scholarly journals Pre-treatment with Curcumin Enhances Plasma Concentrations of Losartan and Its Metabolite EXP3174 in Rats

2012 ◽  
Vol 35 (2) ◽  
pp. 145-150 ◽  
Author(s):  
An-Chang Liu ◽  
Li-Xia Zhao ◽  
Jie Xing ◽  
Tian Liu ◽  
Fu-Ying Du ◽  
...  
1987 ◽  
Author(s):  
M Thomas ◽  
P Lumley ◽  
P Ballard ◽  
J R O'Brien

In-vitro GR32191 is a potent and specific thromboxane receptor blocking drug on platelets, and vascular and airways smooth muscle (Lumley et al this meeting). We have undertaken studies in healthy male subjects (n) to examine the effects of oral GR32191 upon platelet aggregation ex-vivo and template bleeding time. Platelet aggregation was monitored in whole blood by counting platelets electronically. Concentration-effect curves to U-46619 and ADP were constructed prior to and following drug or placebo. The degree of rightward displacement of a curve due to treatment was expressed as a concentration-ratio (CR) which was calculated at the 50% aggregation level (ECso post-treatment ECso pre-treatment). Plasma concentrations of GR32191 were determined by h.p.l.c. After single doses of GR32191 mean peak CR's of 8 and 80 were achieved with 0.125 and 0.25mg/kg (n=4) and values of 74 and 234 with 0.5 and lmg/kg (n=4). Peak effects were seen within 2 hours of dosing while activity was still present between 8 and 24 hours. ADP-induced aggregation was unaffected by drug (CR<2) and placebo was without significant effect upon the sensitivity to either aggregating agent (CR<2). GR32191 was rapidly absorbed and the plasma elimination half-life was about 2 hours. GR32191 17.5mg 12-hourly for 10 days (n=6) produced a progressive antagonism of U-46619 induced aggregation which resulted in a large continuous blockade in all subjects (range of 12htrough CR's 85 to 287). However, plasma concentrations of GR32191 did not accumulate on repeated administration. In a double-blind, placebo-controlled, cross-over study (n=16), a statistically significant (p= 0.002) increase in bleeding time was seen following treatment with GR32191 40mg twice daily for 7 days (pre-treatment mean 3.79 min, post-placebo mean 3.47 min, post-GR32191 mean 5.42 min). Rectal bleeding (n=l) has occurred with GR32191 but otherwise tolerability has been good. No drug related changes have been seen in routine laboratory safety screens. Clinical studies are in progress.


2000 ◽  
Vol 22 (2) ◽  
pp. 51-56 ◽  
Author(s):  
Mônica G Ribeiro ◽  
Eduardo LA Pereira ◽  
Rogério Santos-Jesus ◽  
Eduardo P Sena ◽  
Kátia Petribú ◽  
...  

INTRODUCTION: An optimum range has been suggested for nortriptyline blood levels, above or below which patients respond poorly or do not respond at all to treatment. METHODS: A meta-analysis of published studies was performed to verify the existence of an optimal blood concentration range or therapeutic window in nortriptyline-treated depression patients. A MEDLINE search through the years 1970-1999 was carried out to identify original papers and review articles. Data concerning blood levels and percentage improvement were obtained concerning all included pacients. Univariate and multivariate analyses were performed for data comparison. Possible confounding variables, such as pre-treatment, setting (in or outpatients), and duration of treatment were also evaluated. RESULTS: From the 22 published studies found, only six of them with patients' individual data were included. We found an optimal range for nortriptyline concentrations (OR= 2.25, 95% CI = 1.15 to 4.39, p= 0.02). CONCLUSIONS: There may be a biphasic relationship of efficacy to plasma concentrations of nortriptyline, with a therapeutic window between 46 to 236 ng/ml.


1990 ◽  
Vol 2 (2) ◽  
pp. 173 ◽  
Author(s):  
SR Davis ◽  
JF Smith ◽  
PD Gluckman

Coopworth ewes were either treated with 5 mg recombinant-derived bovine growth hormone per day for each day of the oestrous cycle or were untreated. Ovulation rates at the pre-treatment, post-treatment and a subsequent oestrus were determined by endoscopy. These were 1.34, 1.51, 1.38 for the treated ewes and 1.32, 1.43, 1.39 for the control ewes. The ovulation rate post-treatment was significantly higher than for the other two cycles in the treated ewes but it was not significantly different from the post-treatment value of the control ewes. Plasma concentrations of insulin-like growth factor-I (IGF-I) were elevated during treatment (90-130 nmol L-1) compared with concentrations of 25-50 nmol L-1 in the control ewes. No relationship was found between plasma IGF-I concentration and ovulation rate. Injection of ewes grazing ryegrass/white clover pasture with bovine growth hormone did not result in increased ovulation rate.


1995 ◽  
Vol 147 (1) ◽  
pp. 75-85 ◽  
Author(s):  
M J Hötzel ◽  
S W Walkden-Brown ◽  
M A Blackberry ◽  
G B Martin

Abstract In mature Merino rams, changes in diet to below or above the requirements for maintenance of body weight lead to changes in gonadotrophin secretion and testicular growth. However, the effects on testicular growth persist for much longer than those on LH and FSH secretion so that the gonadal and gonadotrophin responses are poorly correlated over time. This suggests that the gonadal effects may be partly independent of changes in the hypothalamic secretion of GnRH, an hypothesis tested in this study. In a short-term experiment (November, late spring, non-breeding season), we tested whether a high frequency of exogenous GnRH pulses could override the endogenous system and mimic the change in gonadotrophins seen in rams fed a high plane of nutrition. Mature Merino rams (scrotal circumference (mean ± s.e.m.) 33·6 ±0·5 cm, body weight (mean ± s.e.m.) 59·0 ± 0·9 kg) were fed 900 g chaff+1·6 kg lupin grain (High diet) or 360 g chaff+60 g lupin grain (Low diet) and infused with 8 pulses of GnRH or saline daily for 5 weeks (n=5/group). Blood was sampled every 20 min for 12 h on days – 1 and 14 relative to the start of treatments. Relative to pre-treatment levels, LH pulse frequency and FSH concentrations were decreased on day 14 in saline-infused rams fed the Low diet and increased in saline-infused rams fed the High diet (P<0·001). In GnRH-infused rams, gonadotrophin secretion was not affected by diet and the patterns of secretion of LH and FSH were similar to those in saline-infused rams fed the High diet. This model was used for a more complete endocrine analysis in a longer experiment designed to test the hypothesis that the effect of nutrition on testicular growth is partly independent of changes in the secretion of GnRH. The same treatments were imposed for 35 days on a different group of similar rams in March (autumn, mid-breeding season). Body weight and scrotal circumference were measured weekly and blood was sampled on days – 1 and 14. On days – 1 and 35, testosterone secretion in response to LH was tested by injecting exogenous ovine LH (NIADDK-oLH-25; 200 ng/kg body weight) to all rams. Body weight increased in rams fed the High diet and decreased in those fed the Low diet (P<0·001) and was not affected by infusion. The secretion of LH and FSH was affected by treatments as in experiment 1. There was an interaction between the effects of diet and infusion on change in scrotal circumference (P<0·02). In GnRH-infused rams fed the Low diet, scrotal circumference was not changed, so that from week 2 after the change in diet it was higher (P<0·05) than in saline-infused rams fed the Low diet and lower (P<0·05) than in both groups of rams fed the High diet. Changes in diet, GnRH pulse frequency or in testicular size did not affect mean plasma concentrations of inhibin or the testosterone response to LH. In conclusion, we have shown that in mature rams pulsatile exogenous GnRH cannot fully reproduce the effect that feeding a high diet has on testicular growth, suggesting that the effect of nutrition on testicular growth is partly independent of changes in the secretion of GnRH. Our results also show that (i) testicular growth induced by nutrition is not associated with changes in plasma concentrations of inhibin, or peripheral concentrations of testosterone after a pulse of LH, suggesting a dissociation of the endocrine and spermatogenic functions of the testis; (ii) changes in diet alter the secretion of gonadotrophins primarily by changing GnRH pulse frequency; and (iii) an exogenous GnRH pulsatile regimen can override endogenous secretion of a similar pulse frequency. Journal of Endocrinology (1995) 147, 75–85


1984 ◽  
Vol 105 (4) ◽  
pp. 558-566 ◽  
Author(s):  
G. P. M. Moore ◽  
B. A. Panaretto ◽  
A. L. C. Wallace

Abstract. Pregnant ewes at 57, 75 and ≥ 101 days of gestation were infused with approximately 3 mg of epidermal growth factor (EGF) for a period of 24–28 h. The strength of attachment of the wool fibres to the skin became progressively reduced during the week following treatment. After 3 weeks, the mean forces required to pluck staples had declined to between 10 and 30% of the pre-infusion measurements and the fleeces were able to be removed easily by hand. Increases in growth hormone and placental lactogen occurred in plasma of ewes during EGF treatment. Prolactin was not affected by EGF but circulating levels of thyroxine declined. The concentrations of these hormones returned to approximate pre-treatment values within 24 h of the end of infusion. EGF treatment at the dose levels used did not appear to significantly affect the development or viability of the foetus.


2020 ◽  
Author(s):  
Malcolm Lane ◽  
D’Arice Carter ◽  
Joseph D. Pescrille ◽  
Yasco Aracava ◽  
William P. Fawcett ◽  
...  

AbstractThe present study was designed to evaluate the effectiveness of galantamine administered orally as a pre-treatment to mitigate the acute toxicity of 4.0xLD50 soman in Cynomolgus monkeys post-treated with atropine, 2-PAM, and midazolam. Pharmacokinetic experiments revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr were quickly absorbed and produced plasma concentrations of galantamine that generated approximately 20% to 40% reversible inhibition of blood acetylcholinesterase (AChE) activity. This degree of reversible AChE inhibition has been shown to be safe and sufficient to protect AChE from the irreversible inhibition by nerve agents, and, thereby, suppress the acute toxicity of these agents. Thus, in subsequent experiments, adult male Cynomolgus monkeys were pretreated orally with 1.5 or 3.0 mg/kg galantamine, challenged intramuscularly with 4.0xLD50, and post-treated with intramuscular injections of 0.4 mg/kg atropine, 30 mg/kg 2-PAM, and 0.32 mg/kg midazolam. All animals subjected to these treatments survived the soman. By contrast, none of the animals that were pretreated with saline and only 40% of the animals that were pretreated with pyridostigmine survived the soman challenge when post-treated with the same conventional antidotal therapy as that delivered to the galantamine-pretreated, soman-challenged monkeys. In addition, large numbers of degenerating neurons were visualized in the hippocampi of soman-challenged monkeys that had been pretreated with pyridostigmine or saline, but not in the hippocampi of animals that had been pretreated with galantamine. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supra-lethal doses of soman in non-human primates.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2028-2028
Author(s):  
Victor J. Marder ◽  
Valery Novokhatny ◽  
Steve Manyak ◽  
Theresa Gruber ◽  
Jennifer Hunt ◽  
...  

Abstract Background: All thrombolytic agents in current clinical use are plasminogen activators (PA). While effective, PA have a downside because of unavoidable and potentially lifethreatening bleeding complications in vulnerable patients. We previously demonstrated a striking margin of hemostatic safety for the “direct-acting” thrombolytic enzyme, plasmin. Now, a novel recombinant derivative of plasmin has been synthesized which lacks kringles 2-5, consisting only of kringle 1 linked to the serine protease domain. Methods: We evaluated escalating dosages of recombinant D (K2-K5) plasmin in a randomized and blinded manner in comparison with molar equivalent dosages of full-length plasmin in an animal model of fibrinolytic hemorrhage. Hemostatic safety was measured by primary bleeding time (PBT) and plasma concentrations of a-2 antiplasmin, factor VIII and fibrinogen. Results: A dose-related nadir in a-2 antiplasmin, factor VIII and fibrinogen followed administration of 4, 6, 8 and 10 mg/kg of D (K2-K5) plasmin, with residual fibrinogen of 65%, 40%, 30% and 0% of initial pre-treatment concentrations. Hemostasis was undisturbed with 4 mg/kg of D (K2-K5) plasmin (mean PBT 2.2 +/- 0.7 min), minimally so at the 6 or 8 mg/kg dosages (5 +/- 2.9 and 4.4 +/- 2.2 min). Hemostasis was markedly abnormal at the purposefully toxic 10 mg/kg dose (12.8 +/- 18.8 min), in association with complete depletion of plasma fibrinogen. Comparison of agents at 10 mg/kg showed no difference, but at 4 mg/kg (2-4-fold more than needed for efficacy), D (K2-K5) plasmin showed slightly less prolongation of PBT (2.2 +/- 0.7 vs 3.3 +/- 2.1 min). Both agents were equally potent for in vitro whole blood clot lysis, indicating that the safety advantage of D (K2-K5) plasmin was not due to decreased fibrinolytic activity. Conclusions: Recombinant D (K2-K5) plasmin has equivalent hemostatic safety as full-length plasmin in an animal model of fibrinolytic hemorrhage and warrants evaluation in clinical thrombotic disease.


Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 670
Author(s):  
Tom de Waal ◽  
Jari Rubbens ◽  
Michael Grimm ◽  
Vincent Vandecaveye ◽  
Jan Tack ◽  
...  

Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.


1976 ◽  
Vol 128 (4) ◽  
pp. 384-390 ◽  
Author(s):  
S. F. Whyte ◽  
A. J. Macdonald ◽  
G. J. Naylor ◽  
J. P. Moody

SummaryWe studied the relationship between side effects, clinical outcome and the drug plasma levels in 28 female depressed patients treated with protriptyline. After 3½ weeks treatment, patients with plasma levels within a median range (630 to 900 nmol/1) showed better responses to the drug than patients with plasma levels outside this range.There were no statistically significant correlations between plasma levels and side effect scores or ‘corrected’ side effect scores (scores after subtracting pre-treatment values) for the group at any time after starting the treatment. But we found positive correlations between plasma levels and ‘corrected’ side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.


1988 ◽  
Vol 117 (3) ◽  
pp. 381-386 ◽  
Author(s):  
R. F. Parrott ◽  
S. N. Thornton ◽  
J. E. Robinson

Abstract. Plasma concentrations of cortisol, oxytocin, vasopressin and prolactin were measured by radioimmunoassay in eight castrated rams subjected to handling (control), restraint or isolation. Determinations were also made of hematocrit and plasma osmolality. Blood was collected by jugular venipuncture 60 and less than 1 rnin before, and 5, 15, 30, 60 and 120 min after the start of treatment. Plasma cortisol was raised above pre-treatment levels during isolation and restraint but only transiently after handling. In the first 30 min of treatment, cortisol concentrations were higher following isolation than after restraint or handling and, in the final 60 min, levels were higher during both isolation and restraint than after handling. Oxytocin concentrations showed little change but vasopressin levels were reduced 15, 30 and 60 min after the start of isolation and were negatively correlated with those of cortisol. Plasma prolactin concentrations decreased during handling and restraint but remained unaltered after isolation. Osmolality and hematocrit decreased in all three treatment conditions. These findings indicate that stress does not alter oxytocin levels in sheep, but changes in vasopressin secretion and water balance may occur if cortisol release is greatly enhanced.


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