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Article ; Online: Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy.

Scherrmann, J M

The AAPS journal

2020 Volume 22, Issue 4, Page(s) 86

Abstract: The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is ... ...

Abstract	The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/agonists ; Anti-Infective Agents/pharmacology ; Anti-Infective Agents/therapeutic use ; Azithromycin/pharmacology ; Azithromycin/therapeutic use ; COVID-19 ; Coronavirus Infections/drug therapy ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Hydroxychloroquine/pharmacology ; Hydroxychloroquine/therapeutic use ; Pandemics ; Pneumonia, Viral/drug therapy
Chemical Substances	ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; Anti-Infective Agents ; Hydroxychloroquine (4QWG6N8QKH) ; Azithromycin (83905-01-5)
Keywords	covid19
Language	English
Publishing date	2020-06-12
Publishing country	United States
Document type	Journal Article
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-020-00465-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy

Scherrmann, J M

AAPS J

Abstract	The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #596013
Database	COVID19

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Article ; Online: Corrigendum to "Pharmacokinetic simulations to explore dissolution criteria of BCS I and III biowaivers with and without MDR-1 efflux transporter" [European Journal of Pharmaceutical Sciences Volume 61, 30 September 2014, Pages 18-26].

Kortejärvi, H / Malkki, J / Shawahna, R / Scherrmann, J-M / Urtti, A / Yliperttula, M

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2019 Volume 131, Page(s) 254

Language	English
Publishing date	2019-02-20
Publishing country	Netherlands
Document type	Journal Article ; Published Erratum
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2019.03.004
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Article: Drug delivery to brain via the blood-brain barrier.

Scherrmann, J M

Vascular pharmacology

2003 Volume 38, Issue 6, Page(s) 349–354

Abstract: 1. Many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. Despite major advances in neuroscience, the blood-brain barrier (BBB) ensures that many potential therapeutic cannot reach the ... ...

Abstract	1. Many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. Despite major advances in neuroscience, the blood-brain barrier (BBB) ensures that many potential therapeutic cannot reach the central nervous system (CNS). The BBB is formed by the complex tight junctions between the endothelial cells of the brain capillaries and their low endocytic activity. This results in the capillary wall that behaves as a continuous lipid bilayer and prevents the passage of polar and lipid-insoluble substances. It is, therefore, the major obstacle to drugs that may combat diseases affecting the CNS. 2. Several strategies for delivering drugs to the CNS have been developed. These enhance the capacity of therapeutic molecules to cross the BBB by modifying the drug itself, or by coupling it to a vector for receptor-mediated or adsorption-mediated transcytosis. 3. The current challenge is to develop drug-delivery systems that ensure that drugs cross the BBB in a safe and effective manner. This review focuses on the strategies developed to enhance drug delivery across the BBB.
MeSH term(s)	Animals ; Biological Transport ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/physiology ; Brain/metabolism ; Drug Carriers ; Drug Delivery Systems ; Endothelium, Vascular/metabolism ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism
Chemical Substances	Drug Carriers ; Pharmaceutical Preparations
Language	English
Publishing date	2003-01-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2082846-9
ISSN	1537-1891 ; 1537-1891 ; 1879-3649
ISSN (online)	1537-1891
ISSN	1537-1891 ; 1879-3649
DOI	10.1016/s1537-1891(02)00202-1
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Article: Les échanges à travers la barrière hémato-encéphalique.

Scherrmann, J M

Annales pharmaceutiques francaises

2002 Volume 60, Issue 6, Page(s) 372–379

Abstract: The blood-brain barrier (BBB) is the main interface controlling the exchange of nutrients and drugs between the blood and brain. Its specificity is given by some specific properties of the endothelium of the brain capillaries. They include the presence ... ...

Title translation	Exchanges through the blood-brain barrier.
Abstract	The blood-brain barrier (BBB) is the main interface controlling the exchange of nutrients and drugs between the blood and brain. Its specificity is given by some specific properties of the endothelium of the brain capillaries. They include the presence of tight junctions sealing adjacent endothelial cells and the absence of fenestrations preventing paracellular transport pathway across the BBB. The BBB is also a metabolic and pharmacological barrier because of the activity of many cytosolic enzymes and transporters expressed both or either at the luminal or abluminal faces of the brain microvessel endothelial cells. Macromolecules like insulin, leptin and transferrin may cross the BBB via receptor mediated transcytosis. More recently the discovery of P-glycoprotein, an ABC protein, at the luminal membrane of the brain endothelial cells has shown that several lipophilic antimitotic and psychotropic drugs are pumped out of the brain by this transporter. All these properties illustrate how complex the exchanges of nutrients and drugs across the BBB are.
MeSH term(s)	Animals ; Biological Transport, Active/physiology ; Blood-Aqueous Barrier/physiology ; Endothelium, Vascular/cytology ; Endothelium, Vascular/physiology ; Humans
Language	French
Publishing date	2002-11
Publishing country	France
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	307-4
ISSN	0003-4509
ISSN	0003-4509
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Article: Biodynamique de la réaction antigène-anticorps in vivo.

Scherrmann, J M

Bulletin de l'Academie nationale de medecine

2000 Volume 184, Issue 3, Page(s) 637–46; discussion 647–9

Abstract: The success of the toxin neutralization by a specific antibody in a living system depends on multiple factors. First, the type of the actual available antibody structures (immunoglobulin G, Fab2 or Fab fragments) must be selected according to the toxin ... ...

Title translation	Biodynamics of the antigen-antibody reaction in vivo.
Abstract	The success of the toxin neutralization by a specific antibody in a living system depends on multiple factors. First, the type of the actual available antibody structures (immunoglobulin G, Fab2 or Fab fragments) must be selected according to the toxin molecular weight: Fab is adapted to the neutralization of haptens, IgG and Fab2 to macromolecular toxins. Other factors involved in the success of immunotherapy are issued from the pharmacokinetic properties of the toxin: non reversible binding to the receptor, intracellular distribution of a macromolecular toxin are disadvantageous. Finally, the selection of the antibody dose according to its association constant value for the toxin allows to administer the optimal capacity of immunoneutralization. The control of all these factors inserted in the biodynamics of the living system contributes to the success of immunotherapy.
MeSH term(s)	Antigen-Antibody Reactions/immunology ; Humans ; Immunization, Passive
Language	French
Publishing date	2000
Publishing country	Netherlands
Document type	English Abstract ; Journal Article
ZDB-ID	213227-8
ISSN	0001-4079
ISSN	0001-4079
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Article ; Online: Pharmacokinetic simulations to explore dissolution criteria of BCS I and III biowaivers with and without MDR-1 efflux transporter.

Kortejärvi, H / Malkki, J / Shawahna, R / Scherrmann, J-M / Urtti, A / Yliperttula, M

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2014 Volume 61, Page(s) 18–26

Abstract: In this study, a pharmacokinetic simulation model was used to explore the dissolution acceptance criteria for BCS I and III biowaivers and to examine the risk of MDR-1 efflux transporter on bioequivalence of substrates. The compartmental absorption and ... ...

Abstract	In this study, a pharmacokinetic simulation model was used to explore the dissolution acceptance criteria for BCS I and III biowaivers and to examine the risk of MDR-1 efflux transporter on bioequivalence of substrates. The compartmental absorption and transit (CAT) model with one- or two systemic compartments was used. The parameter values used in the simulations were based on the pharmacokinetics of existing 70 BCS I and III drugs. Based on the simulations BCS I drug products with Tmax of >0.9 h, both dissolution criteria "very rapid" and "rapid and similar" were acceptable. For rapidly absorbed and distributed BCS I drug products with Tmax of 0.6-0.9 h, the dissolution criterion "very rapid" is preferred. If Tmax is less than 0.6 h there is a risk of bioinequivalence for the BCS I drug products regardless of the dissolution criteria. Based on the simulations, all BCS III drug products were good biowaiver candidates with both dissolution criteria. Almost all the BCS III drug products (>89%) and many BCS I products (9-57%) showed risks of bioinequivalence, if an excipient in either product inhibits MDR1-efflux transport of the drug. To eliminate these risks excipients with prior use in bioequivalent products should be used for MDR-1 efflux substrates.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Absorption, Physiological ; Biological Transport ; Biopharmaceutics/classification ; Humans ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics ; Therapeutic Equivalency
Chemical Substances	ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; Pharmaceutical Preparations
Language	English
Publishing date	2014-02-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2014.02.004
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Article: Iode stable et prévention de la contamination par les iodes radioactifs : données pharmacologiques et pharmaceutiques.

Hosten, B / Rizzo-Padoin, N / Scherrmann, J-M / Bloch, V

Annales pharmaceutiques francaises

2012 Volume 70, Issue 2, Page(s) 75–81

Abstract: More or less rapid radio-induction of thyroidian cancers is the main pathological consequence of an accidental exposure to ingested or inhaled radioactive iodines following a nuclear power plant accident. The prophylactic administration of potassium ... ...

Title translation	Stable iodine as a prophylaxis therapy following exposure to radioactive iodines: pharmacological and pharmaceutical characteristics.
Abstract	More or less rapid radio-induction of thyroidian cancers is the main pathological consequence of an accidental exposure to ingested or inhaled radioactive iodines following a nuclear power plant accident. The prophylactic administration of potassium iodine in a single oral dose has to be practiced as soon as possible after the nuclear accident. The efficacy of this therapy depends on pharmacokinetics of radioidines. Iodines are rapidly and completely absorbed as iodides. The radioactive iodines, mainly iodine 131, concentrate in the thyroid gland because of a carrier-mediated transport by the Na-I symporter. Administration of stable iodine results in the symporter blockade, which limits the uptake of radioactive iodines by the thyroid and the duration of the internal irradiation. This irradiation will never exceed 3days if the therapy is started between 6h before the accidental exposure and 1h after. The pharmacist asked to dispense the tablets of stable iodine has a important place because, besides his advices on the optimal modalities of taking stable iodine and the risks of unwanted effects, he extend these advices to information on the radioactive risk and on measures of civil and sanitary protection.
MeSH term(s)	Humans ; Inhalation Exposure ; Iodine Compounds/adverse effects ; Iodine Compounds/chemistry ; Iodine Compounds/pharmacokinetics ; Iodine Compounds/pharmacology ; Iodine Compounds/therapeutic use ; Iodine Radioisotopes/adverse effects ; Iodine Radioisotopes/pharmacokinetics ; Lung/metabolism ; Neoplasms, Radiation-Induced/prevention & control ; Radioactive Hazard Release ; Thyroid Gland/metabolism ; Thyroid Hormones/biosynthesis ; Thyroid Neoplasms/etiology ; Thyroid Neoplasms/prevention & control
Chemical Substances	Iodine Compounds ; Iodine Radioisotopes ; Thyroid Hormones
Language	French
Publishing date	2012-03
Publishing country	France
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	307-4
ISSN	0003-4509
ISSN	0003-4509
DOI	10.1016/j.pharma.2012.01.003
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Article: Toxicokinetic-toxicodynamic models describing the relation of plasma and red blood cell potassium with plasma digitalis in acute human digitalis poisoning.

Urtizberea, M / Rochdi, M / Baud, F J / Scherrmann, J M

Toxicology in vitro : an international journal published in association with BIBRA

2010 Volume 4, Issue 4-5, Page(s) 526–531

Abstract: Toxicity of cardiac glycosides involves the inhibition of the Na(+)-K(+) ATPase pump. As a consequence, extracellular K(+) concentration rises and intracellular K(+) concentration strongly decreases. Red blood cell (RBC) K(+) is a practical marker of ... ...

Abstract	Toxicity of cardiac glycosides involves the inhibition of the Na(+)-K(+) ATPase pump. As a consequence, extracellular K(+) concentration rises and intracellular K(+) concentration strongly decreases. Red blood cell (RBC) K(+) is a practical marker of ATPase inhibition. In a group of 15 patients intoxicated by digitoxin and lanatoside C, correlations between the calculated digitoxin ingested dose or plasma digitoxin levels and the kinetics of plasma K(+) and RBC K(+) have been assessed using kinetic-effect modelling. A correlation between the calculated ingested dose of digitoxin with RBC K(+) was found (r = 0.64). A direct relation based on the linear model fitted the relation between extracellular K(+) and digitalis concentration. An indirect relation based on the Emax sigmoid model fitted the relation between RBC K(+) and digitoxin concentrations. Specific parameters were obtained from the linear model with a = 0.0196 +/- 0.0272 and b = 0.455 +/- 0.035. Specific parameters were derived from the Emax sigmoid model with k(eo) = 0.0139 +/- 0.0052/hr and EC(50) = 91.95 +/- 20.55 ng/ml, where k(eo) = first-order rate constant of the disappearance of the toxic effect and EC(50) = digitoxin concentration decreasing the RBC K(+) concentration by 50%. These data showed that the in vitro assays of plasma K(+) and RBC K(+) are convenient and predictive assays for evaluating the severity of human digitoxin poisoning.
Language	English
Publishing date	2010-07-28
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/0887-2333(90)90112-7
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Article: Antibody treatment of toxin poisoning--recent advances.

Scherrmann, J M

Journal of toxicology. Clinical toxicology

1994 Volume 32, Issue 4, Page(s) 363–375

Abstract: The major responses to the administration of specific antibody or toxin-specific fragment are described. Toxin sequestration depends on the extent and rate of antibody distribution, the antibody affinity and its ability to form a non-active immune ... ...

Abstract	The major responses to the administration of specific antibody or toxin-specific fragment are described. Toxin sequestration depends on the extent and rate of antibody distribution, the antibody affinity and its ability to form a non-active immune complex. Toxin redistribution is mainly influenced by the reversible binding and efflux kinetics of the toxin from the receptor. Finally, toxin elimination adopts the antibody elimination properties for low molecular weight compounds. These three basic mechanisms of the immuno-detoxification process could be optimized by designing the ideal antibody, in terms of size and origin, to inactivate the toxic properties. Calculation of the amount of infused antibody should be derived from the slope of the dose-effect curve rather than stoichiometrically.
MeSH term(s)	Animals ; Binding Sites/immunology ; Colchicine/immunology ; Colchicine/poisoning ; Digoxin/immunology ; Digoxin/poisoning ; Humans ; Immunotherapy/methods ; Tissue Distribution/immunology ; Toxins, Biological/immunology ; Toxins, Biological/pharmacokinetics ; Toxins, Biological/poisoning ; Venoms/immunology ; Venoms/pharmacokinetics ; Venoms/poisoning
Chemical Substances	Toxins, Biological ; Venoms ; Digoxin (73K4184T59) ; Colchicine (SML2Y3J35T)
Language	English
Publishing date	1994
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	204476-6
ISSN	1556-9519 ; 0731-3810 ; 0009-9309 ; 1556-3650
ISSN (online)	1556-9519
ISSN	0731-3810 ; 0009-9309 ; 1556-3650
DOI	10.3109/15563659409011037
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