Effect of the milk extract of Semecarpus anacardium nut on adjuvant arthritis—A dose-dependent study in wistar albino rats

• 1.1. Adjuvant-induced arthritis in rats is used as a pathologic model for chronic inflammatory disease to evaluate the efficacy of therapeutic agents.
• 2.2. In the present work, attempts have been made to study the potency of a milk extract of Semecarpus anacardium (Serankottai Nei), a Siddha preparation from Semecarpus anacardium nut, which has been shown to have antiarthritic effects.
• 3.3. Experimental arthritis induces a significant modification in lysosomal enzyme release and total carbohydrate components of glycoprotein.
• 4.4. Milk extract was administered at the dose level of 50, 100, 150, 200, and 250 mg/kg body weight in olive oil orally (volume 0.5 ml) after 14 days from the day of adjuvant injection.
• 5.5. After administration of the extract the lysosomal enzyme activity and protein-bound carbohydrate component levels were significantly normalized.
• 6.6. The data obtained clearly indicate that the Semecarpus anacardium is effective at the dose level of 150 mg/kg body weight in adjuvant-induced arthritis in albino Wistar rats.

     

Aggravation of adjuvant arthritis by carrageenan

• 1.1. We have studied the optimum conditions for the induction of adjuvant carrageenan-induced inflammation (ACII) in male Wistar rats with limited susceptibility to adjuvant arthritis (AA).
• 2.2. ACII was induced by intradermal injection of Freund's complete adjuvant (CFA), containing 10 mg/ml Mycobacterium tuberculosis, followed by a subplantar inoculation of the nonspecific inflammatory stimulus carrageenan at different times.
• 3.3. Data obtained indicate that the arthritis of rats inoculated with CFA is significantly increased by carrageenan, particularly when it is injected 14 days after the adjuvant. Arthritis enhancement was more evident in the joints of the leg that had been previously injected with carrageenan, and remained stable around the peak level for some weeks. The development of joint inflammation was associated histologically with the appearance of inflammatory cells in the synovial membrane of those animals.
• 4.4. We found that the injection of carrageenan aggravated the course of AA in general, but very significantly when administered at the moment of the appearance of arthritis (day + 14). This aggravation affected both the intensity of inflammation and the chronicity of the disease.

     

Preventive and curative effects of Artemisia absinthium on acetaminophen and CCl4-induced hepatotoxicity

• 1.1. Effect of aqueous-methanolic extract of Artemisia absinthium (Compositae) was investigated against acetaminophen- and CCl₄-induced hepatic damage.
• 2.2. Acetaminophen produced 100% mortality at the dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 20%.
• 3.3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for two days) prevented (P < 0.01) the acetaminophen (640 mg/kg) as well as CCl₄ (1.5 ml/kg)-induced rise in serum transaminases (GOT and GPT).
• 4.4. Post-treatment with three successive doses of extract (500 mg/kg, 6 hr) restricted the hepatic damage induced by acetaminophen (P < 0.01) but CCl₄-induced hepatotoxicity was not altered (P > 0.05).
• 5.5. Plant extract (500 mg/kg) caused significant prolongation (P < 0.05) in pentobarbital (75 mg/kg)-induced sleep as well as increased strychnine-induced lethality in mice suggestive of inhibitory effect on microsomal drug metabolizing enzymes (MDME).
• 6.6. These results indicate that the crude extract of Artemisia absinthium exhibits hepatoprotective action partly through MDME inhibitory action and validates the traditional use of plant in hepatic damage.

     

Effects of vinca alkaloids on rat parotid and submandibular glands function in vivo

• 1.1. Vincristine (1 mg/kg) and vinblastine (2 mg/kg) were injected intraperitoneally into the rats, 24 hr before the experiments.
• 2.2. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and saliva was collected from vincristine-treated, vinblastine-treated and control animals using 8 mg/kg of pilocarpine as secretagogue.
• 3.3. Parotid saliva was analyzed for protein, amylase and Ca²⁺ content, and submandibular saliva for flow rate, protein and Ca²⁺ concentration.
• 4.4. Saliva from two treated groups was significantly lower (P < 0.01) in flow rate, amylase and protein content than that of control groups. Calcium level was significantly increased (P < 0.05) in treated animals.
• 5.5. It is concluded that the antisecretory effects of vinca alkaloids may be consistent with their actions on salivary cell microtubules.

     

Increased toxicity of methamphetamine in morphine-dependent mice

• 1.1. The effect of methamphetamine on morphine-dependent mice was investigated by calculating the LD₅₀ (IP), measuring motor activity, anorectic actions, and body temperature.
• 2.2. Methamphetamine was more toxic in morphine-dependent mice (LD₅₀=20.6 mg/kg) than in normal mice (LD₅₀=43.2 mg/kg).
• 3.3. Methamphetamine-induced locomotor activity was greater in morphinized than in nonmorphinized mice at doses of 2.5 and 5 mg/kg IP.
• 4.4. Methamphetamine also increased the body temperature of morphinized mice more than that of normal mice (P<0.05).
• 5.5. These findings suggest that methamphetamine is more toxic in morphine-dependent than in nondependent mice.

     

Serotonin-induced paw edema in the rat: Pharmacological profile

• 1.1. Serotonin (5-HT) induced a linear increase in paw weight in rats within 1hr of an intraplantar injection (50μ1 vol) over a concentration range of 0.005–0.2mg/ml. At the 0.2 mg/ml concentration, a 16-fold increase in paw weight was observed as compared to saline-injected controls.
• 2.2. Serotonin antagonists, such as LY53857, were the most effective antagonists of 5-HT induced paw swelling, producing near complete antagonism and an approximate ED₅₀ of 0.1 mg/kg. A mixed 5-HT/histamine antagonist, cyproheptadine, also produced a nearly complete inhibition of the 5-HT response with an approximate ED₅₀ of 1.3 mg/kg.
• 3.3. Dopamine agonists (pergolide, quinpirole), yohimbine, dexamethasone and nifedipine also produced a significant degree of antagonism of the 5-HT response.
• 4.4. Clonidine, prazocin, chlorpheniramine, cimetidine, various dopamine antagonists, imipramine, cyclosporine A, piroxicam and superoxide dismutase were all ineffective at altering the paw swelling response to 5-HT.

     

The therapeutic effect of a combination of cofpropamine,a caffeine derivative,and cyclophosphamide on the development of adjuvant arthritis of rats and collagen arthritis of mice

• 1.1. Cofpropamine (Cofa), a caffeine derivative that inhibits polyadenoribosylation, enhances the therapeutic effect of cyclophosphamide (CPA) in two animal models of arthritis.
• 2.2. The development of adjuvant arthritis of rats is reduced by treatment with 2 × 50 mg/kg IP CPA and 2 × 50 mg/kg IP Cofa.
• 3.3. The development of collagen arthritis in mice is prevented by treatment with 12.5 mg/kg IP CPA and 150 mg/kg IP Cofa three times per week.

     

Selective protective effect of an extract from Fumaria parviflora on paracetamol-induced hepatotoxicity

• 1.1. The hepatoprotective activity of an aqueous-methanolic extract of Fumaria parviflora was investigated against paracetamol- and CCl₄-induced hepatic damage.
• 2.2. Paracetamol (1 g/kg; orally) produced 100% mortality in mice; pretreatment of animals with the plant extract (500 mg/kg; orally) reduced the death rate to 50%.
• 3.3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for 2 days) prevented (P<0.001) the paracetamol (640 mg/kg)-induced rise in serum enzymes alkaline phosphatase (ALP) and transaminases (GOT and GPT), whereas the same dose of the extract was unable to prevent (P>0.05) the CCl₄-induced rise in serum enzyme levels.
• 4.4. Posttreatment with 3 successive doses of the extract (500 mg/kg, 6 hourly) also restricted the paracetamol-induced hepatic damage.
• 5.5. The plant extract (500 mg/kg; orally) caused significant prolongation in pentobarbital (75 mg/ kg)-induced sleep as well as increased strychnine-induced lethality in mice (P<0.05), suggestive of an inhibitory effect on microsomal drug metabolizing enzymes (MDME).
• 6.6. It is conceivable therefore, that Fumaria parviflora extract exhibits a selective protective effect against paracetamol-induced hepatotoxicity, probably mediated through MDME inhibition.

     

3-(3-Hydroxyphenyl)-N-(1-Propyl)piperidine elicits convulsant effects in mice

• 1.1. The behaviour and EEG effects of the dopamine and sigma (σ) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice.
• 2.2. (+) 3-PPP dose-dependently (60–100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures.
• 3.3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.).
• 4.4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

     

Direct inhibition by taurine of the ATP-sensitive K+ channel in guinea pig ventricular cardiomyocytes

• 1.1. Effects of taurine on the ATP-sensitive K⁺ channel in isolated guinea pig ventricular cardiomyocytes were examined using an inside-out patch voltage-clamp mode. All experiments were performed at 36°C.
• 2.2. The ATP-sensitive K⁺ channel was activated outwardly. ATP-free and 140 mM K⁺ solution in the bath and 140 mM K⁺ in the pipette solution were used. The amplitude was 2.2 ± 0.3 pA (n=9) at + 50 mV. The channel conductance was 31 ± 3 pS (n=9). Glibenclamide (1 μM) blocked the channel opening.
• 3.3. Taurine decreased the open probability (as a mean patch current for 30 sec) of the channel by 21.5 ± 2.4% (n = 8, P< 0.01) at 10 mM, and almost blocked it (n = 8, P< 0.001) at 20 mM.
• 4.4. Taurine did not affect the channel conductance; these responses were reversible.
• 5.5. These results suggest that taurine directly modulates the open probability of the ATP-sensitive K⁺ channel, resulting in regulation of the cell functions.

     

Sodium nonivamide acetate: A non-pungently antinociceptive capsaicin derivative with unusual anti-inflammatory properties

• 1.1. Bradykinin-induced vascular pain in conscious rats, hyperalgesia in the rat hind paw, rat hind paw edema induced by compound 48/80 and carrageenin and dye exudation induced by intraperitoneal injection of 0.7% acetic acid in mice were all inhibited by sodium nonivamide acetate (SNA).
• 2.2. Collagen and arachidonic acid-induced rabbit platelet aggregations were inhibited by SNA and capsaicin. In human platelet microsomes, prostaglandin E₂ formation in arachidonic acid metabolite was not inhibited by SNA but was inhibited by capsaicin and indomethacin; thromboxane B₂ formation and its synthetase activity were inhibited by SNA and capsaicin.
• 3.3. In the extracellular recording, SNA could not decrease the action potential amplitude of the vagus nerve.
• 4.4. The motor activity of mice induced by caffeine (1.0 mg/kg) was inhibited by SNA and capsaicin.

     

Critical insights into the beneficial and protective actions of the kallikrein–kinin system

Hypertension is characterized by an imbalance between the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II AT-1 receptor antagonists (also known as sartans or ARBs) are potent modulators of these systems and are highly effective as first-line treatments for hypertension, diabetic nephropathies, and diseases of the brain and coronary arteries. However, these agents are mechanistically distinct and should not be considered interchangeable. In this mini-review, we provide novel insights into the often neglected roles of the KKS in the beneficial, protective, and reparative actions of ACEIs. Indeed, ACEIs are the only antihypertensive drugs that properly reduce the imbalance between the RAS and the KKS, thereby restoring optimal cardiovascular homeostasis and significantly reducing morbidity and the risk of all-cause mortality among individuals affected by hypertension and other cardiovascular diseases.Synopsis and bullet points

• •Hypertension, a disease derived from an imbalance between two endogenous systems, the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS)
• •Effective mediators of these two systems include the octapeptide angiotensin II (Ang II) and the nonapeptide bradykinin (BK)
• •Disease pathology involves an increase in peripheral resistance (↑PVR), an increase in cardiac output (↑CO), hypertrophy of the heart and peripheral vessels, and nephropathies.
• •Preventive measures include a healthy diet, regular exercise, smoking cessation, and limiting salt and alcohol consumption.
• •Rational therapy consists of drugs that aim not only to reduce blood pressure (BP) but also to decrease morbidity and mortality.
• •The goal of therapy is to inhibit the RAS and potentiate the KKS, both of which can be achieved with ACE Inhibitors (ACEIs), thereby restoring optimal cardiovascular homeostasis.

     

The effect of topical CCNU(1-(2-Chloroethyl)-3 cyclohexyl 1 nitrosurea) treatment on lipid peroxidation of glial tumours transplanted on rat brain

• 1.1. The effect of topical CCNU treatment on lipid peroxidation of glial tumors transplanted on rat brain has been investigated in 22 rats.
• 2.2. Four groups have been selected as normal brain tissue, normal brain tissue + CCNU, tumour tissue, tumour tissue + CCNU. In these groups malondialdehyde (MDA) levels have been measured as a marker of lipid peroxidation.
• 3.3. Lipid peroxidation was high in tumour tissue in respect to controls (P < 0.05). In normal tissues topical CCNU treatment caused increase in lipid peroxidation (P < 0.05). In tumor tissues, topical CCNU decreased lipid peroxidation (P < 0.05). It is concluded that further studies have to be performed in order to determine whether increases in lipid peroxidation on CCNU treated normal brain tissues is a result of the inhibitory effect on cellular defence systems or promotion of free radical production.

     

Some pharmacologic and toxicologic studies on rhazya stricta decne in rats,mice and rabbits

• 1.1. This work examines some in vivo and in vitro pharmacologic and toxicologic effects of extracts of Rhazya stricta, a medicinal plant in the United Arab Emirates.
• 2.2.R. stricta extracts at doses of 0.1–10 mg reduced the mean arterial blood pressure (MBP) of anesthetized rats in a dose-dependent manner. The depressor effect was partially sensitive to atropine (5 μM). Although the MBP was reduced by 50% by both doses of extracts, the normal electrocardiogram pattern and the heart rate remained unaltered.
• 3.3. Acute treatment of rats with the lyophilized extract at doses of 4 g/kg produced a significant rise in insulin concentration. In streptozotocin-diabetic rats loaded orally with glucose (1 g/kg), R. stricta at doses of 8 g/kg produced significant decreases in plasma glucose concentration at 0.5 and 1 h after treatment.
• 4.4. Chronic treatment of rats and mice for 28 days with the lyophilized extract of R. stricta did not affect the plasma glucose or insulin concentration or any of the hematological or biochemical indices measured.
• 5.5. The extracts of R. stricta (0.5–4 g/kg) dose-dependently decreased the gastrointestinal transit time in mice by 4–50%.
• 6.6. The butanolic extract of R. stricta (1 and 2 g/kg) significantly reduced the carrageenan-induced increase in raw paw edema 3 and 4 h after the extract administration.
• 7.7. The rectal temperatures of normothermic and pyrexic rats were reduced significantly 0.5 and 1 h after administration of butanolic R. stricta at doses of 1 and 2 g/kg.
• 8.8. The butanolic extract of R. stricta at doses of 1 and 2 g/kg significantly increased the reaction time on the hot plate 30 and 60 min after administration to rats.
• 9.9. At concentrations <0.05 mg/ml (bath concentration), lyophilized water and butanol extracts of R. stricta potentiated the twitch responses induced by indirect electrical stimulation in the rat phrenic nerve diaphragm preparation. The responses were inhibited by concentrations >0.05 mg/ml. Neostigmine (2 × 10⁻⁴M) did not alter these effects of the extracts.
• 10.10. R. stricta extracts dose-dependently decreased the force of contraction and heart rate of the isolated rabbit heart. Atropine (1×10⁻⁵M) had no effect on the inhibitory activity of these extracts. The lyophilized water extract (> 10 mg) and butanol extract (>5 mg) produced irreversible inhibition and disturbances in the force of contraction and heart rate.

     

Effect of piroxicam β-cyclodextrin complex on experimental inflammation

• 1.1. The effectiveness of the inclusion product of piroxicam with β-cyclodextrin was compared to that of free piroxicam on inflammatory reactions by using three experimental inflammatory models in rats.
• 2.2. The inclusion compound showed anti-inflammatory effects similar to those of simple piroxicam on granuloma tissue formation and arthritis induced by complete Freund adjuvant.
• 3.3. In carrageenin-induced pleurisy, the piroxicam β-cyclodextrin reduced leukocyte mobilization more intensely than non-complexed piroxicam.
• 4.4. These results suggest that β-cyclodextrin is a useful tool for improving the efficacy of piroxicam.

     

Studies on protective effect of Cyperus Scariosus extract on acetaminophen and CCl4-induced hepatotoxicity

• 1.1. The hepatoprotective activity of aqueous-methanolic extract of Cyperus scariosus (Cyperaceae) was investigated against acetaminophen and CCl₄-induced hepatic damage.
• 2.2. Acetaminophen produced 100% mortality at a dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 30%.
• 3.3. Acetaminophen at a dose of 640 mg/kg produced liver damage in rats as manifested by the rise in serum levels of alkaline phosphatase (ALP), glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) to 430 ± 68, 867 ± 305 and 732 ± 212 IU/1 (n = 10) respectively, compared to respective control values of 202 ± 36, 59 ± 14 and 38 ± 7.
• 4.4. Pretreatment of rats with plant extract (500 mg/kg) significantly lowered (P < 0.05) the respective serum ALP, GOT and GPT levels to 192 ± 31, 63 ± 9 and 35 ± 8.
• 5.5. The hepatotoxic dose of CCl₄ (1.5ml/kg; orally) raised serum ALP, GOT and GPT levels to 328 ± 30, 493 ± 102 and 357 ± 109 IU/1 (n = 10) respectively, compared to respective control values of 177 ± 21, 106 ± 15 and 47 ± 12.
• 6.6. The same dose of plant extract (500 mg/kg) was able to significantly prevent (P < 0.05) CCl₄-induced rise in serum enzymes and the estimated values of ALP, GOT and GPT were 220 ± 30, 207 ± 95 and 75 ± 38, respectively.
• 7.7. The plant extract also prevented CCl₄-induced prolongation in pentobarbital sleeping time confirming hepatoprotectivity.
• 8.8. These results indicate that the Cyperus scariosus possesses hepatoprotective activity and thus, rationalizes the folkloric use of this plant in hepato-biliary disorders.

     

Examination of coumarins,flavonoids and polysaccharopeptide for antibacterial activity

• 1.1. Coumarins, flavonoids and polysaccharopeptide were tested for antibacterial activity.
• 2.2. The bacteria used for this study included clinical isolates of Staphylococcus aureus, Shigella flex-neri, Salmonella typhi, Escherichia coli and Pseudomonas aeruginosa.
• 3.3. Most of the coumarins tested failed to inhibit the bacteria at 25 mg/l. Edultin at 128 mg/l inhibited 4 of the 8 P. aeruginosa strains and 1 of the S. aureus strains tested. O-acetylcolumbianetin and imperatorin did not inhibit any isolate, even at 128 mg/l.
• 4.4. When tested at the dose of 128 mg/l, the flavonoids (rutin, naringin and baicalin) inhibited 25% or less of P. aeruginosa and only baicalin was active against S. aureus.
• 5.5. Arbutin and 4-(β-D-glucopyranosyloxyl)-benzaldehyde inhibited 3 of the 8 P. aeruginosa strains when tested at 128 mg/l.
• 6.6. Polysaccharopeptide from the fungus Coriolus versicolor failed to inhibit any P. aeruginosa or S. aureus strain at 128 mg/l.

     

Effects of cisapride on ulcer formation and gastric secretion in rats: Comparison with ranitidine and omeprazol

• 1.1. The antiulcerogenic effects of cisapride, a potent benzamide-stimulating gastrointestinal motility agent, were studied on cold-restraint and pylorus-ligated gastric ulcers. Acidity, composition of gastric secretion, and quantitative and qualitative changes on mucus glycoprotein content were also determined. These effects were compared with those of ranitidine (50 mg/kg) and omeprazol (10 mg/kg).
• 2.2. Oral cisapride (10–100 mg/kg) dose-relatedly and significantly (P<0.01, P<0.05) decreased the severity of the lesions induced by cold-restraint stress. In stressed rats, cisapride increased the amount of mucus secretion and markedly enhanced the glycoprotein content. Morphometric evaluation of mucus secretion revealed a significant increase in both the PAS area (neutral glycoproteins) and Alcian blue area (sulfated glycoproteins).
• 3.3. In 4 h pyloric-ligated animals, cisapride (10–100 mg/kg) showed a significant reduction in the number and severity of ulcers (P<0.01) and histamine concentration (P<0.01, P<0.001). In addition, at the highest doses (50–100 mg/kg), cisapride produced a significant decrease in acidity; however, it did not alter the gastric volume secretion or pepsin concentrations.
• 4.4. These results suggest that cisapride shows antiulcerogenic effects which could possibly be explained through antisecretory and cytoprotective mechanisms involving an enhancement of cuality and production of gastric mucus.

     

Opposite effects of sex steroids on 11β-hydroxysteroid dehydrogenase activity in the normal and adrenalectomized rat testis

• 1.1. Sex steroids have been shown to regulate the biosynthesis of 11β-hydroxysteroid dehydrogenase (11β-HSD).
• 2.2. In vitro studies showed that oestradiol (E2) or testosterone (T) can interfere with the bioassay of enzyme activity, but not progesterone (P4).
• 3.3. For in vivo studies, the activity of 11β-HSD in the testis of normal and adrenalectomized (ADX) adult male Wistar rats was determined following a daily IM injection of sex steriods for 7 days.
• 4.4. The 11β-HSD activity was significantly reduced (P<0.01) either by E2 or T in normal and ADX rats. The enzyme activity in normal rats given both T and E2 was even lower (P<0.001) than when E2 was given alone.
• 5.5. P4 given to normal and ADX rats increased the enzyme activity higher than normal (P<0.001).
• 6.6. The presence of corticosteroids influenced the effects of E2, but not of T and P4, on 11β-HSD activity.
• 7.7. E2 and T downregulate 11β-HSD activity, whereas P4 increased it. E2 did not act through lowering T level.

     

Preclinical studies on the broad-spectrum neuropeptide growth factor antagonist G

• 1.1. Antagonist G is a broad-spectrum neuropeptide growth factor antagonist that inhibits the growth of small cell lung cancer (SCLC) cells both in vitro and in vivo.
• 2.2. Antagonist G is metabolized in peripheral tissues by a chymotrypsin-like serine carboxypeptidase causing C-terminal deamidation and removal of the methionine residue.
• 3.3. The metabolites of Antagonist G retain neuropeptide antagonist properties and are thought to contribute to the parent peptide's antitumor activity.
• 4.4. Pharmacokinetic studies following systemic (IP) administration to nude mice revealed that the tissue distribution of Antagonist G is likely to be determined by vascular permeability.
• 5.5. Preclinical toxicology studies have been completed, and we have now started a phase I clinical trial.