and analgesic, as well as antimicrobial. Despite these many uses in traditional herbal medicine, there are few reports of its toxic-genetic effect. This work aimed to investigate the genotoxic and mutagenic potential in vivo of the dry decoction of M. urundeuva leaves on somatic cells of Drosophila melanogaster, through the Comet assay and somatic mutation and recombination test (SMART). Six concentrations (0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 mg/mL) were studied after feeding individuals for 24 hr in culture medium hydrated with extracts of M. urundeuva. In the Comet assay, all concentrations showed a genotoxic effect significantly higher than the negative control group, treated with distilled water. The two highest concentrations were also superior to the positive control group, treated with cyclophosphamide (1 mg/mL). In the SMART, there was a mutagenic effect at all concentrations tested, with a clear dose-dependent relationship. Both recombination and mutation account for these mutagenic effects. The set of results indicate that the dry decoction of M. urundeuva leaves is genotoxic and mutagenic for D. melanogaster under the experimental conditions of this study. Environ. Mol. Mutagen. 61:329-337, 2020. © 2019 Wiley Periodicals, Inc.

A comparative assessment of acute oral toxicity and traditional pharmacological activities between extracts of Fritillaria cirrhosae Bulbus and Fritillaria pallidiflora Bulbus.

ETHNOPHARMACOLOGICAL RELEVANCE: Fritillariae Bulbus ("Beimu" in Chinese) is a famous traditional Chinese medicine used to treat cough, expectoration and asthma for more than 2000 years, which belongs to the Fritillaria genus in Liliaceae family. Bulbs of Fritillaria cirrhosa D.Don (BFC) and bulbs of Fritillaria pallidiflora Schrenk (BFP) are two important drugs of Beimu. Due to the significant similarities in their outward appearance characters and chemical profiles, BFC has often been adulterated with BFP in Chinese Traditional Medicine markets. AIM OF THE STUDY: This study aims to compare the oral acute toxicity and the traditional pharmacological activities including antitussive, expectorant and anti-inflammatory effects between the extract of BFC and BFP, to clear and definite if the BFP can be used as a substitute of the BFC in the application of traditional medicine. MATERIALS AND METHODS: The extracts were prepared through refluxing with 80% ethanol solvent. For the acute toxicity tests, graded doses of BFP extracts and the maximum dose of BFC extracts were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. For the pharmacological activities tests, graded doses of BFP and BFC extracts were administered orally to mice. To observe the effects relieving cough, expelling phlegm and lessening the ear swelling of BFC extracts and BFP extracts through ammonia liquor inducing cough, phenol red apophlegmating in mice and the xylene-induced auricular swelling of mouse, respectively. RESULTS: In the acute toxicity study, the LD50 value of BFP in mice was calculated to be 213.57 g/kg body weight, and the maximum feasible dose (MFD) value of BFC in mice was 452.14 g/kg. Histopathological analysis has shown inflammatory cells infiltration and cells edema in liver, multinucleated giant cell proliferation in spleen, perivascular exudate and hemorrhage in lung, glomerulus atrophy in kidney of mice after oral administrations of BFP extracts. But only liver cells edema was observed in BFC group. Both BFC extract and BFP extract significantly increased latent period of cough and inhibited cough frequency in mice induced by ammonia. Besides, the two extracts also obviously enhanced mice's tracheal phenol red output in expectorant assessment and inhibited the development of ear edema in anti-inflammatory evaluation assay. CONCLUSION: To summarize, the BFP has the significant similarities in morphological characteristics, chemical profiles and traditional pharmacological activities compared with the BFC. The result of this study provide some valid scientific support for using BFP as a plant substitute of the BFC, but considering the toxicity of BFP is much higher than BFC, we don't recommend long-term oral administration of BFP or exceeding recommended dosage of Chinese Pharmacopoeia 2015.

Novel Heterocyclic Hybrids Based on 2-Pyrazoline: Synthesis and Assessment of Anti-Inflammatory and Analgesic Activities.

AIM AND OBJECTIVE: A series of new 2-pyrazoline analogues were synthesized. The structures of the synthesized compounds were elucidated by the analytical and spectroscopic data. Some selected compounds were screened for the anti-inflammatory activity by using animal model of carrageenan-induced paw edema in mice. Additionally, the analgesic and acute toxicity of these compounds were evaluated and exhibited reasonable results. The anti-oxidant and anti-inflammatory effects of these compounds were established by measuring the contents of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) in the edema paw tissue. MATERIALS AND METHODS: All chemicals and reagents used in current study were of analytical grade. Melting points were determined using APP. Digital ST 15 melting point apparatus and are uncorrected. FT-IR spectra were recorded on a Pye-Unicam SP3-100 spectrophotometer in KBr pellet. All 1H and 13C NMR spectra were recorded on AVANCE-III (400 MHz) High Performance FT-NMR Spectrometer Brucker (Switzerland) and some 1H NMR spectra were recorded on Varian EM-360L NMR Spectrophotometer (60 MHz) (USA) in CDCl3 or DMSO-d6 as solvent. Chemical shifts are reported in δ units and the coupling constants (J) are reported in hertz. C, H, N and S analyses were performed with a Vario EL C, H, N, S Analyzer. Carrageenan (product number C1013) was obtained from Sigma-Aldrich (USA). RESULTS: The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analyses. The results of pharmacological activity revealed that compounds 5, 6, 7, and 15 could be recognized as potential multi-potent anti-inflammatory. CONCLUSION: A simple and suitable method for the synthesis of new pharmacophore was reported. We have designed nineteen heterocycles related to pyrazoline ring, and evaluated eleven of them for their antiinflammatory, analgesic and acute toxicity activities. Compounds 5, 6, 7, and 15 proved to be the interesting compounds, they have high anti-inflammatory activity. However, all the selected compounds show remarkable analgesic activity.

Stems and leaves of Aconitum carmichaelii Debx. as potential herbal resources for treating rheumatoid arthritis: Chemical analysis, toxicity and activity evaluation.

According to folk usage of Aconitum carmichaelii Debx., the present study was designed to determine the feasibility of the stems and leaves of Aconitum carmichaelii Debx. as a new medicinal resource. Fourteen alkaloids in mother roots, fibrous roots, stems, and leaves of Aconitum carmichaelii Debx. were measured by HPLC-MS/MS. And multivariate analysis methods, such as clustering analysis and principal component analysis, were applied to analyze the difference among various parts. In addition, the acute toxicity, analgesia, and anti-inflammatory tests were carried out. The results suggested that the contents of alkaloids in mother roots and fibrous roots were approximate, but those of leaves and stems were different from mother roots and fibrous roots. The results of the acute toxicity testing demonstrated the toxicity of fibrous root was strongest, and mother roots were slightly less toxic than fibrous roots. The stems and leaves were far less toxic than mother and fibrous roots. In addition, the analgesia and inflammatory tests showed the effects of the various tissues had no difference each other. These results provided a basis for developing new complementary and alternative treatments for rheumatoid arthritis patients. Simultaneously, the approach may also turn wastes into treasure and promote the development of circular economy.

Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs.

BACKGROUND: Intrathecal methylprednisolone acetate (MPA) has been used in patients with chronic pain syndromes. Its safety has been debated after reports of adverse events. No systematic preclinical evaluation of MPA has been reported. In the current study, the acute and long-term effects of intrathecal MPA on dog spinal tissue was studied with the injectate reformulated to include minimal adjuvants. METHODS: Seventeen dogs were implanted with intrathecal catheters and randomized to three groups: vehicle (lidocaine; 4 dogs), MPA 20 mg/ml (human dose; 7 dogs), and MPA 80 mg/ml (maximum deliverable dose; 6 dogs). In parallel with the human protocols, dogs received four injections at 7-day intervals. Clinical observations and plasma methylprednisolone measurements were done before and at intervals after intrathecal delivery. One week (acute) or 6 weeks (long-term) after the last injection, animals were sacrificed and spinal tissues harvested for histopathology. RESULTS: Other than a brief motor block, no adverse clinical event occurred in any animal. Group A (vehicle) showed minimal histologic changes (median histology-score; acute: 1.3, long-term: 1.0). Group B (MPA 20 mg/ml) had a diffuse inflammatory reaction (acute: 2.0, long-term: 3.0), group C (MPA 80 mg/ml) a severe inflammatory response, with large inflammatory masses (acute: 4.0, long-term: 7.0) The severity of the inflammatory reaction increased significantly with increasing dose at long-term sacrifice (acute P = 0.167, long-term P = 0.014). No neuronal injury, demyelination, or gliosis was seen in any animal. CONCLUSION: These results, showing dose-dependent intrathecal inflammatory reactions at MPA doses and injectate concentrations comparable to those used in humans, indicate that the continued use of this modality in humans is not recommended.

Summary of a workshop on nonclinical and clinical immunotoxicity assessment of immunomodulatory drugs.

The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-alpha inhibitors), anti-adhesion molecule antibodies (e.g., anti-alpha-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion.

Assessment of the renal toxicity of novel anti-inflammatory compounds using cynomolgus monkey and human kidney cells.

PF1, an anti-inflammatory drug candidate, was nephrotoxic in cynomolgus monkeys in a manner that was qualitatively comparable to that observed with the two previous exploratory drug candidates (PF2and PF3). Based on the severity of nephrotoxicity, PF1 ranked between the other two compounds, withPF2 inducing mortality at all doses and PF3 eliciting only mild nephrotoxicity. To further characterize nephrotoxicity in monkeys and enable direct comparisons with humans, primary cultures of proximal tubular (PT) cells from monkey and human kidneys were used as in vitro tools, using lactate dehydrogenase release as the biomarker of cytotoxicity. In both human and monkey PT cells, PF2was by far the most cytotoxic compound of the three drugs. PF1 exhibited modest cytotoxicity at the highest concentration tested in human PT cells but none in monkey kidney cells whereas PF3 exhibited the reverse pattern.Because these drugs are organic anions, mechanistic studies using human organic anion transporters 1 and 3 (hOAT1 andhOAT3) transfected cell lines were pursued to evaluate the potential of these compounds to interact with these transporters. All three drugs exhibited high affinity for hOAT3 (PF1 exhibited the lowest IC50 of 6M) but only weakly interacted with hOAT1 (with no interaction found for PF2). PF2 was a strong hOAT3 (not hOAT1) substrate, whereas PF1 and PF3 were substrates for both hOAT1 and hOAT3.Upon pretreatment of monkeys with the OAT substrate probenecid, PF3 systemic exposure (AUC) and half-life (t1/2) increased approximately 2-fold whereas clearance (CL) and volume of distribution (Vdss) decreased, as compared to naïve monkeys. This indicated that PF3 competed with probenecid for hOAT1 and/or hOAT3mediated elimination of PF3. Thus, hOAT1 and/or hOAT3 may be responsible for the uptake of this series of drugs in renal PT cells, which may directly or indirectly lead to the observed nephrotoxicity in vivo.

Anti-inflammatory and antinociceptive activity assessment of plants used as remedy in Turkish folk medicine.

Ethanolic and aqueous extracts from seven plant species used in Turkish traditional medicine were evaluated for in vivo anti-inflammatory and antinociceptive activities; Helleborus orientalis Lam. roots and herbs, Juglans regia L. leaves, Laurocerasus officinalis Roemer leaves, Nerium oleander L. dried and fresh flowers and leaves, Rhododendron ponticum L. leaves, Rubus hirtus Walds. et Kit aerial parts and Rubus sanctus Schreber aerial parts and roots. All the plant extracts, except the aqueous extract of Rubus hirtus, were shown to possess significant antinociceptive activity in varying degrees against p-benzoquinone-induced abdominal contractions in mice. However, only the ethanolic extracts of Helleborus orientalis roots, Juglans regia leaves, Laurocerasus officinalis leaves, Nerium oleander dried and fresh flowers, and Rhododendron ponticum leaves exhibited potent anti-inflammatory activity against carrageenan-induced hind paw edema model in mice without inducing any gastric damage. Results of the present study confirmed the folkloric claim that all the selected materials to possess potent antinociceptive and anti-inflammatory activity.

Safety issues related to DMARD therapy.

The old pyramidal approach to treatment of rheumatoid arthritis depended most fundamentally upon the beliefs that the most effective agents were also the most toxic, that toxic-therapeutic ratios of different drug categories were about the same, and that one should first use the least effective and least toxic drugs. Recent data, however, demonstrate the often severe toxicity of the nonsteroidal antiinflammatory drugs and the surprisingly good safety record of certain disease modifying antirheumatic drugs. New analyses tend, in general, to support less aggressive monitoring strategies. Some of the fundamental assumptions of the old pyramidal strategy are shown to have been inaccurate.

An assessment of faecal blood loss from Ro 21-5521, a novel non-steroidal anti-inflammatory agent, in normal volunteers.

Faecal blood loss arising from Ro 21-5521, a novel non-steroidal anti-inflammatory agent with a long plasma half-life of about 41 hours, was evaluated in a double-blind crossover study against matched placebo in 12 volunteers. After a 1-week run-in period to determine baseline values, subjects were allocated at random to receive either 250 mg Ro 21-5521 per day or placebo for 2 weeks before being crossed over to the alternative treatment for 2 weeks. They were then followed-up for a further 2 weeks. Blood loss was calculated from 51Chromium tagged red blood cells in stools collected for a 96-hour period during each week of the study. Plasma levels of Ro 21-5521 were also measured twice weekly throughout the study. The results showed that with a drug of this long half-life, faecal blood loss may continue for at least 4 weeks after cessation of trial therapy of 2 weeks. It is recommended that in the evaluation of faecal blood loss resulting from drugs with a long half-life, a parallel group study, each group receiving only one drug (or one drug crossed against placebo), is the study design of choice.