Macrolide antibiotic; Antiviral; HIV-1
50S ribosomal subunit of susceptible microorganisms (inhibits RNA-dependent protein synthesis by blocking transpeptidation and/or translocation) [1]

Macrophages (MPhis) are a major source of HIV-1 especially in patients with tuberculosis. There are MPhis that are permissive and those that restrict HIV-1. Regulation of hematopoietic cell kinase (Hck) activity and selective expression of CCAAT enhancer binding protein beta (C/EBPbeta) isoforms greatly contribute to determine distinct susceptibility of MPhis to HIV-1. Resistance is attributable to reduced expression of Hck and augmented expression of an inhibitory small isoform of C/EBPbeta. Derivatives of erythromycin A (EMA) EM201 and EM703 inhibit the replication of HIV-1 in tissue MPhis, at posttranscriptional and translational levels. We demonstrate that EM201 and EM703 convert tissue MPhis from HIV-1 susceptible to HIV-1 resistant through down-regulation of Hck and induction of small isoforms of C/EBPbeta. These drugs inhibit p38MAPK activation which is expressed only in susceptible tissue MPhis. Activated CD4(+)T cells stimulate the viral replication in HIV-1 resistant MPhis through down-regulation of small isoforms of C/EBPbeta via activation of ERK1/2. EM201 and EM703 can inhibit the MAPK activation and inhibit the burst of viral replication produced when CD4(+)T cells and MPhis interact. These EM derivatives may be highly beneficial for repression of residual HIV-1 in the lymphoreticular system of HIV-1-infected patients and offer great promise for the creation of new anti-HIV drugs for the future treatment of AIDS patients [4].

In Sweden there are several reports of mares developing acute colitis while their foals were being treated orally for Rhodococcus equi pneumonia with the combination of erythromycin and rifampicin. In this study 6 adult horses were given low oral dosages of these antibiotics, singly or in combination. Within 3 days post administration of erythromycin, in one case in combination with rifampicin, 2 horses developed severe colitis (one fatal). Clostridium difficile was isolated from one of the horses, whereas no specific pathogens were isolated from the other. Both horses had typical changes in blood parameters seen in acute colitis. Clostridium difficile was also isolated from the faeces of a third horse given an even lower dosage of erythromycin in combination with rifampicin. This horse developed very mild clinical symptoms and recovered spontaneously. In the fourth horse given erythromycin only, very high numbers of Clostridium perfringens were isolated. The horses given rifampicin only did not develop any clinical symptoms and there were no major changes in their faecal flora. In conclusion, it has been demonstrated that low dosages of erythromycin ethylsuccinate can induce severe colitis in horses associated with major changes of the intestinal microflora. Clostridium difficile has been demonstrated as a potential aetiological agent in antibiotic-induced acute colitis [5].

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Treatment of infantile Chlamydia trachomatis pneumonia with erythromycin ethylsuccinate (50 mg/kg/day, for two to three weeks) resulted in symptomatic improvement in five to seven days and negative cultures by nine days. [1]

HIV-1 Strain and Infection. M-tropic HIV-1 strain, HIV-1BaL, was collected from culture supernatant of the HIV-1 strain-infected M-MΦs as a viral resource. Mo-derived MΦs were incubated for 2 h at 37°C with 100 pg/ml p24 antigen of DNase-treated viral supernatant (p24, the 50% tissue culture infective dose (TCID50) and multiplicity of infection (MOI) are 50 ng/ml, ∼3,000 and 0.05, respectively) and then cultured in RPMI MEDIUM 1640 containing 10% FCS and CSF. If necessary, the viral inoculum was pretreated with 100 μM AZT for 2 h at 4°C. Fresh culture medium containing CSF was added every 3–4 d (20% of the volume). Heat-inactivated virus (1 h, 56°C) was used as negative control. Viral production was assayed by sequential measurement of p24 antigen in supernatants by an ELISA using a combination of two antibodies; anti-gag-p24 monoclonal antibody (Nu24) and peroxidase-labeled 10B5, or the RETRO-TEK HIV-1 p24 antigen ELISA kit for high-affinity detection of low levels of p24 antigen[4].

Coculture of HIV-1 Infected GM-MΦs with the Activated CD4+T Cells. CD4+ T cells were positively isolated from CD14− PBMCs using a MACS with anti-CD4 mAb coated microbeads. The selected population was >93% positive for CD3 and CD4. Activated CD4+ T cells were prepared by stimulation with PHA and cultured with IL-2 (30 unit/ml). GM-MΦs were incubated for 2 h at 37°C with 100 pg/ml p24 antigen of DNase-treated viral supernatant, washed twice, and then cocultured with the activated CD4+ T cells in the presence of IL-2 [4].

Absorption, Distribution and Excretion
Erythromycin succinate is dissociated within the intestine; both erythromycin and the undissociated ester are absorbed, and hydrolysis in the blood releases free erythromycin. Erythromycin succinate…is well absorbed after oral administration, especially on an empty stomach. Peak plasma concentrations are 1.5 μg/mL (0.5 μg/mL base) 1 to 2 hours after administration of a 500 mg tablet. In patients, the mean concentration of erythromycin in bile is approximately 10 times the corresponding serum concentration 1 hour after intravenous (erythromycin lactobionate) and intramuscular (erythromycin succinate) administration. Pharmacokinetics of various erythromycin formulations were studied in healthy adult subjects and adult patients with bronchial infections. Oral erythromycin ethyl succinate is superior to erythromycin stearate because the former is rapidly and stably absorbed.

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After a single oral dose of 500 mg erythromycin ethyl succinate in adults, the peak serum concentration of total drug (ester plus base) was 1.2 μg/ml, and the free base concentration was 0.6 μg/ml. The time to peak concentration was 0.5 to 2.5 hours after administration. [1]
The mean peak concentration of erythromycin ethyl succinate in middle ear secretions (acute otitis media) was 0.8 μg/ml (range 0.2–1.0 μg/ml). [1] The mean peak concentration of erythromycin ethyl succinate in tonsillar tissue was 0.45 μg/ml (range 0.2–1.3 μg/ml). [1]

The characteristic syndrome of cholestatic hepatitis is primarily associated with esters, but erythromycin ethosuccinate can also induce the syndrome. [1]
Five infants developed hypertrophic pyloric stenosis while taking erythromycin ethosuccinate, suggesting a potential class-related risk associated with esters, including ethosuccinate. [1]

[1]. Erythromycin. Med Clin North Am. 1982 Jan;66(1):79-89.

[2]. Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro. Acta Trop. 2006 Dec;100(3):185-91. Epub 2006 Nov 28.

[3]. Construction of universal quantitative models for determination of roxithromycin and erythromycin ethylsuccinate in tablets from different manufacturers using near infrared reflectance spectroscopy. J Pharm Biomed Anal. 2006 May 3;41(2):373-84.

[4]. Erythromycin derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoforms of C/EBPbeta. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12509-14.
[5]. The association of erythromycin ethylsuccinate with acute colitis in horses in Sweden. Equine Vet J. 1997 Jul;29(4):314-8.

Erythromycin ethosuccinate is a derivative of erythromycin A, with its 3R hydroxyl group replaced by (4-ethoxy-4-oxobutyryl)oxy. It is used to treat a variety of bacterial infections. It is a succinate, cyclic ketone, erythromycin derivative, and ethyl ester. Its function is related to erythromycin A. Erythromycin ethosuccinate is the ethosuccinate form of erythromycin, a broad-spectrum topical macrolide antibiotic with antibacterial activity. Erythromycin ethosuccinate can diffuse across the bacterial cell membrane and reversibly bind to the 50S subunit of the bacterial ribosome. This inhibits bacterial protein synthesis. The mechanism of action of erythromycin ethosuccinate depends on the drug concentration at the site of infection and the susceptibility of the pathogen, and may manifest as either bacteriostatic or bactericidal effects. It is a macrolide antibiotic produced by Streptomyces erythreus. The compound is an ester of erythromycin base and succinic acid. It primarily functions as a bacteriostatic agent. In susceptible bacteria, it inhibits protein synthesis by binding to the 50S ribosomal subunit. This binding process inhibits the activity of peptidyl transferases and interferes with amino acid translocation during translation and protein assembly.
See also: Erythromycin (containing the active moiety); Erythromycin ethylsuccinate; Sulfamethoxazole acetyl (component).
Therapeutic Uses
Macrolide antibiotic; enzyme inhibitor; gastrointestinal drug; protein synthesis inhibitor
Relatively less irritating…so it is well-suited for intramuscular injection. …Its action and uses are essentially the same as erythromycin…It is converted to erythromycin in vivo.
Erythromycin is…an antibacterial agent…Erythromycin is effective against most Gram-positive bacteria, many anaerobes…and Legionella. /Erythromycin/
Erythromycin may have…bacteriostatic or bactericidal effects, depending on the nature of the microorganism and the drug concentration. In vitro studies have shown that erythromycin has significant antibacterial activity against Gram-positive cocci (such as Staphylococcus aureus (sensitive or resistant to penicillin G), Group A streptococci, enterococci, and pneumococci) and many Gram-positive bacilli. /Erythromycin/
A review of the antibacterial spectrum, pharmacology, and therapeutic uses of erythromycin and its derivatives. (Reference 24).

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Erythromycin ethyl succinate is an ester derivative of erythromycin base. It is an oral formulation designed to improve stability and absorption. The ester itself is inactive and must be hydrolyzed in vivo back to free erythromycin base to exert its antibacterial activity. [1]
It has been mentioned as an option for the treatment of infantile chlamydial pneumonia. [1]
Due to the risk of hepatotoxicity, the U.S. Food and Drug Administration (FDA) is working to remove erythromycin ester solid dosage forms from clinical use. While this move is specifically aimed at esters, it also highlights concerns about the regulation of erythromycin ester drugs. [1]

C43H75NO16

862.0527

861.508

C, 59.91; H, 8.77; N, 1.62; O, 29.69

1264-62-6

Erythromycin;114-07-8;Erythromycin ethylsuccinate-13C,d3

443953

White to off-white solid powder

1.2±0.1 g/cm3

874.1±65.0 °C at 760 mmHg

219-224ºC

482.4±34.3 °C

0.0±0.6 mmHg at 25°C

1.529

Saccharopolyspora erythraea

4.1

4

17

14

60

1450

18

O([C@@]1([H])[C@@]([H])([C@]([H])(C([H])([H])[C@@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])OC(C([H])([H])C([H])([H])C(=O)OC([H])([H])C([H])([H])[H])=O)[C@@]1([H])[C@@](C([H])([H])[H])(C([H])([H])[C@@]([H])(C([H])([H])[H])C([C@]([H])(C([H])([H])[H])[C@]([H])([C@@](C([H])([H])[H])([C@@]([H])(C([H])([H])C([H])([H])[H])OC([C@]([H])(C([H])([H])[H])[C@]([H])([C@]1([H])C([H])([H])[H])O[C@@]1([H])C([H])([H])[C@](C([H])([H])[H])([C@]([H])([C@]([H])(C([H])([H])[H])O1)O[H])OC([H])([H])[H])=O)O[H])O[H])=O)O[H]

NSYZCCDSJNWWJL-YXOIYICCSA-N

InChI=1S/C43H75NO16/c1-15-29-43(11,52)36(48)24(5)33(47)22(3)20-41(9,51)38(25(6)34(26(7)39(50)57-29)59-32-21-42(10,53-14)37(49)27(8)56-32)60-40-35(28(44(12)13)19-23(4)55-40)58-31(46)18-17-30(45)54-16-2/h22-29,32,34-38,40,48-49,51-52H,15-21H2,1-14H3/t22-,23-,24+,25+,26-,27+,28+,29-,32+,34+,35-,36-,37+,38-,40+,41-,42-,43-/m1/s1

(2S,3R,4S,6R)-4-(dimethylamino)-2-(((3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-7,12,13-trihydroxy-4-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecan-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl ethyl succinate

Erythromycin ethylsuccinate; E-Mycin E; E.E.S; Wyamycin; Wyamycin E;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~58.00 mM)
Ethanol :≥ 33.33 mg/mL (~38.66 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)