A comparison of the chronic toxicities of synthetic sweetening agents.
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Alkaloids↗
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Studies in ergot. I. Ergotamine phthalate.
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Claviceps↗
The pharmacognosy of smooth brome ergot.
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Bromus↗
The quantitative estimation of ergotamine and ergotoxine by paper chromatography.
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Cardiovascular Agents↗
Hepatic ischemia-reperfusion injury modification during liver surgery in rats: pretreatment with nifedipine or misoprostol.
The aim of the study was to determine if pretreatment with misoprostol (a prostaglandin analogue) or nifedipine (a calcium antagonist), know protectants of the whole liver, would ameliorate the ischemia-reperfusion injury (IRI) of resected liver associated with vascular occlusion. Male Wistar rats were allocated to 5 groups (n = 20 each group): sham-operated, liver resection only, liver resection plus pretreatment with 0.1 mg/kg misoprostol, 10 mg/kg, or 2 mg/kg nifedipine during the 3 days before IRI with liver resection. Fifteen percent of the liver was made ischemic by 30-minute continuous vascular occlusion, and the remaining 85% nonischemic liver was resected. The model was designed to have survival of the rats so that liver function could be studied over 3 weeks. Seventeen of 20 control resection rats survived indicating a suitable model for study. The bilirubin level was reduced by 25% on postoperative days 3 through 23 with misoprostol. The serum alanine aminotransferase (ALT) peak was significantly lower on day 1 with misoprostol and high-dose nifedipine (both reduced to half the control resection value). There was a modest but significant reduction of serum alkaline phosphatase (SAP) for low-dose nifedipine on days 1, 2, and 23. Prothrombin had a lower peak and lower values on days 1 through 4 with misoprostol. Liver histological changes were minor, being cytoplasmic vacuolization only, and was slightly more marked in the nifedipine groups. Preoperative misoprostol 0.1 mg/kg and nifedipine 10 mg/kg each ameliorate the IRI associated with liver resection, as measured by liver function tests. Different aspects of liver function were altered by the different agents. These results justify initiating a trial for human liver resections.
Animals↗
Biochemical evaluation of serum and flexor tenosynovium in carpal tunnel syndrome.
In total, 41 consecutive patients with "idiopathic carpal tunnel syndrome" and abnormal electrophysiologic findings who underwent carpal tunnel release were studied prospectively. The focus of this investigation was the evaluation of the levels of specific chemical mediators within the serum and flexor tenosynovium of these patients. Blood was collected from these patients within 1 week prior to carpal tunnel release, and flexor tenosynovium was obtained at time of surgery. Specimens were then analyzed to determine the levels of interleukins 1 and 6, prostaglandin E(2) (PGE(2)), and malondialdehyde bis diethyl acetal. These values were compared to those of controls who had no evidence of carpal tunnel syndrome. A significant increase was noted in the serum malondialdehyde and tenosynovial levels of malondialdehyde, interleukin 6, and prostaglandin PGE(2) compared to controls. The elevated levels of these biologic factors and the absence of interleukin 1 elevation support a noninflammatory ischemia-reperfusion etiology for so-called "idiopathic carpal tunnel syndrome" that causes progressive edema and fibrosis of the tissues within the carpal canal. These findings correlate with previous histopathology reports. We believe that "idiopathic carpal tunnel syndrome" is an "-osis" not an "-itis."
Carpal Tunnel Syndrome↗
Effect of a dysmenorrhea Chinese medicinal prescription on uterus contractility in vitro.
Dysmenorrhea is a common gynecologic complaint. After their first menstrual period, 30%-60% of American women suffer from some level of discomfort. It is estimated that 6 billion work hours are lost in this manner every year in the United States which equals an economic loss of nearly US$200 million. Dysmenorrhea is not only a problem for women but also one which affects quality of life and even reduces productivity in general. Dysmenorrhea is directly related to elevated levels of PGF2alpha (prostaglandins F2alpha) and is treated using nonsteroid anti-inflammatory drugs in Western medicine. Though efficacy of the latter is rapid, there are many side effects to the liver, kidney, and digestive system. The anti-inflammatory effect is temporary, and such drugs are unable to provide a long-term cure. Because of this, Chinese medicinal therapy is being considered as a feasible alternative medicine. In this study, Wen-Jing Tang (one of the dysmenorrhea Chinese medicinal prescriptions) was selected. A 50% alcoholic solution was used to extract active ingredients and create a freeze-dried product. At first, Wen-Jing Tang was used to suppress spontaneous contractions and prostaglandins F2alpha-induced contractions of rat uterine smooth muscle in vitro. Then, an assessment was performed to determine the mechanism of the prescription. Acetylcholine, ergonovine, propranolol, oxytocin, and KCl were used to analyze the physiological mechanisms of WJT. The results show that antagonism of both PGF2alpha and ACh are the major mechanisms for treating dysmenorrhea by Wen-Jing Tang. Furthermore, the antagonistic effect of KCl-depolarization contractions may be an auxiliary mechanism of the curative effect.
Acetylcholine↗
Activity of aqueous extract of the bark of Vitex doniana on uterine muscle response to drugs.
The activity of Vitex doniana on the uterine muscle response was investigated. The bark of Vitex doniana was extracted in boiled water at 100 degrees C, and the extracted solution filtered and centrifuged with refrigeration. The extract prepared from the dry powder extract was tested on uterine muscle strip preparations. The bark extract of Vitex doniana was analysed elementally and found to contain much more potassium and phosphate than calcium, magnesium, zinc and iron. The presence of potassium ions in excess may also be partly responsible for the effect of the crude extract on uterine muscle activity. In another study, Vitex doniana extract induced graded uterine muscle contractions and also potentiated the contractile effects of prostaglandins, ergometrine and oxytocin. However, the potentiating effect was not significant on the contractile responses to acetylcholine and potassium chloride. The investigation therefore suggests that the effect of the Vitex doniana bark extract may be not only voltage operated but may act via uterotonic receptors. Therefore, the use of Vitex doniana to control postpartum bleeding after child birth may be justified.
Animals↗
Effects of Dai-kenchu-to, a herbal medicine, on uterine and intestinal motility.
The effects of both Dai-kenchu-to and PGF(2alpha) on intestinal and uterine motility were studied in anaesthetized rabbits with force transducers implanted in the jejunum, ileum and uterus. A single intraduodenal administration of Dai-kenchu-to (300 mg/kg) enhanced the intestinal motility but not the uterine motility. However, intravenous administration of PGF(2alpha) (20 microg/kg) enhanced both intestinal and uterine motility. The effects of Dai-kenchu-to on the spontaneous contraction and contractile response of the isolated rat uterine strips to oxytocin, PGF(2alpha) or ACh were also studied. Oral administration of Dai-kenchu-to at 300 mg/kg for one week had no effect on either the spontaneous contraction or the contractile response of the uterus. These results indicate that Dai-kenchu-to may exert stimulatory effects on intestinal motility, as PGF(2alpha), but has no effect on the uterine motility, suggesting a selective effect on the gastrointestinal tract. Hence, Dai-kenchu-to may be safer than PGF(2alpha) in the treatment of postoperative adhesive ileus in women. However, more studies are needed to determine whether Dai-kenchu-to could be administered to pregnant women.
Animals↗
Use of the equivalence approach in reproductive health clinical trials.
An equivalence trial is appropriate when it is desired to demonstrate equivalence between two treatments, regimens or interventions (methods) or non-inferiority of a new one compared to a standard one. The conduct of an equivalence trial requires different techniques during design and analysis compared to a superiority trial. The existing formulae for sample size calculation to demonstrate equivalence between two methods using the confidence interval approach are reviewed. The establishment of the margin of equivalence and the choice of the type of test are discussed. Plots of sample sizes required to demonstrate equivalence in the case of binary outcomes are presented for values of proportions and margins of equivalence common in the reproductive health field. Examples are given of method comparisons in the reproductive health field in which the relevant question is to demonstrate non-inferiority. The approach to equivalence is described in the trials included in three published systematic reviews in which these comparisons were conducted, addressing the statement of hypotheses, sample size calculation and the interpretation of results. The use of the conventional superiority approach to design equivalence trials has led to underpowered trials to show equivalence within clinical relevant margins. The analysis and interpretation of results from such trials has resulted in conclusions of equivalence based on lack of significance. We draw attention to the lack of awareness of the appropriate techniques for equivalence trials among researchers in the field of reproductive health. Finally, the issue of interim analyses and stopping rules in equivalence trials is addressed.
Confidence Intervals↗
Sample size formula for proportional hazards modelling of competing risks.
To test the effect of a therapeutic or prognostic factor on the occurrence of a particular cause of failure in the presence of other causes, the interest has shifted in some studies from the modelling of the cause-specific hazard to that of the subdistribution hazard. We present approximate sample size formulas for the proportional hazards modelling of competing risk subdistribution, considering either independent or correlated covariates. The validity of these approximate formulas is investigated through numerical simulations. Two illustrations are provided, a randomized clinical trial, and a prospective prognostic study.
Administration, Intravaginal↗
Prostaglandin E2 induced polymerization of human alpha-1-antichymotrypsin and suppressed its protease inhibitory activity: implications for Alzheimer's disease.
Different molecular forms of alpha-1-antichymotrypsin (ACT) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD) were detected. Monomeric and polymeric ACT were observed by polyacrylamide gel electrophoresis of both sera and cerebrospinal fluids. ACT polymers were increased in AD patients with the apolipoprotein E (APOE) 4 allele. Increased levels of inactive ACT molecules were also detected in brain homogenates of patients with the APOE 4 allele. Experimental conditions promoting in vitro polymerization of ACT and the effect of polymerization on the biological activity of this serpin were also explored. Incubation of this serpin with prostaglandins of E series (PGE 2) induced ACT polymerization and decreased its activity. Amyloid beta-peptide1-42 did not significantly affected the biological activity of ACT. Inactivation of protease inhibitors by inflammatory molecules such as PGE 2 released from activated microglia in AD brains may promote amyloid deposition and neurodegeneration.
Alzheimer Disease↗
Transcriptional regulation of the cyclooxygenase-2 gene by diverse ligands in murine osteoblasts.
Osteoblasts produce prostaglandins in response to a wide variety of stimuli. Induced prostaglandin synthesis is generally the consequence of elevated cyclooxygenase-2 (COX-2) expression. Agents as diverse as serum, bFGF, PDGF, PGE(2), or [TNFalpha + IL1beta] rapidly induce expression of COX-2 protein in murine MC3T3-E1 osteogenic cells. Transient transfection studies using reporter constructs containing either wild-type COX-2 regulatory sequences or mutated cis-acting sequences linked to a luciferase reporter gene identify a CRE site and two NF-IL6 (C/EBP) sites which play important roles in the regulation of COX-2 expression in response to all these agents in osteoblasts. Induction of wild-type COX-2 reporter gene expression in MC3T3-E1 cells by all these agents involves signaling through the MEKK/JNK pathway and activation of both c-Jun and the C/EBP family of transcription factors.
Animals↗
Lymphotoxin-beta and TNF regulation in T cell subsets: differential effects of PGE2.
The effects of prostaglandin E2 (PGE2) on lymphotoxin beta (LT-beta) and tumour necrosis factor alpha (TNF) were assessed in murine CD4+ Th1 and Th2 T cell clones. LT-beta mRNA was constitutively expressed by both T cell subsets. However, PGE2 inhibited its accumulation only in Th1, but not Th2 clones. PGE2 inhibited TNF mRNA accumulation and production and release of bioactive material by both Th1 and Th2 T cells. The effects of PGE2 were also evaluated on production of IL-3, another cytokine produced by both T cell subsets, and interleukin 4 (IL-4), which is produced only by Th2 cells. Though IL-3 was produced by both T cell subsets it was only inhibited in Th1 cells, a pattern similar to that observed for LT-beta. Accumulation of IL-4 mRNA in Th2 cells was not inhibited by PGE2. These results demonstrate that PGE2 does not affect LT-beta, IL-4, or IL-3 in Th2 cells, but inhibits TNF mRNA accumulation and production in this T cell subset. Thus, TNF appears to be the only cytokine susceptible to inhibition by PGE2 in Th2 cells. The fact that PGE2 inhibits LT-beta and IL-3 in Th1 but not Th2 cells points to a different mechanism of regulation of the same cytokine in different subsets. The mechanisms that contribute to TNF mRNA accumulation also may differ in the two CD4+ T cell subsets, because cycloheximide superinduced TNF mRNA in Th2 cells, but not in Th1 cells. The inhibitory effects of PGE2 on TNF mRNA accumulation by either T cell subset did not require de novo protein synthesis since preincubation with the protein synthesis inhibitor, cycloheximide, did not alter the PGE2-mediated effects. Cross-regulation of cytokine production and function has been demonstrated for both T cell subsets, and PGE2 may modulate the outcome of an immune response via differential regulation of cytokine production.
Animals↗
The hormonal control of birth behavior in the gray short-tailed opossum (Monodelphis domestica).
In all major groups of Australian marsupials, prostaglandin F2alpha (PGF) or oxytocin injection initiates birth behavior in adult females, adult males and pouch young. Because inhibitors of PGF synthesis block this initiation, oxytocin may activate birth behavior via the stimulation of PGF synthesis. In this study, the role of PGF and oxytocin in the activation of birth behavior was examined in an American marsupial, the gray short-tailed opossum (Monodelphis domestica). Adult male and female gray opossums were given PGF, oxytocin, or saline (control) before behavioral observation. On the next day, the animals in the oxytocin group were injected with the PGF inhibitor flunixin meglumide (Finadyne, Schering Corp., U.S.A.) before oxytocin reinjection and behavioral observation. Both males and females showed birth behavior in response to PGF but only females responded to oxytocin. There was no significant difference in the latency of response of females to oxytocin alone versus response to oxytocin after receipt of the PGF inhibitor. These results suggest that, in contrast to Australian species, in this American marsupial, oxytocin initiates birth behavior only in females and does not operate via stimulation of prostaglandin secretion.
Animals↗
Effects of prostaglandin F2alpha treatment on the behavior of pseudopregnant pigs in an extensive environment.
In seminatural environments, prepartum sows leave the herd and construct a maternal nest (a dug out hollow lined with vegetation) prior to the birth of their piglets. The endocrine drives motivating this behavior are not understood, but may involve prostaglandin (PG) F2alpha. This study examined the effect of PGF2alpha treatment on the behavior of pseudopregnant gifts housed in a large enclosure. Pseudopregnancy was induced using 5 mg/ml estradiol valerate/day im from days 11 to 15 of the estrous cycle (first day of estrus = day 0). The gifts' behavior was recorded on a control day, during which no treatment was given, and a test day (= 45.9 +/- 0.42 days of pseudopregnancy) when gilts received either 15 mg PGF2alpha (dinoprost: Lutalyse, Upjohn, Crawley, UK, n = 11) or 0.9% saline (n = 10) im at 11.00 h. PGF2alpha-treated gilts traveled further and were more frequently >10 m from the nearest pig than saline-treated animals. In the hour following injection, PGF2alpha-treated animals also showed increased frequencies of rooting and pawing the ground and stood for longer than saline-treated animals. However, gathering and carrying nest materials were not increased. These results suggest that PGF2alpha, given as a single dose to extensively housed gilts, initiated many, but not all, of the behaviors characteristic of prepartum nest building. The dose and duration of PGF2alpha treatment may have limited the observed behaviors. In addition, environmental feedback is likely to affect the degree to which some nest building behaviors are expressed.
Animals↗
Effects of prostaglandin F2alpha treatment of pseudopregnant pigs on nest building and interactions with newborn piglets.
Previous studies showed that prostaglandin (PG)F2alpha treatment stimulated nest building behaviors in prepartum and pseudopregnant pigs. This experiment studied behaviors of PGF2alpha-treated pseudopregnant nulliparous pigs (gilts) exposed to newborn piglets. Penned pseudopregnant gilts (days 46-53) were injected with either 10 mg PGF2alpha (n = 8) or saline (n = 8) im, and behavior was recorded for 2 h (period A). Between 2 and 6 h (period B), gilts were given two male piglets (< 12 h old) and a novelty object (house brick) and recordings continued. During period A, PGF2alpha animals showed greater frequencies of standing, pawing, rooting, lifting, and carrying straw (indices of nest building) and scratching than saline treated animals. During period B, one PGF2alpha- and two saline-treated gilts attacked piglets, which were removed from the pen and the gilts excluded from further analysis. There were no treatment differences in period B in gilt posture, nest building behavior, or interactions with piglets or novelty object, except for a reduced frequency to trap piglets beneath their bodies and an increased frequency to attempt to escape from the pen in PGF2alpha-treated animals. Piglet position relative to the gilts' head and udder was unaffected by treatment. Gilts in both groups approached and nosed piglets more within the first 30 min of period B than subsequently. PGF2alpha-induced nest building had only a weak impact upon subsequent interactions between gilts and piglets, suggesting that mechanisms controlling porcine nest building and maternal behavior in this model were not directly linked.
Aggression↗
Anastomosis between ovarian and mesenteric veins in sheep: induction of a physiological hyperstimulation of the ovary.
Progesterone (P4) and estradiol 17 beta are essential for the dialogue between the ovary and the hypothalamohypophysial system. Immunization against steroids, although a valuable tool, displays limits. We propose a straightforward method to suppress steroids from the peripheral circulation by using the liver to catabolize steroids, through an anastomosis of the ovary to the mesenteric vein. Twelve mature cycling Ile-de-France ewes were unilaterally ovariectomized during the breeding season and subsequently randomly assigned to be anastomosed (n = 6; A) or sham-operated (n = 6; SO) on Day 10 of a synchronized estrous cycle. The ovarian vein was anastomosed to the superior mesenteric vein and all collateral veins to the ovarian vein were ligatured. Sham-operated ewes had only their collateral vein ligatured without anastomosis. Four days following surgery, ewes from both treatments were injected with PGF-2 alpha and autopsied between 9 and 14 days following surgery. Blood progesterone and estradiol 17 beta were measured daily from Day 4 before surgery until 7 days after castration. Estradiol levels measured at the level of the ovarian vein indicated that anastomosis allowed normal ovarian activity in all but 1 ewe in which collateral veins to the ovarian duct had developed. In the 5 A ewes, progesterone in peripheral blood decreased to low levels the day following surgery but this fall was not accompanied by an increase in estradiol. Estradiol levels measured at the output of the liver from hepatic vein were lower in A ewes (46.6 pg/ml) than in the ovarian vein of SO ewes (334.1 pg/ml). Ovarian hypertrophy was observed in 5 A ewes in which numerous large follicles were observed. These results indicate that the experimental model is functional and permits the study of the stimulation and hyperstimulation of the ovary and the control of the terminal follicular growth in the endocrine environment of the animal itself.
Anastomosis, Surgical↗