Effect of 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide isolated from the roots of Withania somnifera on stress indices in Wistar rats

OBJECTIVE: Isolation of biologically active fractions and compounds from the roots of Withania somnifera, a plant used extensively as a constituent of rasayana, in Ayurveda and to test their adaptogenic activity on stress indices using the cold-hypoxia-restraint (C-H-R) model. DESIGN: Bioactivity-guided fractionation of an aqueous extract of the roots of Withania somnifera led to the isolation of a new species of withanolide 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide. Structure elucidation, was carried out using proton nuclear magnetic resonance, infrared (IR), ultraviolet (UV), and mass spectroscopic analysis. Stress-related indices were evaluated, namely serum creatine phosphokinase (CPK) activity, serum lactate dehydrogenase (LDH) activity, serum corticosterone levels, and serum lipid peroxidation (LPO) levels. RESULTS: There was a significant decrease in a serum CPK, LDH, and LPO levels in animals pretreated with (1) fraction-I (20 mg/kg body weight), (2) 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (2.5 mg/kg body weight) in comparison to control when subjected to C-H-R stress. CONCLUSIONS: The results show that the a new species of withanolide, 1-oxo-5beta, 6beta-epoxy-witha-2-ene-27-ethoxy-olide (compound-1) could prove to be an effective agent to counteract C-H-R stress.     

The effect of diminazene,an angiotensin-converting enzyme 2 activator,on adenine-induced chronic kidney disease in rats

The present study investigated the effect of diminazene, lisinopril, or valsartan on adenine-induced chronic kidney disease (CKD) in rats. The animals were divided into five groups (n = 6). The first and second groups received normal diet and adenine in the feed at a dose of 0.25% w/w for 35 days, respectively. The third, fourth, and fifth groups were treated as the second group but also received diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), and valsartan (30 mg/kg/day), respectively, for 35 days. Adenine significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), calcium, phosphorus, and uric acid. In addition, adenine increased urinary albumin/creatinine ratio and N-Acetyl-β-D-glucosaminidase (NAG)/creatinine ratio and reduced creatinine clearance. Adenine also significantly increased the plasma concentrations of inflammatory cytokines (plasma tumor necrosis factor–alpha [TNF-α] and interleukin-1beta [IL-1β]) and significantly reduced antioxidant indices (catalase, glutathione reductase [GR], and superoxide dismutase [SOD]). Histopathologically, renal tissue from adenine-treated rats showed necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. All drugs ameliorated adenine-induced biochemical and histopathological changes. The protective effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Our results show that administration of diminazene, lisinopril, or valsartan had a comparable effect on the reversal of the biochemical and histopathological indices of adenine-induced CKD in rats.     

N‐feruloylserotonin in preventive combination therapy with methotrexate reduced inflammation in adjuvant arthritis

Many of disease‐modifying anti‐rheumatic drugs often have side effects at high doses and/or during long‐term administration. Increased efficacy without increased toxicity is expected for combination therapy of rheumatoid arthritis (RA). The aim of the study was to examine the effect of N‐feruloylserotonin (N‐f‐5HT) and methotrexate (MTX) in monotherapy and in combination therapy on disease progression and inflammation in arthritic rats. Adjuvant arthritis was induced by intradermal injection of Mycobacterium butyricum in incomplete Freund′s adjuvant in Lewis rats. The experiment included healthy animals, arthritic animals without any drug administration, arthritic animals with administration of N‐f‐5HT in the oral daily dose of 15 mg/kg b.w., arthritic animals with administration of MTX in the oral dose of 0.3 mg/kg b.w. twice a week and arthritic animals treated with the combination of N‐f‐5HT and MTX. N‐f‐5HT in monotherapy reduced only activation of NF‐κB and did not have any significant effect on other parameters monitored. Low‐dose treatment of MTX decreased the level of IL‐1β and MCP‐1 on day 14 and activation of NF‐κB in liver without significant effect on other parameters. N‐f‐5HT and MTX combination showed both the anti‐arthritic (hind paw volume and arthritic score) and anti‐inflammatory effect (plasmatic levels of IL‐1β, IL‐17, MCP‐1, CRP, and activation of NF‐κB in liver). In combination with MTX, N‐f‐5HT markedly potentiated the therapeutic effect of MTX low dose, which resulted in significant improvement of all parameters measured. The findings showed that the combination therapy simultaneously decreased multiple markers of inflammation, a result crucial for future therapy of RA.     

Effects of simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination on the inflammatory process and on the liver metabolic changes of arthritic rats

In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low‐dose adjuvant‐induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 μg) in mineral oil [complete Freund’s adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin_40mg/kg, atorvastatin_10mg/kg, ezetimibe_10mg/kg, ezetimibe_10mg/kg + simvastatin_{20mg/kg or 40mg/kg} were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol‐independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe_10mg/kg + simvastatin_40mg/kg combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.     

Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.     

Urinary N-acetyl-beta-D-glucosaminidase as a marker of renal injury in adjuvant arthritis

In the present study we have determined if renal damage occurs with adjuvant arthritis (AA). As a sensitive indicator of renal injury in tubular cells, urinary N-acetyl-beta-D-glucosaminidase (NAG) was measured at predetermined times after arthritis induction. Urinary protein, sodium and potassium excretion were also evaluated. NAG levels in arthritic animals were higher than those in healthy ones from day 12 after induction and the levels remained high during the study period. A significant positive correlation was noted between urinary NAG excretion and disease severity reflected by hind paw edema. Protein excretion also increased in arthritic animals but there was no correlation between urinary protein, NAG levels, and degree of inflammation. Changes in urine sodium and potassium levels did not reach statistical significance. Thus, we can conclude that some renal damage occurred in this experimental model of chronic inflammation.     

Protective effect of taurine against alendronate-induced gastric damage in rats

Alendronate (ALD) causes serious gastrointestinal adverse effects. The aim of this study was to investigate whether taurine (TAU), a semi-essential amino acid and an antioxidant, improves the alendronate-induced gastric injury. Rats were administered 20 mg/kg ALD by gavage for 4 days, either alone or following treatment with TAU (50 mg/kg, i.p.). On the last day of treatment, following drug administration, pylorus ligation was performed and 2 h later, rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation and glutathione (GSH) levels, myeloperoxidase (MPO) activity as well as the histologic appearance of the stomach tissues were determined. Chronic oral administration of ALD induced significant gastric damage, increasing lipid peroxidation, MPO activity and collagen content, as well as decreasing tissue GSH levels. Treatment with TAU prevented the damage and also the changes in biochemical parameters. Findings of the present study suggest that ALD induces oxidative gastric damage by a local irritant effect, and that TAU ameliorates this damage by its antioxidant and/or membrane-stabilizing effects.     

Efficiency of combined methotrexate/chloroquine therapy in adjuvant-induced arthritis

The present study evaluates the effects of methotrexate (MTX) and chloroquine (CQ), and of combined MTX + CQ treatment, on the inflammatory response and on plasma and liver phosphatase and transaminase activities, employing an adjuvant-induced arthritis model in rats. Arthritis was induced by the intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil into the plantar surface of the hind paws. Development of the inflammatory response was assessed over a 21-day period. Animal groups received either: (i) MTX, administered i.p., weekly, in 0.15, 1.5, 3, 6 or 12 mg/kg doses; (ii) CQ, given intragastrically, in daily 25 or 50 mg/kg doses; or (iii) MTX + CQ, administered in two combinations (MTX1.5 mg/kg + CQ50 mg/kg, or MTX6 mg/kg + CQ50 mg/kg). At the end of the experimental period, the animals were anesthetized and killed, blood and liver samples were collected and prepared for measurement of acid and alkaline phosphatase (AP, ALP), and aspartate (AST) and alanine aminotransferase (ALT) activities. MTX at 6 and 12 mg/kg reduced the inflammatory response while CQ had no effect. MTX6 mg/kg + CQ50 mg/kg reduced the inflammatory response similar to MTX12 mg/kg, without affecting the bone marrow. Plasma AP and liver ALP activities were very elevated in the arthritic rats. While MTX treatment partially reduced both plasma AP and liver ALP activities at all doses used in the arthritic rats, CQ treatment reduced plasma AP, but increased liver AP activity. MTX + CQ treatment decreased plasma AP and liver ALP activities in the arthritic rats to control values. Plasma and liver AST activities were unaltered in the arthritic rats, and were unaffected by treatment. However, plasma and liver ALT activities were significantly reduced in the arthritic rats. While MTX or CQ treatment did not alter plasma transaminase activity in the arthritic rats, after MTX + CQ treatment, plasma ALT activity returned to normal values. In conclusion, the present data suggest that MTX + CQ treatment provides more effective anti-inflammatory protection against adjuvant-induced arthritis than does MTX alone, reverting the alterations in enzyme activities induced by this inflammatory disease in rats.     

Anti-inflammatory activity of BF389, a Di-T-butylphenol, in animal models of arthritis.

Biofor 389 (BF389), dihydro-4-[[3,5-bis(1,1-dimethyl)-4-hydroxyphenyl] methylene]-2-methyl-2H-1,2-oxazin-3(4H)-one, was tested for anti-inflammatory activity in various animal models of arthritis. Initial evaluation in the lipoidalamine (LA) arthritis model in rats (5-day dosing protocol) resulted in an oral ED50 of 4.9 mg/kg for inhibition of paw swelling. No effects on splenomegaly were observed, suggesting that the compound was efficacious as a result of anti-inflammatory rather than immunomodulatory effects. BF389 was efficacious in interleukin 1 (IL-1)-enhanced type II collagen arthritis in rats (oral ED50 less than 1.0 mg/kg) as assessed by paw volume measurement and histologic evaluation of joints. Mice with IL-1-enhanced type II collagen arthritis given 30 mg/kg of BF 389 had significantly lower histological scores for joint damage than did untreated controls. Normal rats given single oral doses of BF389 had significant suppression of arachidonate-stimulated whole blood prostaglandin E2 and thromboxane B2 production 2 hr postdosing (ED50 = 0.1 mg/kg). Leukotriene B4 production in these animals was not decreased. After it became apparent that the compound was a potent inhibitor of prostaglandin production in vivo, a study was done to compare the efficacy and toxicity of BF389 with several currently marketed nonsteroidal anti-inflammatory drugs, piroxicam, naproxen and diclofenac. Lipoidalamine-injected rats were given daily oral doses of BF389 or the comparators for 21 days. Quantitation of effects on arthritis on day 21 resulted in ED50 values of 0.9 mg/kg (BF389), 3.9 mg/kg (naproxen), 4.9 mg/kg (diclofenac) and 0.6 mg/kg (piroxicam).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chloramphenicol, gentamicin, and ciprofloxacin against murine scrub typhus.

Ciprofloxacin (120 mg/kg of body weight per day), chloramphenicol (300 mg/kg per day), and gentamicin (30 mg/kg per day) were compared with placebo in a BALB/cj mouse model of scrub typhus. All animals treated with ciprofloxacin and chloramphenicol survived. All animals treated with gentamicin or placebo died. All surviving animals showed evidence of seroconversion. Ciprofloxacin and chloramphenicol were statistically more effective in preventing death than gentamicin or placebo.     

Asparagus root regulates cholesterol metabolism and improves antioxidant status in hypercholesteremic rats

Hyperlipidemia/hypercholesteremia are major risk factors for atherosclerosis and cardiovascular diseases. Root of Asparagus racemosus (AR) is widely used in Ayurvedic system of medicine in India and is known for its steroidal saponin content. This study was designed to investigate the hypocholesteremic and antioxidant potential of AR root in both normo- and hypercholesteremic animals. Normal and hypercholesteremic male albino rats were administered with root powder of AR (5 and 10 g% dose levels) along with normal and hypercholesteremic diets, respectively, for a duration of 4 weeks. Plasma and hepatic lipid profiles, fecal sterol, bile acid excretion and hepatic antioxidant activity were assessed. Inclusion of AR root powder in diet, resulted in a dose-dependant reduction in plasma and hepatic lipid profiles, increased fecal excretion of cholesterol, neutral sterol and bile acid along with increases in hepatic HMG-CoA reductase activity and bile acid content in hypercholesteremic rats. Further, AR root also improved the hepatic antioxidant status (catalase, SOD and ascorbic acid levels). No significant changes in lipid and antioxidant profiles occurred in the normocholesteremic rats administered with AR root powder. AR root appeared to be useful as a dietary supplement that offers a protection against hyperlipidemia/hypercholesteremia in hypercholesteremic animals. The results of the present study indicate that the potent therapeutic phyto-components present in AR root i.e. phytosterols, saponins, polyphenols, flavonoids and ascorbic acid, could be responsible for increased bile acid production, elimination of excess cholesterol and elevation of hepatic antioxidant status in hypercholesteremic conditions.     

In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin E's may be significant physiological modulators of the renal response to vasopressin.     

In Vivo Studies with Ambruticin in Murine Histoplasmosis

Ambruticin (W7783) was evaluated in vivo in mice subacutely or nonlethally infected with Histoplasma capsulatum. Results were compared with those obtained with amphotericin B, the drug of choice in human histoplasmosis. In one experiment, ambruticin was shown to be capable of curing infected animals as evidenced by totally negative liver and spleen cultures obtained when mice were sacrificed after 4 weeks of oral treatment with 150 mg of drug per kg per day. The 50% cure dose for ambruticin was between 75 and 150 mg/kg per day; the 50% cure dose for oral amphotericin B in this experiment was between 1.56 and 6.25 mg/kg per day. In a second experiment, both oral ambruticin (150 mg/kg per day) and oral amphotericin B (25 mg/kg per day) were again curative, but to a lesser degree than in the first experiment. Biological cures were obtained with both drugs after 3 and 4 weeks of treatment but not after 2 weeks.     

Polyaspartic acid protects against gentamicin nephrotoxicity in the rat

Polyamino acids including polyaspartic acid (PAA) have been reported to provide protection against the development of aminoglycoside-induced nephrotoxicity in the rat as assessed by histopathology scoring. We sought to confirm and extend these observations by determining whether PAA also prevented functional and biochemical lesions of gentamicin-nephrotoxicity in an animal model studied extensively in our laboratory. Rats were given injections of: 1) 0.9% NaCl at 2.5 ml/kg b.wt. per day; 2) PAA (mol.wt. 15,000) at 500 mg/kg per day; 3) gentamicin at 100 mg/kg per day or 4) gentamicin at 100 mg/kg per day and PAA at 500 mg/kg per day for 6 days. Rats injected with gentamicin exhibited: 1) increased urinary excretion of the brush border membrane enzyme alanine aminopeptidase and the lysosomal enzyme N-acetyl-beta-d-glucosaminidase after the first injection; 2) increased total phospholipid and malondialdehyde but decreased catalase activity in the renal cortex; 3) elevation of serum creatinine and depression of creatinine clearance and 4) extensive proximal tubular cell necrosis all determined 24 hr after the last injection of gentamicin. Rats injected with gentamicin plus PAA also exhibited increased urinary excretion of alanine aminopeptidase not different in magnitude from that of rats injected with gentamicin alone, whereas N-acetyl-beta-d-glucosaminidase rose more slowly and returned to base line by day 4. Total renal cortical phospholipid was elevated to the same extent in the two groups. Malondialdehyde was not different from control and catalase activity was significantly less depressed in rats injected with gentamicin plus PAA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P >0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.     

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Renal hemodynamics increase dramatically during pregnancy, and pressor responsiveness to exogenous administration of vasoconstrictors is attenuated. We investigated whether or not vasodilatory prostaglandins mediate these phenomena. Trained, chronically instrumented, conscious pregnant rats were used. Control values of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated at midgestation (P less than 0.01 and P = 0.05 from prepregnant means, respectively), and effective renal vascular resistance was decreased (P = 0.05). Indomethacin (4.5-6.5 mg/kg body weight [BW]) failed to decrease renal hemodynamics at this stage of pregnancy; in fact, it raised GFR somewhat further (P less than 0.05). Systemic pressor responsiveness to bolus administration of norepinephrine and angiotensin II (AII) was significantly attenuated by at least gestational day 20. Neither indomethacin (7 mg/kg BW) or meclofenamate (6 mg/kg BW) affected the refractory response. The renal vasculature was also relatively unresponsive to an intravenous infusion of AII (5 ng X kg-1 X min-1) during late gestation (day 19); in particular, the fall in ERPF in response to AII (16 +/- 3%) was markedly less than that observed in the prepregnant condition (34 +/- 3%; P less than 0.05). Indomethacin (6 mg/kg BW) failed to restore this blunted response, and further attenuation was evident, despite the presence of the inhibitor (gestational day 21). We conclude that vasodilatory prostaglandins do not appear to mediate the rise in renal hemodynamics, and the attenuation of the systemic and renal pressor responsiveness observed during pregnancy, insofar as these phenomena were unaffected by acute cyclooxygenase inhibition in unstressed, conscious rats.     

Efficacy of PLD-118, a novel inhibitor of candida isoleucyl-tRNA synthetase, against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant C. albicans

PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring beta-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant Candida albicans in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 microg/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P 相似文献   

Divergent effects of suramin on in vitro and in vivo assays of cartilage degradation

Proteinases are thought to be responsible for cartilage and bone erosion noted in chronic inflammatory conditions. Suramin [8-(3-benzamindo-4-meta-1-benzamindo)naphthalene-1,3,5-trisulfonic acid], 10(-5) and 10(-4) M, inhibited the release of a mouse macrophage-derived cartilage proteoglycan-degrading enzyme. At 10(-5) M it antagonized the activity of beta-glucuronidase and cathepsin D derived from the mouse macrophage, as well as similar enzymes secreted by rat macrophages in vivo. When cultured at 10(-4) M with rabbit knee cartilage, it antagonized the autolytic release of proteoglycan, indicating an inhibitory activity against a chondrocyte-derived neutral proteinase. After in vivo treatment at 10 mg/kg/day s.c., it was ineffective in preventing the cartilage and bone erosion noted in the adjuvant arthritic rat.     

Atorvastatin attenuates testosterone‐induced benign prostatic hyperplasia in rats: role of peroxisome proliferator‐activated receptor‐γ and cyclo‐oxygenase‐2

Diabetes and obesity have been reported to alter sex steroid hormone metabolism. In this study, an attempt was made to investigate the protective effect of atorvastatin (ATR) in combination with celecoxib (CEL) or pioglitazone (PIO) on testosterone‐induced BPH in rats. Male Wistar rats (200–250 g) were randomly divided into nine groups (n = 8) and orally treated as follows for 28 consecutive days: group 1: vehicle control (10 mL/kg); group 2: vehicle testosterone (10 mL/kg); groups 3 ‐ 5: ATR (0.5, 2.5, and 5 mg/kg, respectively); group 6: CEL (20 mg/kg); group 7: PIO (20 mg/kg); and groups 8–9: ATR 0.5 mg/kg, and 15 min later, animals were given CEL (20 mg/kg) or PIO (20 mg/kg), respectively. One hour post‐treatment, animals in groups 2–9 were given testosterone propionate (3 mg/kg, s.c.). Twenty‐four hours after last treatment on day 28, blood was collected for serum testosterone and prostate‐specific antigen (PSA) analysis. Prostate was harvested for biochemical and histological assays. Subcutaneous injection of testosterone increased serum levels of testosterone and PSA which was ameliorated by pretreatments of rat with ATR, celecoxib, or pioglitazone. Similarly, testosterone‐induced increase in MDA and reduction in the activity of GSH, superoxide dismutase (SOD), and catalase were attenuated by ATR. Conversely, celecoxib or pioglitazone treatment failed to affect the activity of antioxidant enzymes. The histology of the prostate showed significant improvement in prostatic cells of ATR, celecoxib, or pioglitazone treated. Findings from the study showed that atorvastatin attenuated testosterone‐induced BPH. Moreover, synergistic effect was observed when atorvastatin was combined with celecoxib.     

Therapy of experimental murine brucellosis with streptomycin alone and in combination with ciprofloxacin, doxycycline, and rifampin.

The in vivo efficacy of streptomycin (STR), doxycycline (DOX), rifampin (RIF), ciprofloxacin (CIP), and their combinations was evaluated for a Brucella melitensis experimental infection in a mouse model. Animals were infected with 2 x 10(4) to 4 x 10(4) CFU of B. melitensis intraperitoneally on day 0 and were randomized to receive, starting on day 7, STR alone at 75, 150, or 300 mg/kg of body weight per day intraperitoneally or DOX at 6 mg/kg/day orally, RIF at 3 mg/kg/day orally, or CIP at 200 mg/kg/day orally, each of the last three drugs alone or in combination with STR at 75, 150, or 300 mg/kg/day, for 14 days. Therapy failure (defined as nonsterile spleens) was observed in all animals treated with STR at all doses and with CIP given as monotherapy. Mean log CFU isolated from the spleens remaining infected following monotherapy with STR or CIP were not different from those in control mice. RIF at a low dose did not have an effect on cure rates; however, a reduction in CFU relative to the CFU in untreated animals was obtained. DOX at low levels achieved a 35% cure rate and a reduction in CFU in animals not cured. All animals treated with DOX or RIF combined with any STR dose were cured, but none of the animals receiving the STR-CIP combinations was cured, and the splenic CFU remained similar to those in the controls. These results demonstrate that the combinations DOX-STR and RIF-STR are synergistic against B. melitensis, while the combination STR-CIP is indifferent and ineffective in the management of acute murine brucellosis. The results also appear to support the clinical superiority of combination drug therapy over monotherapy.