The Phenothiazinetranquilizers: Biochemical and Biophysical Actions

Guth, Paul S.; Spirtes, Morris A.

doi:10.1016/s0074-7742(08)60269-x

Cited by 143 publications

(29 citation statements)

References 101 publications

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“…Thus, it has been reported that the nonprotonated drug present at high pH values demonstrated a dramatic increase in the surface activity (37). It was also reported that as the hydrophobicity of compounds increased, their effect on membranes increased (10,25). This might be the reason beyond the increased antibacterial effects of azelastine against the tested isolates at high pH values especially at pH 8 (Fig.…”

Section: Resultsmentioning

confidence: 80%

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates

El-Nakeeb¹,

Abou-Shleib²,

Khalil³

et al. 2011

Braz. J. Microbiol.

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Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 g/ml azelastine was also determined and reached up to 3.36 h.

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Section: Resultsmentioning

confidence: 80%

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates

El-Nakeeb¹,

Abou-Shleib²,

Khalil³

et al. 2011

Braz. J. Microbiol.

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“…Chlorpromazine in high concentrations (10-3M) has been shown to inhibit brain mitochondrial monoamine oxidase in vitro (Nakajima, 1959), but there are no experimental data to suggest that low doses activate monoamine oxidase. There is considerable evidence that high and low doses of chlorpromazine have opposite effects on the permeability characteristics of membranes (Guth & Spirtis, 1964).…”

Section: Discussionmentioning

confidence: 99%

Effects of chlorpromazine on the metabolism of catecholamines in dog brain

Guldberg

Yates

1969

British J Pharmacology

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1. The effect of chlorpromazine (CPZ) on the metabolism of dopamine and 5-hydroxytryptamine in dog brain was investigated by following the concentrations of the acid metabolites of these amines, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid, in the ventricular cerebrospinal fluid (C.S.F.) of dogs over a period of 5 hr after intravenous administration of CPZ (2'5, 5, 10 and 15 mg/kg), using the technique of serial sampling of lateral ventricular C.S.F. "Low" doses (25-10 mg/kg) produced a rise in the concentration of homovanillic acid and smaller increases in the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. "High" doses (10-15 mg/kg) had a lesser effect on the concentration of homovanillic acid and had no effect on, or decreased, the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. The concentration of 3,4-dihydroxyphenylacetic acid was maximal in the ventricular C.S.F. 2 hr after CPZ 5 mg/kg and was unaltered from the control level 2 hr after 15 mg/kg. 2. The effects on the metaibolism of brain amines of CPZ (5 mg/kg), doses which the serial sampling of C.S.F. experiments had indicated as producing maximal and minimal effects on dopamine metabolism in brain tissue, were studied by estimating the concentrations of adrenaline, noradrenaline, dopamine, metanephrine, methoxydopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the hypothalamus, midbrain, thalamus, hindbrain, cortex, globus pallidus and caudate nucleus of control dogs and of dogs treated with CPZ intravenously 2 hr before killing. The concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid were estimated in samples of ventricular C.S.F. withdrawn from these dogs 2 hr after the injection of CPZ (i.e., immediately before death).3. The following changes in concentrations were observed. Dopamine: CPZ 5 mg/kg produced no change in the concentration in the caudate nucleus, globus pallidus and midbrain and increased the concentration in the thalamus; CPZ 15 mg/kg appeared to cause a reduction in the concentration of this amine in the caudate nucleus and globus pallidus. Homovanillic acid and 3,4-dihydroxyphenylacetic acid: CPZ 5 mg/kg increased the concentrations of both acids in the caudate nucleus and had no effect on the concentrations * Present address:

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“…The ability of the macrophage to concentrate CPZ had previously been established (20,23), and Crowle et al (10) postulated that the intracellular killing activity of CPZ is due to this concentrating ability of the macrophage. At that time (the early 1990s) the problem of tuberculosis (TB) was not significant in most Western countries.…”

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confidence: 99%

“…Because this compound is concentrated by human macrophages (10,20,23) and is active against intracellular Staphylococcus aureus, regardless of its susceptibility or resistance to methicillin (32), we have repeated the latter studies with M. tuberculosis in place of staphylococci. The results of this study provide strong direct evidence that TZ, a neuroleptic that is milder and less toxic than CPZ, kills intracellular M. tuberculosis isolates that are resistant to two or more antibiotics when the concentration of TZ in the medium approaches that in the plasma of a patient chronically managed with this compound.…”

mentioning

confidence: 99%

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

Ordway

Viveiros

Leandro

et al. 2003

Antimicrob Agents Chemother

191

168

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The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro activities against antibiotic-sensitive and -resistant Mycobacterium tuberculosis. These compounds have not been used as anti-M. tuberculosis agents because their in vitro activities take place at concentrations which are beyond those that are clinically achievable. In addition, chronic administration of CPZ produces frequent severe side effects. Because CPZ has been shown to enhance the killing of intracellular M. tuberculosis at concentrations in the medium that are clinically relevant, we have investigated whether TZ, a phenothiazine whose negative side effects are less frequent and serious than those associated with CPZ, kills M. tuberculosis organisms that have been phagocytosed by human macrophages, which have nominal killing activities against these bacteria. Both CPZ and TZ killed intracellular antibiotic-sensitive and -resistant M. tuberculosis organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant M. tuberculosis isolates. Nevertheless, we must await the outcomes of clinical trials to determine whether TZ itself may be safely and effectively used as an antituberculosis agent.

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The Phenothiazinetranquilizers: Biochemical and Biophysical Actions

Cited by 143 publications

References 101 publications

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates

Effects of chlorpromazine on the metabolism of catecholamines in dog brain

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

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