4-Chloro-m-cresol Triggers Malignant Hyperthermia in Susceptible Swine at Doses Greatly Exceeding Those Found in Drug Preparations

1999 ◽  
Vol 90 (6) ◽  
pp. 1723-1732. ◽  
Author(s):  
Paul A. Iaizzo ◽  
Brooks A. Johnson ◽  
Kaoru Nagao ◽  
William J. Gallagher
Keyword(s):  
Malignant Hyperthermia ◽  
Blood Chemistry ◽  
Response Curves ◽  
End Tidal ◽  
In Vivo Effects ◽  
Higher Doses ◽  
End Tidal Co2 ◽  
Cardiovascular Reactions

Background Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. Methods Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. Results Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). Conclusions 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

In Vivo Studies On The Inhibition Of Coagulation By A Heparin Analogue

1981 ◽  
Author(s):  
U Schmitz-Huebner ◽  
F Asbeck ◽  
J van de Loo
Keyword(s):  
Plasma Sample ◽  
Anticoagulant Activity ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
At Iii ◽  
In Vivo Effects ◽  
Higher Doses ◽  
Free Plasma

SSHA, a semi-synthetic heparin analogue belonging to the chondroitin family, was reported to induce considerable anti-Xa activity in vivo being practically inactive in vitro. In a study designed to elucidate further the in vivo effects of this drug, SSHA and sodium heparin from porcine intestinal mucosa were injected subcutaneously into six volunteers on separate occasions over a period of three days in a cross-over trial. Before injection and 2,4,6,8 hours afterwards, the heparin-like activity was measured by means of the APTT, the anti -Xa clotting test and two chromogenic substrate assays. The results show that SSHA mediates both anti-Xa and antithrombin activities in vivo. A comparison between the effects of SSHA and heparin is problematical, due to the heterogeneity of different heparin preparations. Low doses of the analogue (45 mg s.c.) induce proportionally higher and longer lasting anti-Xa activities than higher doses (90 mg s.c.). In an attempt to identify the mediator involved in the anticoagulant activity induced by SSHA in vivo, antithrombin III AT III) was removed from a plasma sample of one the subjects obtaining SSHA injections by immunosorption using Sepharose IVb coupled with antibodies against AT III. The AT III free plasma obtained was found to be devoid of heparin-like activity in the anti-Xa clotting test but it maintained its anticoagulant activity in the APTT assay. When purified AT III was added to this plasma its anti-Xa activity was largely restored. In conclusion, the inhibitory effect of SSHA on coagulation seems to involve at least two mechanisms: a direct one which does not depend on AT III and an indirect one, induced in vivo and mediated by AT III.

RELEASE OF THYROTROPHIN IN VIVO AND IN VITRO BY SYNTHETIC NEUROHYPOPHYSIAL HORMONES

1964 ◽  
Vol 42 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Frank S. LaBella
Keyword(s):  
Dose Response ◽  
In Vitro Release ◽  
Optimal Level ◽  
Response Curves ◽  
Low Concentrations ◽  
Pituitary Glands ◽  
In Vivo Effects ◽  
Synthetic Oxytocin

The influence of synthetic oxytocin and synthetic lysine-8-vasopressin on the release of thyrotrophin (TSH) from slices of the "basophilic" zone of bovine anterior pituitary glands was determined. Up to 10-fold stimulation of TSH release occurred in the presence of the peptide hormones at low concentrations (approximately 10−11 to 10−9 M). Concentrations greater than 10−9 M were less stimulatory, ineffective, or inhibitory. In general, vasopressin stimulated at lower concentrations than did oxytocin. The dose–response curve of oxytocin began to descend at lower concentrations than did that of vasopressin.Stimulation of I131 discharge from the thyroids of propylthiouracil (PTU)-treated, day-old chicks was produced by the intraperitoneal injection of as little as 4 ng vasopressin or 25 ng oxytocin. As the injected dose of either peptide was increased beyond an optimal level, there was less enhancement of I131 discharge, and, with further increases, inhibition. The decreasing response began with lower doses of oxytocin than of vasopressin. The similarities of the dose–response curves of thyroid I131 discharge and of in vitro release of TSH indicate that the in vivo effects of injected neurohypophysial peptides are mediated through the release of endogenous TSH.

scholarly journals Propofol is a ‘Safe’ Anaesthetic Agent in Malignant Hyperthermia Susceptible Patients

1992 ◽  
Vol 20 (2) ◽  
pp. 165-168 ◽  
Author(s):  
A. J. McKenzie ◽  
K. G. Couchman ◽  
N. Pollock
Keyword(s):  
Literature Review ◽  
Malignant Hyperthermia ◽  
Muscle Biopsy ◽  
Anaesthetic Agent ◽  
Anaesthetic Technique ◽  
Malignant Hyperthermia Susceptible ◽  
Therapeutic Procedures ◽  
In Vivo Effects

In this study we investigated in vitro and in vivo effects of propofol in malignant hyperthermia susceptible (MHS) patients in order to assess the safety of propofol infusion as a non-triggering anaesthetic technique for diagnostic and therapeutic procedures. In vitro, human MHS muscle samples were exposed to propofol and changes in (a) baseline tension and (b) contracture tension on exposure to halothane and caffeine were measured. In vivo, (a) anaesthesia was induced in ten muscle biopsy positive MHS patients with propofol 2.5 mg/kg and (b) anaesthesia was produced in five muscle biopsy positive MHS patients with infusions of propofol up to 10 mg/kg/hr. In vitro, human MHS muscle did not develop contractures with propofol alone. Propofol had no significant effect on contracture development in response to halothane and caffeine. In vivo, no evidence of an MH response was detected following induction or maintenance of anaesthesia with propofol. Our results and literature review are in agreement that propofol is a ‘safe’ induction and maintenance agent in MHS patients. Propofol can be used for muscle biopsy anaesthesia because it does not alter the sensitivity of diagnostic muscle biopsy testing.

scholarly journals Effects of Theophylline on Anesthetized Malignant Hyperthermia-Susceptible Pigs

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
Marko Fiege ◽  
Ralf Weisshorn ◽  
Kerstin Kolodzie ◽  
Frank Wappler ◽  
Mark U. Gerbershagen
Keyword(s):  
Malignant Hyperthermia ◽  
Body Core Temperature ◽  
Central Venous ◽  
Blood Concentrations ◽  
Malignant Hyperthermia Susceptible ◽  
Body Core ◽  
Genetically Determined ◽  
In Vivo Effects

Background. Theophylline was shown to induce contracture development in porcine malignant hyperthermia (MH) susceptible (MHS) skeletal muscles in vitro. The purpose of the current study was to investigate the in vivo effects of theophylline in MHS and MH normal (MHN) swine.Methods. MH-trigger-free general anesthesia was performed in MHS and MHN swine. Theophylline was administered intravenously in cumulative doses up to 93.5 mg⋅kg-1. The clinical occurrence of MH was defined by changes of central-venous pCO2, central-venous pH, and body core temperature.Results. Theophylline induced comparable clinical alterations in the anesthetized MHS and MHN swine, especially in regard to hemodynamic data. No pig developed hypermetabolism and/or MH according to defined criteria. All animals died with tachycardia followed by ventricular fibrillation.Conclusions. The cumulative theophylline doses used in this study were much higher than doses used therapeutically in humans, as demonstrated by measured blood concentrations. Theophylline is thus not a trigger of MH in genetically determined swine.

In vitro Stimulation of Granulosa Cells by a Combination of Different Active Ingredients of Unkei-to

2004 ◽  
Vol 32 (04) ◽  
pp. 569-578 ◽  
Author(s):  
Wen-Shu Sun ◽  
Atsushi Imai ◽  
Keiko Tagami ◽  
Michiyo Sugiyama ◽  
Tatsuro Furui ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Response Curves ◽  
Vitro Fertilization ◽  
Human Granulosa Cells ◽  
Estradiol Secretion ◽  
Paeoniae Radix ◽  
In Vivo Effects ◽  
Stimulation Of

Unkei-to is widely used in traditional Japanese herbal medicine for its ovulation-inducing effect. In the present study, we investigated the in vivo effects of Unkei-to and its compounds on the steroidogenesis and cytokine secretion in human granulosa cells. Unkei-to stimulated the secretions of 17β-estradiol and progesterone from highly luteinized granulosa cells obtained from in vitro fertilization patients; the stimulated effect on estradiol secretion occurred with 0.3 μg/ml, while a significant effect on progesterone secretion was obtained at 10 μg/ml. The Unkei-to stimulation of estradiol secretion could be accounted for by the effects of its ingredients, Shakuyaku (paeoniae radix, Paeonia lactiflora Pallas) and Keihi (cinnamomi cortex, Cinnamomum cassia Blume); while dose response curves for Unkei-to and Keihi to induce progesterone production were superimposable. Exposure of the cells to Unkei-to caused dose-dependent increases in the concentrations of interleukin (IL)-1β, IL-6 and IL-8 in the culture medium. Similar results were obtained when cells were incubated with the ingredient Ninjin (ginseng radix, Panax ginseng C.A. Meyer), but not Shakuyaku and Keihi. These results indicate that Unkei-to has direct stimulatory effects on human granulosa cells to stimulate the steroidogenesis and secretion of cytokines (IL-1β, IL-6 and IL-8). The various beneficial actions of Unkei-to on the ovary may result from a combination of different ingredient herbs with different stimulatory effects on both steroidogenesis and the ovulatory process within the ovary, as well as stimulatory effect on the hypothalamus-pituitary axis.

In Vitro  and In Vivo  Effects of the Phosphodiesterase-III Inhibitor Enoximone on Malignant Hyperthermia–susceptible Swine

2003 ◽  
Vol 98 (4) ◽  
pp. 944-949 ◽  
Author(s):  
Marko Fiege ◽  
Frank Wappler ◽  
Ralf Weisshorn ◽  
Mark U. Gerbershagen ◽  
Kerstin Kolodzie ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Cardiovascular Failure ◽  
In Vitro Contracture Test ◽  
Circulatory Insufficiency ◽  
Phosphodiesterase Iii Inhibitor ◽  
Genetically Determined ◽  
In Vivo Effects ◽  
Phosphodiesterase Iii

Background In human skeletal muscles, the phosphodiesterase-III inhibitor enoximone induces in vitro contracture development, and it has been suggested that enoximone could trigger malignant hyperthermia (MH). In this study, the in vitro and in vivo effects of enoximone in MH-normal (MHN) and MH-susceptible (MHS) swine were investigated. Methods Malignant hyperthermia trigger-free general anesthesia was performed in MHS and MHN swine. Skeletal muscle specimens were excised for an in vitro contracture test with 0.6 mm enoximone. Thereafter, MHS and MHN swine were exposed to cumulative administration of 0.5, 1, 2, 4, 8, 16, and 32 mg/kg enoximone intravenously. Clinical occurrence of MH was defined by a Pco(2) greater than 70 mmHg, a pH less than 7.20, and an increase in body temperature of more than 2.0 degrees C. Results Enoximone induced marked contractures in all MHS muscle specimens in vitro. In contrast, only small or no contracture development was observed in MHN muscle specimens, without an overlap in contractures between MHS and MHN muscles. However, in vivo, no clinical differences were found between MHS and MHN swine following cumulative enoximone doses. According to the defined criteria, none of the swine developed MH during the experiment. Furthermore, high enoximone doses induced progressive circulatory insufficiency, and after receiving 32 mg/kg enoximone, all animals died of cardiovascular failure. Conclusions The cumulative enoximone doses used in this study were 30- to 50-fold higher than therapeutic doses in humans. Enoximone does not trigger MH in genetically determined swine. However, enoximone might be useful for in vitro diagnosis of MH.

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

1986 ◽  
Vol 56 (03) ◽  
pp. 318-322 ◽  
Author(s):  
V Diness ◽  
P B Østergaard
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Protamine Sulfate ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

Pharmacology of 5-HT1A Receptors: Critical Aspects

CNS Spectrums ◽  
1998 ◽  
Vol 3 (10) ◽  
pp. 17-38 ◽  
Author(s):  
Franco Borsini
Keyword(s):  
Receptor Subtypes ◽  
Laboratory Conditions ◽  
In Vivo Effects ◽  
Critical Aspects

AbstractMyriad difficulties exist in analyzing the pharmacology of the serotonin 1A (5-HT1A) receptor. The receptor may demonstrate a different activity depending on the tissue or species used for analysis, the agent used, laboratory conditions, and differences between in vitro and in vivo effects of compounds. Affinity for 5-HT receptors also varies widely, presenting difficulties in drawing definitive conclusions on affinity values for various compounds. At least two possibilities exist to explain the diversity of pharmacology of 5-HT receptors. First, it is possible that different 5-HT1A receptor subtypes exist. Second, the 5-HT1A receptors may play a far more complex role than previously believed.

In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone

2021 ◽  
pp. 096032712199945
Author(s):  
AT Aliyev ◽  
S Ozcan-Sezer ◽  
A Akdemir ◽  
H Gurer-Orhan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Antitumor Effects ◽  
Antiestrogenic Activity ◽  
Er Positive ◽  
In Vivo Effects ◽  
Mcf 7

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

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