Lauric Acid-Induced Thrombocytopenia and Thrombosis in Rabbits

1967 ◽  
Vol 18 (01/02) ◽  
pp. 057-065 ◽  
Author(s):  
G Zbinden
Keyword(s):  
Acid Solution ◽  
Intravenous Injection ◽  
Lauric Acid ◽  
Repeated Administration ◽  
Intravenous Dose ◽  
Acid Injection ◽  
Small Doses ◽  
High Doses

SummaryIntravenous injection of 0.5% lauric acid solution into rabbits caused moderate to marked thrombocytopenia. With small doses (2.5 mg/kg) this thrombocyte decrease was reversible and microscopically demonstrable thrombosis in the lungs was only seen or suspected in a small number of rabbits 10 to 30 min after lauric acid injection. High doses were followed by partly reversible thrombocytopenia and by moderate to marked, sometimes lethal, thrombosis in the lungs still demonstrable 24 hrs after injection. Repeated administration of small doses of lauric acid did not lead to a depletion of the circulating thrombocytes. Thrombocytopenic response, however, appeared to be less pronounced after the second and subsequent injections. Studies with Cr51-labeled platelets indicate that during the reversible thrombocytopenia following a small intravenous dose of lauric acid platelets are retained in various organs, particularly the lungs.

FURTHER STUDIES OF THE PHARMACOLOGY OF THE PYLORIC REGION: ANALYSIS OF THE EFFECTS OF INTRA-ARTERIAL HISTAMINE, SEROTONIN, PHENYLDIGUANIDE, MORPHINE, AND OTHER DRUGS ON THE ANTRUM AND DUODENAL BULB

1966 ◽  
Vol 44 (6) ◽  
pp. 981-1019 ◽  
Author(s):  
E. E. Daniel
Keyword(s):  
Intravenous Injection ◽  
Contractile Activity ◽  
Duodenal Bulb ◽  
Gastroepiploic Artery ◽  
Low Doses ◽  
Common Site ◽  
Site Of Action ◽  
Small Doses ◽  
Release Of Acetylcholine ◽  
High Doses

The actions of drugs on the antrum and duodenum of the dog were analyzed by the use primarily of intra-arterial injections into the gastroepiploic artery while the electrical and contractile activity of these regions was recorded. Histamine (0.1 to 5 μg) usually caused excitation of second potentials (antrum) or fast spikes (duodenum), and contractions (both) and other effects similar to those produced by acetylcholine, though usually delayed in onset and more prolonged. Its effects were diminished or prevented by atropine, nicotine, and hexamethonium as well as by antihistaminics such as antazoline, cyproheptadine, and phenoxybenzamine. In the duodenum, histamine excitation was usually preceded by inhibition, and most antihistaminics also depressed responses to serotonin (5-HT), acetylcholine, or both. Low doses of serotonin (0.1 to 1 μg) most frequently caused excitation of the antrum and duodenum similar to that evoked by acetylcholine. This response was sometimes prolonged. These effects in the antrum were diminished or prevented by atropine, nicotine, methysergide, and bromolysergic acid (BOL), and less effectively antagonized by hexamethonium, morphine, and pronethalol. Phenoxybenzamine did not prevent excitation of the antrum by low doses of 5-HT, but tachyphylaxis following high doses of 5-HT (5 to 100 μg) or of phenyldiguanide (25 to 500 μg) did prevent such responses. Several of these agents also inhibited excitation of the duodenum induced by 5-HT and cross tachyphylaxis between 5-HT and phenyldiguanide was also observed. It was suggested that low doses of 5-HT, like phenyldiguanide, acted at a preganglionic site in the antrum and duodenum different from that at which histamine acts, presumably the non-medullated mucosal mechanoreceptors, and ultimately caused release of acetylcholine from postganglionic fibers. Phenyldiguanide in small doses (2 to 25 μg) acted like 5-HT to excite the antrum and duodenum. Analysis of its action with antagonists yielded results similar to those with 5-HT, and the occurrence of cross tachyphylaxis with 5-HT suggested a common site of action. Morphine (10 to 1000 μg) usually inhibited electrical and contractile activity in the antrum and stimulated these activities in the duodenum. The same results were obtained with intravenous injection (0.1 to 0.35 mg/kg). It. diminished responses to histamine, 5-HT, phenyldiguanide, and to a lesser extent, acetylcholine.

INVESTIGATIONS INTO THE MECHANISM OF DEXTRAN-INDUCED EDEMA IN RATS

1963 ◽  
Vol 41 (1) ◽  
pp. 1855-1863
Author(s):  
B. Gözsy ◽  
L. Kátó
Keyword(s):  
Mast Cell ◽  
Intravenous Injection ◽  
Anaphylactoid Reaction ◽  
Serotonin Release ◽  
Cell Disruption ◽  
Edema Formation ◽  
Physical Presence ◽  
High Doses

In the rat, intravenous injection of minute amounts (7.9 mg/kg) of dextran induced edema formation of the same intensity as high doses (300–600 mg/kg). With the high doses, mast-cell disruption (histamine and serotonin release), vasodilatation, hypothermia, hypotension, hemoconcentration, and edema occurred. Since minute doses of dextran induced only vasodilatation and edema formation, this response is considered as the pure anaphylactoid reaction. The syndrome provoked by high doses is a consequence of conditions created by the physical presence of large quantities of dextran in the blood, rather than an integral part of the proper anaphylactoid sequence. Minute doses of dextran induced edema without mast-cell disruption, hypothermia, hypotension, or hemoconcentration, thus showing that the dextran response in the rat is mediated by factors other than histamine and serotonin of mast-cell origin.

The vagus nerve in the thermoregulatory response to systemic inflammation

1997 ◽  
Vol 273 (1) ◽  
pp. R407-R413 ◽  
Author(s):  
A. A. Romanovsky ◽  
C. T. Simons ◽  
M. Szekely ◽  
V. A. Kulchitsky
Keyword(s):  
Intravenous Injection ◽  
Systemic Inflammation ◽  
Second Phase ◽  
Thermoregulatory Response ◽  
Cool Environment ◽  
Bolus Intravenous Injection ◽  
High Doses ◽  
Colonic Temperature ◽  
Dose Dependent ◽  
Higher Doses

Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Szekely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.

CALCITONIN AND INTESTINAL CALCIUM ABSORPTION

1974 ◽  
Vol 61 (1) ◽  
pp. 83-94 ◽  
Author(s):  
R. SWAMINATHAN ◽  
J. KER ◽  
A. D. CARE
Keyword(s):  
Absorption Rate ◽  
Calcium Absorption ◽  
Intestinal Calcium Absorption ◽  
Initial Rise ◽  
High Calcium ◽  
High Calcium Diet ◽  
Small Doses ◽  
Small Intestinal ◽  
High Doses ◽  
Unidirectional Transfer

SUMMARY The effect of calcitonin (CT) on small intestinal calcium absorption was studied using Thiry—Vella loops in one intact sheep, one intact pig and three parathyroidectomized pigs. Net calcium absorption rate was measured after recirculating through the loop a known volume of a solution containing calcium and polyethylene glycol 4000. Calcitonin was infused intravenously and its effect on the net calcium absorption rate was measured. When relatively high doses of CT (10 mu./min/kg) were infused for up to 45 h, there was an initial rise in net calcium absorption associated with hypocalcaemia, followed by a marked reduction in calcium absorption. When small doses of CT (0·5 mu./min/kg) were infused for 100 h, the increase in the net absorption rate was not observed or was less marked, but there was a significant reduction in net calcium absorption 2 days after the CT infusion was stopped. A reduction in net calcium absorption rate was seen both in intact and parathyroidectomized animals. In one experiment in which the true absorption rate of calcium from lumen to blood was measured using 47Ca, a reduction in unidirectional transfer of calcium from lumen to blood was seen 2 days after the CT infusion was stopped. The possible mechanism of this action of CT and its significance in calcium homeostasis during the ingestion of a high calcium diet is discussed.

The Effect of Repeated Administration of Cyclophosphamide on CYP2B1 and 2B2 in Rat.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4460-4460
Author(s):  
Parvaneh Afsharian ◽  
Ylva Terelius ◽  
Stefan Lundgren ◽  
Moustapha Hassan
Keyword(s):  
Formation Rate ◽  
Conditioning Regimen ◽  
Clinical Importance ◽  
Repeated Administration ◽  
Repeated Dose ◽  
Pharmacokinetic Parameters ◽  
Induction Effect ◽  
Activity Levels ◽  
Protein Levels ◽  
High Doses

Abstract Cyclophosphamide is used in high doses as a part of the conditioning regimen prior to stem cell transplantation. It is usually given for two or four consecutive days, primarily to facilitate engraftment of donor cells. Cyclophosphamide is a prodrug that is activated in liver by a 4-hydroxylation reaction catalyzed by cytochrome P450 (CYP) enzymes. Several studies have shown that cyclophosphamide induces its own metabolism, which affects its pharmacokinetic parameters after repeated dose (Chang TK, Yu L et al. Cancer Res1997; 57:1946–54 and Schuler U, Ehninger G et al. Cancer Chemother Pharmacol1987; 20:248–52). In the present study, we aimed to investigate the effect of repeated doses of cyclophosphamide on the CYPs in rat. mRNA, protein, and enzyme activity levels were investigated. Animals received (200 mg/kg, i.v.) at time 0, 20, 48 h. Additionally another group of animals was treated at 0, 6, 20, 26, 48 and 54 h. At each time point three animals were killed 30 min after the administration (Xie H, Afsharian P et al. Xenobiotica2005; 35:239–51). mRNAs of CYP2B1 and 2B2 were significantly induced up to 458- and 8.3-fold at 6h, 983- and 102-fold at 26 h, and 342- and 33-fold at 54 h. CYP2B protein levels were increased and their peaks was observed at 20 and 48 h. Microsomal activity of CYP2B was determined at three different concentration of cyclophosphamide (1, 0.5, 0.1 mM) by measuring the formation rate of 4-hydroxy-cyclophosphamide (4-OH-CPA). The microsomal activity increased as reflected in an increase in cyclophosphamide 4-hydroxylation at all concentrations used using microsomes from rats treated at 6, 20 and 48 h. A significant increase of 4-hydroxylation of cyclophosphamide (0.1 mM) by 2.9-, 4.4- and 4.2- fold, respectively compared to the control rats. However, a decrease in the hydroxylation rate was observed using microsomes from rats treated at 26 and 54 h and in all concentrations used that might due to hepatotoxicity effect of cyclophosphamide when administered in short time period of repeated dose. A significant (p<0.05) decrease in CPA concentration and a significant (p<0.05) increase in its metabolite (4-OH-CPA) level in plasma were observed with repeated administration of CPA. In conclusion, an induction effect on CYP2B and a substantial up regulation of its mRNA expression were observed after repeated administration of CPA. This information can have a high clinical importance when a dosing schedule for cyclophosphamide considering the polymorphism of CYPs in cancer patient.

Oxidants and antioxidative defense

2002 ◽  
Vol 21 (2) ◽  
pp. 61-62 ◽  
Author(s):  
T Grune
Keyword(s):  
Free Radicals ◽  
Oxygen Free Radicals ◽  
Expression Patterns ◽  
Signal Transduction Pathways ◽  
Low Doses ◽  
The Past ◽  
Small Doses ◽  
Long Time ◽  
High Doses

The role of oxygen free radicals and other oxidants in several diseases has been well established over the past decade. Whereas it was long known that high doses of oxidants may damage or kill cells, the effect of low doses or long-time exposure to small flux rates of oxidants have been the focus of the free radical research until now. Here one has to take into account that most physiological and pathophysiological actions of oxidants and free radicals are based on the permanent action of small doses and flux rates. This includes effects of oxidants on signal transduction pathways and gene expression patterns. Therefore, only a few answers can be given today on the relevance of the effects of low doses of oxidants.

scholarly journals Dose Related Analgesic, Motor and Reinforcing Effects of Nalbuphine in Rats

2021 ◽  
Vol 41 (04) ◽  
pp. 487-492
Author(s):  
Shazia Nawaz
Keyword(s):  
Partial Agonist ◽  
Repeated Administration ◽  
Locomotor Sensitization ◽  
Nociceptive Response ◽  
Moderate Dose ◽  
Hot Plate Test ◽  
Analgesic Effects ◽  
Reinforcing Effects ◽  
Single And Repeated Administration ◽  
High Doses

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain.

scholarly journals Effects of levamisole on experimental infections by Plasmodium berghei in mice

1987 ◽  
Vol 20 (4) ◽  
pp. 193-198 ◽  
Author(s):  
Enrique Melendez C. ◽  
Antoniana U. Krettli
Keyword(s):  
Immune Response ◽  
Body Weight ◽  
Plasmodium Berghei ◽  
Resistant Strain ◽  
Mortality Rates ◽  
Drug Induced ◽  
Stimulant Effect ◽  
Swiss Mice ◽  
Small Doses ◽  
High Doses

Levamisole (phenylimidothiazol), considered a strong immunostimulant, when administered to healthy Swiss mice did not cause a significant increase in -the weight of their thymus, liver and spleen, even though the drug was used at different times before removing such organs. High doses ofdrug used in the 4-day prophylactic scheme had no antimalarial effect. However, when given to malaria infected mice 24 hours before, at the same time, and 24 hours after the inoculation of a chloroquine-sensitive or a chloroquine-resistant strain of Plasmodium berghei small doses of the drug induced a somewhat decreased parasitemia, the dose of 1 mg/kg body weight before the inoculum being the best scheme. The mortality rates by malaria in the levamisole treated groups were also delayed although all mice finally died. The data suggest that levamisole may display a stimulant effect on the depressed immune response caused by malaria.

Interactions between hypoxic and almitrine-induced vasoconstriction in the rat lung

1992 ◽  
Vol 82 (3) ◽  
pp. 265-272 ◽  
Author(s):  
P. C. Russell ◽  
C. J. Emery ◽  
J. Nicholl ◽  
G. R. Barer ◽  
P. Howard
Keyword(s):  
Chronic Obstructive ◽  
Response Curves ◽  
Stimulus Response ◽  
Pulmonary Vasoconstriction ◽  
Hypoxic Vasoconstriction ◽  
Small Doses ◽  
Sigmoid Curve ◽  
Obstructive Airways Disease ◽  
High Doses ◽  
Parallel Fashion

1. To test whether almitrine might improve the arterial partial pressure of O2 in patients with chronic obstructive airways disease by improvement of ventilation-perfusion matching, we looked at the interaction between hypoxic and almitrine-induced vasoconstriction in isolated rat lungs perfused with blood at constant flow. Increases in pressure represented increases in resistance. 2. Almitrine, given in increasing doses between challenges with 2% O2, enhanced hypoxic vasoconstriction at low doses but attenuated it at high doses. 3. Stimulus-response curves to hypoxia of increasing severity gave a sigmoid curve. 4. Almitrine solvent caused small changes in pulmonary artery pressure and shifted the stimulus-response curve slightly in a parallel fashion. 5. Small doses of almitrine enhanced the action of mild to moderate hypoxia, medium doses attenuated moderately severe hypoxia, whereas high doses depressed vasoconstriction due to all degrees of hypoxia. 6. These effects of almitrine on hypoxic vasoconstriction were compared with the effect of solvent by analysis of variance; the results substantiated significant enhancement of hypoxia by small doses and attenuation by large doses. 7. In patients, if similar effects apply, small doses of almitrine would assist ventilation-perfusion matching, but large doses might worsen it. 8. Almitrine-induced vasoconstriction was attenuated by a fall in perfusate temperature in a similar manner to hypoxic vasoconstriction. It was also attenuated by three drugs, chlorpheniramine, propanolol and diethylcarbamazine, all of which also decrease hypoxic vasoconstriction. The similarity between hypoxic and almitrine-induced pulmonary vasoconstriction is further confirmed.

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