Lipid solubility of a series of drugs and its relevance to fatal poisoning

Cassidy, S.L.; Lympany, Penny; Henry, John A.

doi:10.1111/j.2042-7158.1988.tb05197.x

Cited by 16 publications

(5 citation statements)

References 18 publications

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“…4), suggesting that lipid emulsion-mediated attenuation of local anesthetic-induced vasodilation does not appear to be associated with the lipid emulsion-mediated enhancement of phenylephrine-induced contraction. As diltiazem is a relatively lipid-soluble calcium channel antagonist (octanol/water partition coefficient: 19.4), we used diltiazem in this study 18,27. We examined the effects of lipid emulsions on diltiazem-induced vasodilation to investigate whether the lipid emulsion-mediated attenuation of local anesthetic-induced vasodilation is a non-specific action indicating binding of lipid-soluble drug by lipid emulsions.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether lipid emulsion-mediated attenuation of local anesthetic-induced vasodilation is a non-specific action associated with entrapment of lipid-soluble drug by lipid emulsion, we assessed the effects of lipid emulsions on diltiazem, a relatively lipid-soluble calcium channel antagonist, which induced vasodilation in endothelium-denuded aorta precontracted with 10 -7 M phenylephrine 18. After phenylephrine (10 -7 M)-induced contractions had stabilized in endothelium-denuded aorta pretreated with or without lipid emulsions (1.40 and 2.61%) for 20 min, incremental concentrations of diltiazem (10 -8 to 3×10 -4 M) were added to the organ bath to produce diltiazem concentration-response curves.…”

Section: Methodsmentioning

confidence: 99%

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Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

Lee

Sung

et al. 2013

Yonsei Med J

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PurposeIntravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics.Materials and MethodsThe effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10-4 M levobupivacaine, 2×10-3 M ropivacaine, and 7×10-3 M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed.ResultsLipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10-3 M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics.ConclusionTaken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

Lee

Sung

et al. 2013

Yonsei Med J

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“…6 ] 8 Other estimates of relative drug toxicity have been based on their noctanol/water partition coefficients, 1,9 their solubi-lities in n -octanol 9 and their median fatal blood concentrations reported in the literature. 10,11 Synergistic effects of drugs and alcohol have been studied in vitro with regard to their cell membrane stabilizing activity (MSA), 12 which is suggested to be an important non-specific mechanism of acute toxicity. 13 ] 15 Clinical interaction has typically been assessed in human psychomotor performance tests and in animal toxicology experiments.…”

Section: Introductionmentioning

confidence: 99%

Interaction of alcohol and drugs in fatal poisonings

Koski

Ojanperä²,

Vuori

2003

Hum Exp Toxicol

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In Finnish data from 1995 / 2000, 1006 fatal poisonings due to alcohol (ethanol), a single drug or both were statistically analysed in retrospect to evaluate the interaction between alcohol and drugs. In 53% of these cases, low concentrations of some common benzodiazepines were present. The median postmortem blood alcohol concentration (BAC) was 3.3 (w/w) in the 615 alcohol poisonings, but significantly lower, ranging from 1.3 to 1.7, when promazine, doxepin, amitriptyline or propoxyphene were found together with alcohol. When levomepromazine, temazepam or zopiclone were present, the median BAC was also significantly lower, 2.5 trations of a drug (excluding citalopram), suggesting a positive concentration / effect relationship. Fatal toxicity indices (FTIs) were calculated by relating the number of deaths caused by a drug to the corresponding sales figures. Promazine had an extremely high FTI, followed by levomepromazine, propoxyphene, doxepin and amitriptyline. The other drugs had relatively low FTIs. The results reflect not only the acute toxicity of a given drug / alcohol combination but also the manners of use and abuse of these drugs.

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“…The apparent solubility of the HCl salt of TRH was reported to be 38.5 mg/ml 29 and 22 mg/ml at a pH of 5.0 30 . The n-octanol water partition coefficient of TRH was found to be 63.3 at pH 7.4 31 . It is clear that the inclusion of this drug to oil core nanocapsule will increase its loading and entrapment into the nanocapsules.…”

Section: Resultsmentioning

confidence: 93%

Trazodone Loaded Lipid Core Poly (ε-caprolactone) Nanocapsules: Development, Characterization and in Vivo Antidepressant Effect Evaluation

Elhesaisy

Swidan

2020

Sci Rep

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trazodone Loaded Lipid core poly (ε-caprolactone) nanocapsules: Development, characterization and in Vivo Antidepressant Effect evaluation nahla elhesaisy 1 & Shady Swidan 1,2* Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. to enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy. Depression is one of the most common, chronic and debilitating psychological disorders that may lead eventually to patient suicide 1. It is characterized by many symptoms like feeling hopelessness or inappropriate guilt, low energy, change in sleep, change in appetite and recurrent thoughts of suicide. Its consequences not only affect the patient, but also affect negatively the whole society. The financial consequences of this disease are tremendous and cause an overwhelming burden on the society. This burden is due to the dramatically decrease in productivity and absenteeism in the workplace. Depression mainly occurred due to the deficiency of both serotonin and norepinephrine neurotransmitters in the brain 2. Trazodone hydrochloride (TRH) is one of the most potent drugs used for the treatment of depression (Fig. 1). It is a triazolopyridine derivative with antidepressant effect 3. It is thought that the mechanism of action of TRH is due to its activity at 5-HT1, 5-HT2 serotonergic receptors. It also acts on poorly blocking serotonin reuptake and selectively blocking presynaptic receptors. In addition, TRH blocks alpha-2 adrenoceptors 4. TRH possesses unique properties compared to other antidepressants. TRH causes fewer anticholinergic side effects compared to the tricyclic antidepressant. It also has an activity against anxiety which is concomitant to depressed patients. Several studies showed that at therapeutic doses TRH is less likely to cause cardiotoxicity than imipramine. TRH also does not result in neurologic side effects and seems to be well tolerat...

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Lipid solubility of a series of drugs and its relevance to fatal poisoning

Cited by 16 publications

References 18 publications

Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

Interaction of alcohol and drugs in fatal poisonings

Trazodone Loaded Lipid Core Poly (ε-caprolactone) Nanocapsules: Development, Characterization and in Vivo Antidepressant Effect Evaluation

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