TamaFlex™-A novel nutraceutical blend improves lameness and joint functions in working horses.

BACKGROUND: Lameness is one of the major causes of reduced physical performance and early retirement in working horses. TamaFlex™ (NXT15906F6) is a standardized synergistic anti-inflammatory botanical formulation containing Tamarindus indica seed extract and Curcuma longa rhizome extract at a 2:1 ratio. METHODS: We conducted a 12-week single-center, randomized, blinded, placebo-controlled trial demonstrating the efficacy of NXT15906F6 in horses with lameness grade 2-4 on the American Association of Equine Practitioners (AAEP) scale. Twenty-two lame horses were supplemented with NXT15906F6 (2.5 gram/day) or placebo over a period of 84 days. Improvement in lameness over placebo was the primary endpoint, and changes in the levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and anti-cyclic citrullinated peptide (ACC-peptide) in serum, and pro-inflammatory cytokines including interleukin (IL-1ß and IL-6), tumor necrosis factor-α (TNF-α) and prostaglandin-E2 (PGE2 ) in serum and synovial fluid were the secondary endpoints. RESULTS: NXT15906F6 exhibited significant relief from lameness in a time-dependent manner. NXT15906F6 also reduced levels of ANA, PGE2 , IL-1ß, TNF-α and IL-6. Moreover, NXT15906F6 supplementation is safe and tolerable in alleviating joint pain in lame horses, and protects the joints from further degradation by reducing pro-inflammatory mediators. CONCLUSION: NXT15906F6 significantly reduces the lameness during walking and trotting, leading to an improvement in their joint flexibility, health, and working performances.

Plasma renin, aldosterone, and urinary prostaglandin E2 levels in children with hypocalcemia due to vitamin D deficiency rickets.

We investigated the effect of hypocalcemia on plasma renin, aldosterone, and urine PGE2 levels in children with vitamin D deficiency rickets (VDDR). In the study group, 25 patients with VDDR-induced hypocalcemia were treated with a single dose of 150,000-300,000 IU cholecalciferol and 50 mg/kg/day elemental Ca for 10 days. On any day between 21th and 30th days after the treatment, the patients' clinical, biochemical and radiologic findings were re-evaluated. The healthy children with the same sex and similar age as the study group comprised the control group. Plasma sodium (Na), potassium (K), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25- hydroxy vitamin D (25OHD), renin, aldosterone; and urinary Ca, creatinine (Cr) and prostaglandin E2 (PGE2) levels were measured in both the study (pre-treatment and post-treatment) and the control group. Plasma Ca, P, 25OHD and renin levels and urinary PGE2/Cr ratio in the post-treatment group were significantly higher than those in the pre-treatment group while K, ALP, and PTH concentrations were significantly lower. Plasma ALP and PTH levels in pre-treatment group were significantly higher than in the control group while Ca, P, 25OHD, aldosterone and renin concentrations and urinary PGE2/Cr ratio were significantly lower. Post-treatment plasma Ca level was significantly decreased in normal limits compared to the control group while other biochemical parameters were not different from the control group. Plasma Ca concentration was positively correlated with renin level and urinary PGE2/Cr ratio. The findings suggest that hypocalcemia may inhibit the production of renin, aldosterone and PGE2 and a blunt aldosterone secretion may develop even after recovery from hypocalcemia.

Citric Acid-Enriched Extract of Ripe Prunus mume (Siebold) Siebold & Zucc. Induces Laxative Effects by Regulating the Expression of Aquaporin 3 and Prostaglandin E2 in Rats with Loperamide-Induced Constipation.

Previously, we demonstrated that extracts of the ripe fruit (rPM) and unripe fruit (uPM) of Prunus mume (Siebold) Siebold & Zucc. and citric acid have a laxative effect, which is at least partially mediated by the increase in fecal parameters as seen in the low-fiber diet-induced constipation model rats. This study aims at investigating the laxative effects of citric acid-enriched aqueous extracts of rPM, uPM, and its active compounds, such as citric acid and malic acid, on loperamide-induced constipation rat models. Animal studies were conducted with loperamide-induced constipation animal models. The results showed that rPM and citric acid, the major organic acid compounds, significantly improved stool parameters (number, weight, and water content of the stools) generated in loperamide-induced constipation rats, without adverse effects of diarrhea. The gastrointestinal (GI) motility was activated fully in the rPM- and citric acid-treated rats than in rats treaded with loperamide alone. In addition, when rPM and citric acid were added to RAW264.7 cells and used to treat loperamide-induced constipation model rats, the secretion of prostaglandin E2 (PGE2) increased significantly in cells and tissue. Furthermore, rPM and citric acid decreased the expression of the aquaporin 3 (AQP3) in the rat colons. Our results demonstrated that rPM and citric acid, the major organic acid compound in rPM, can effectively promote defecation frequency and regulate PGE2 secretion and AQP3 expression in the colon, providing scientific evidence to support the use of rPM as a therapeutic application.

Vasodilating prostaglandins attenuate ischemic renal injury only if thromboxane is inhibited.

Ischemia-induced renal injury is prevented by inhibition of thromboxane (Tx) synthesis. This protection was believed to be secondary to a high prostaglandin (PG)/TxA2 ratio. This study tests whether increasing the PG/Tx ratio by administration of vasodilating PGs protects the reperfused ischemic kidney. Anesthetized rats underwent right nephrectomy and 45 minutes of left renal pedicle clamping. Beginning 10 minutes before clamp release, animals were treated intravenously with the following: saline placebo (n = 10); the cyclooxygenase inhibitor ibuprofen (Ibu), 12.5 mg/Kg in a bolus (n = 8); a stable analogue of prostacyclin (PGI2), 500 ng/kg/minute for 2 hours (n = 9); PGE1, 400 ng/kg/minute for 2 hours (n = 8); the combination Ibu and PGI2 (n = 8) or PGE1 (n = 8). In saline treated ischemic controls, 5 minutes after reperfusion plasma, thromboxane (TxB2) and 6-keto-PGF1 levels were 2537 and 317 pg/ml, respectively--higher than the TxB2 and 6-keto-PGF1 levels of 750 and 80 pg/ml, respectively, in nephrectomized but nonischemic sham controls (n = 7) (p less than 0.05). In ischemic control animals at 24 hours, creatinine levels were 4.6 mg/dl, relative to 0.9 ml/dl in sham animals (p less than 0.05); the weight of the left (L) ischemic kidney relative to the right (R) normal kidney was 118%, compared with 99% in sham animals (p less than 0.05); and renal histology of ischemic control animals at 24 hours showed acute tubular necrosis (ATN) relative to normal findings in sham animals. Pretreatment with Ibu led to: TxB2 and 6-keto-PGF1 levels of 116 and 40 pg/ml, lower than those of sham animals (p less than 0.05); creatinine levels of 4.6 mg/dl, L/R renal weight of 119%; and ATN similar to that of ischemic controls. Treatment with a PGI2 analogue or PGE1 was not protective and led to increases in TxB2, 6-keto-PGF1, creatinine, L/R renal weight, and ATN similar to that of ischemic controls. The combination of Ibu and either PGI2 or PGE1 led to: reduced levels of TxB2 and 6-keto-PGF1 (p less than 0.05); attenuated increases in creatinine to 2.2 and 2.3 mg/dl, respectively (p less than 0.05); and limited ATN (p less than 0.05). These data indicate that the vasodilating PG protect the ischemic reperfused kidney only when Tx is inhibited.

Rioprostil: a clinical experience in gastric ulcer treatment.

The efficacy and tolerability of the prostaglandin E1 derivative rioprostil (Bay o 6893) was studied in a randomized, double-blind, placebo-controlled trial in 40 patients affected by acute gastric ulcer. At the end of the eight weeks period ulcer healing was achieved in 85% of the rioprostil-treated patients and in 60% of the placebo-treated ones (p less than 0.05). Rioprostil produced a significant reduction of pain and also improved the clinical status. This positive outcome was noted both in smokers and in non-smoking patients, while only this last group improved during the placebo treatment.

Effects of antimuscarinic agents and prostaglandin E2 on the gastric mucosal lesions induced by necrotizing agents and water-immersion stress in rats.

The role of antimuscarinic action in gastric mucosal protection against necrotizing agents and the role of such mucosal protection in antiulcerogenic action were studied in rats with i.v. administered antimuscarinic agents. Pirenzepine, as well as PGE2, prevented the gastric mucosal lesions induced by all necrotizing agents (99.5% ethanol, 0.6 N HCI, 0.15 N NaOH, 0.4 N HCI-50 mM taurocholate), but atropine did not prevent the HCI-induced lesions. Cimetidine inhibited only the ethanol-induced lesions even at the antisecretory dose. Higher doses of pirenzepine (5-fold) and atropine (10-fold) were required to inhibit the gastric secretion in Shay rats than in vagally stimulated rats. There was no difference between the antisecretory doses of cimetidine in Shay rats and vagally stimulated rats. PGE2 (0.03-0.1 mg/kg) did not affect gastric secretion. The protective doses of pirenzepine and atropine against mucosal lesions induced by necrotizing agents were similar to the dose in inhibiting vagally stimulated acid secretion and water-immersion stress-induced lesions. PGE2 (100 micrograms/kg) did not prevent the water-immersion stress induced gastric lesions. These results suggested that antimuscarinic agents protect the gastric mucosa from necrotizing agents via a blocking action on the activation of the intrinsic cholinergic nerve. However, antiulcerogenic action is more deeply concerned with antisecretory action than cytoprotection.

Beneficial effects of long-term prostaglandin E2 infusion on the course of postischemic acute renal failure. Long-term studies in chronically instrumented conscious dogs.

The effect of a continuous intra-aortal infusion of prostaglandin E2 (PGE2) (0.03 microgram . min-1 . kg-1) on the course of postischemic renal failure (180 min cessation of blood flow by inflation of a pneumatic cuff) has been investigated in 11 conscious sodium-replete dogs. The glomerular filtration rate (51Cr-EDTA: endogenous creatinine clearance) was less decreased in the PGE2 group (group B, n = 6) than in the control group (group A, n = 5; 13 ml . min-1 vs. 22 ml . min-1; p less than 0.05). Renal blood flow (electromagnetic flow probe) was markedly lower in the control group (82 ml . min-1) than in the PGE2 group (130 ml . min-1; p less than 0.05), even exceeding baseline levels in the latter group. Accordingly, the excessive rise in renal vascular resistance in the control group (+277%) was abolished in the PGE2 group (-20%) (p less than 0.05). Nitrogen retention was also markedly improved. Plasma renin activity, which was markedly raised initially (25.8 ng angiotensin I . ml-1 . h-1) was not significantly further increased during the subsequent 7 days. Urinary excretion of PGE2 was diminished in the control group and elevated following PGE2 infusion. It is suggested that the beneficial effects of PGE2 are mediated by preservation of renal perfusion. Additional effects of prostanoids on the ultrafiltration coefficient (KF) and cytoprotection by reduction of intracellular calcium accumulation must also be taken into consideration.

[Experimental prostaglandin E2 therapy of acute kidney failure due to the crush syndrome]. / Eksperimental'naia terapiia prostaglandinom E2 ostroi pochechnoi nedostatochnosti, vyzvannoi krash-sindromom.

It has been shown for the first time that intraaortal injection of PGE2 to dogs with acute renal failure caused by the crush syndrome makes renal function (glomerular filtration, tubular reabsorption, renal plasmaflow, maximal tubular secretion, minute and diurnal diuresis) return to normal.

Scleroderma: therapeutic options.

Although the cause of scleroderma remains elusive, pharmacologic advances and increased understanding of the pathophysiology of this disease provide therapeutic options. Therapy usually addresses the fibrotic, vascular, or immunologic alterations, but general measures can be helpful and should not be overlooked.

The anti-ulcerogenic activity of the unripe plantain banana (Musa species).

Various preparations of dried unripe plantain banana were found to be anti-ulcerogenic against aspirin-induced ulceration in the rat and were effective both as a prophylactic treatment and in healing ulcers already induced by aspirin. Ripe fruit bananas were inactive. The active factor(s) were water soluble and were concentrated by extraction to approximately three hundred times that in the dried banana powder. The anti-ulcerogenic action of banana preparations appears to be due to their ability to stimulate the growth of gastric mucosa. Aluminium hydroxide, cimetidine, prostaglandin E2, N6, O2-dibutyryl adenosine 3',5' cyclic monophosphate but not 5-hydroxytryptamine were also anti-ulcerogenic when used prophylactically in rats but were ineffective in healing ulcers already formed by aspirin. These substances did not stimulate the growth of gastric mucosa.

Prostaglandins and acute pancreatitis--experimental and clinical studies.

Acute pancreatitis has a mortality of 10-20 per cent, and in cases of acute haemorrhagic pancreatitis this rises to 80-90 per cent. At present there is no reliable treatment for this condition. Based on the hypothesis that the release locally and systemically of the intracellularly activated pancreatic digestive enzymes is due to cell membrane instability, we have studied the cytoprotective (cell membrane stabilizing) role of prostaglandins in this condition. In the first part of this study, an animal model of acute pancreatitis with a mortality of 100 per cent by 14 days has been established by feeding mice a choline-deficient ethionine supplemented diet. Using this model we have demonstrated improved survival (16 out of 50 survived 14 days or longer) by administering prostaglandin E2 subcutaneously (P less than 0 X 02). We have demonstrated that the improved survival is dose-dependent, in the range 2 X 5-5 X 0 mg/kg body weight 8 hourly (P less than 0 X 02) and time-dependent, still being effective if treatment is delayed for 24 h (P less than 0 X 02). Great emphasis has been placed on not commencing treatment until after the induction of acute pancreatitis. In the second part we have used cell membrane marker enzymes to study the cell membrane stabilizing effect of prostaglandin E2 in the human. It has been demonstrated that cell membrane instability occurs. In 12 of 50 episodes treated by prostaglandin E2 infusion, the lysosomal, mitochondrial and cell membranes are stabilized, thus decreasing the release of intracellular enzymes.

Protective effects of PGE2 on diet-induced acute pancreatitis in mice.

Prostaglandins have been noted to have a "protective" effect against gastrointestinal mucosal injury induced by a wide variety of agents although possible protective effects of prostaglandins on injury to other tissues have not been reported. We have tested the effect of prostaglandin E2 (PGE2) on acute experimental pancreatitis induced by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet for 24 hr. Administration of 0.05--0.20 microgram PGE2/g body wt 1 hr before and 4 hr after institution of the CDE diet lowered the mortality rate of diet-induced pancreatitis from 56% to 31%. Larger and smaller doses of PGE2 were without effect. Administration of PGE2 (0.10 microgram/g body weight) diminished the rise in in-vitro LDH discharge and the increase in "free" Cathepsin D activity which occur during diet-induced pancreatitis. Similarly, PGE2 (0.10 microgram/g body wt) diminished the magnitude of the increase in in-vitro protein discharge and the elevated concentrations of trypsinogen and chymotrypsinogen in pancreas fragments taken from mice given the CDE diet. These findings indicate the PGE2 has a protective effect against CDE diet-induced acute experimental pancreatitis. The Cathespin D and LDH changes noted during CDE diet-induced pancreatitis suggest that this diet may decrease membrane integrity and thus allow these enzymes to leak out of the lysosomes and acinar cell, respectively, during pancreatitis. Although the basis for the protective effect of PGE2 remains unclear, our observations suggest that the prostaglandin may act to reduce the alteration in membrane integrity which occurs during CDE-diet induced pancreatitis.

Protective effect of prostaglandin E2 in the gastrointestinal tract during indomethacin treatment of rheumatic diseases.

Nonsteroidal antiinflammatory drugs (NSAID) induce the formation of bleeding gastric and intestinal ulcers in experimental animals. The damage can be prevented by prior local administration of prostaglandins, indicating that prostaglandins have protective properties on the gastrointestinal mucosa. The protective effect was studied in humans by measuring the fecal blood loss during indomethacin treatment of 18 patients with rheumatic diseases with and without concomitant oral supplementation with 1 mg prostaglandin E2 three times daily. The study had a randomized double-blind crossover design using 51Cr-labeled erythrocytes as marker of gastrointestinal bleeding. Indomethacin increased the daily fecal blood loss from 1.0 +/- 0.3 to 2.8 +/- 0.6 ml (P less than 0.005). When oral PGE2 was taken concomitantly, the blood loss was reduced to 1.1 +/- 0.2 ml daily (P less than 0.01), i.e., to the control level. Side effects of prostaglandin E2 were negligible, and the beneficial effect of indomethacin on joint status and symptoms was not interfered with. No changes were recorded in repeated blood tests except for a slightly reduced hemoglobin and a small but statistically significant reduction of serum-calcium during indomethacin treatment, an effect hitherto not described in normocalcemic human subjects. A protective effect on the gastrointestinal mucosa by oral prostaglandin E2 has by the present study been demonstrated also in humans. The protection is unrelated to the gastric acid secretion, which is not inhibited by oral prostaglandin E2. The finding may have clinical application, as gastrointestinal side effects and bleeding are common reasons for discontinuation of NSAID in patients with rheumatic diseases.

The actions of prostaglandins I2 and E2 on arrhythmias produced by coronary occlusion in the rat and dog.

Prostaglandins E2 and I2 were compared with known antiarrhythmics for their actions against arrhythmias produced by occlusion of the left anterior descending coronary artery in the anaesthetised rat while PGI2 was also examined in the dog. PGI2 in the dog suppressed early arrhythmias produced during occlusion but did not influence those produced by occlusion-release or those occurring 24 hours after a permanent occlusion; none of the A,B,C or D series prostaglandins tested markedly reduced 24 hour arrhythmias. In the rat PGE2 was antiarrhythmic against early occlusion arrhythmias (30 minutes occlusion) in a dose related manner (infusions of 1-4 microgram/kg/min) whereas PGI2 infusions potentiated the arrhythmogenic effect of occlusion. PGE2 was as effective an antiarrhythmic as 10mg/kg Org. 6001 which was more effective in this test situtation than dl-propranolol. No obvious mechanisms for the actions of PGE2 or PGI2 were apparent although both agents lowered blood pressure and reduced the size of the occluded zone produced by ligation.

Influence of PGE1 on renal function in severe hemorrhagic shock.

The influence of intravenously administered PGE1 on renal function in standardized hemorrhagic shock in dogs was examined in this study. Infusion rates as high as 1.04 micrograms/min/kg were evaluated. Although arterial blood levels as high as 2.47 ng/ml of plasma compared to control values of less than 0.20 ng/ml were attained during postreinfusion treatment, no beneficial influences on renal functional parameters (hemodynamics, electrolyte and water handling) were observed. In fact, treated animals took up blood from the arterial reservoir more quickly and expired sooner following blood transfusion than an untreated series. A further deleterious change in renal function was a decrease in renal concentrating capability. It is concluded that with the severe grade of hemorrhagic shock employed in these studies, organ blood perfusion was restricted to the extent of limiting effective PGE action.