Macrolide antibiotics effect

Pinto AG, Wang YH, Chalasani N, et al. Inhibition of human intestinal wall metabolism by macrolide antibiotics effect of clarithromycin on cytochrome P450 3A4/5 activity and expression. Clin Pharmacol Ther 2005 77(3) 178-188. 

Amphotericin is a macrolide antibiotic effective against fungi. It binds to ergosterol in the fungal cell membrane and this makes the cell leaky. Loss of intracellular potassium ions in particular leads to cell death. 

Sedlmayr, T., Peters, F., Raasch, W., and Kees, F. (1993). Clarithromycin, a new macrolide antibiotic. Effectiveness in puerperal infections and pharmacokinetics in breast milk [in German]. Geburtshilfe Frauenheilkd. 53, 488-491. 

A. Clinical Evidence of Macrolide Antibiotics Effect on Cytokine Production... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack. Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. 

Sowinski and coworkers40 reported a structure of vacidin A (63), an aromatic hep-taene macrolide antibiotic. The constitution of vacidin A, a representative of the aromatic heptaene macrolide antibiotics, was established on the basis of 13C and H- H double quantum filtered correlated spectroscopy, rotating frame nuclear Overhauser effect spectroscopy, 7-resolved 11 as well as H-13C correlation NMR spectra. The geometry of the polyene chromophore was determined as 22E, 24E, 26E, 28Z, 30Z, 32E, 34E. 

The macrolide antibiotic bafilomycin Al and concanamycin A are specific inhibitors of vacuolar-type H(- -)-ATPase, which prevents the acidification of endosomes and lysosomes and increases the intralysosomal pH from about 5.1-5.5 to about 6.3 (61,84-87). Bafilomycin Al is applied in concentrations ranging from 25-1000 nM and is incubated for 30 to 60 minutes in the presence or absence of serum. We observed maximal effects in COS-7 and HUVEC with concentrations of 100-200 nM and an incubation time of 60 minutes. 

Er hromycin Sulfisoxazole (Eryzole, Pediazole) [Anti-infective, Macrolide/Sulfonamide] Uses Upper lower resp tract bacterial Infxns H. influenzae otitis media in children Infxns in PCN-allergic pts Action Macrolide antibiotic w/ sulfonamide Dose Adults. Based on erythromycin content 400 mg erythromycin/1200 mg sulfisoxazole PO q6h Feds > 2 mo. 40-50 mg/kg/d erythromycin 150 mg/kg/d sulfisoxazole PO -s- q6h max 2 g/d erythromycin or 6 g/d sulfisoxazole x 10 d in renal impair Caution [C (D if near term), +] w/ PO anticoagulants, hypoglycemics, phenytoin, cyclosporine Contra Infants <2 mo Disp Susp SE GI upset Additional Interactions T Effects of sulfonamides W/ ASA, diuretics, NSAIDs, probenecid EMS See Erythromycin OD See Erythromycin... 

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

Adverse effects include abdominal cramps, diarrhoea, headache, convulsions and extrapyramidal effects. When used with imidazole antifungals/macrolide antibiotics, it may lead to Q-T prolongation and ventricular arrhythmias. 

Among macrolide antibiotics, clarithromycin is effective against M. leprae as an alternative multidrug therapy (MDT) regimen (detailed pharmacology is discussed in Macrolide antibiotics ). 

Nefazodone substantially decreases the clearance rate for triazolam, which results in a 400% increase in triazolam s serum levels (131). Erythromycin can also interfere with the metabolism of triazolam, resulting in decreased clearance and increased plasma levels, possibly causing toxicity. Troleandomycin and other macrolide antibiotics, such as clarithromycin, flurithromycin, josamycin, midecamycin, or roxithromycin, also may inhibit triazolam s metabolism (132). The coadministration of itraconazoie and triazolam can produce a marked elevation of triazolam plasma levels associated with statistically significant impairment of psychomotor tests and a prolongation of other effects (e.g., amnesia, lethargy, and confusion) for hours after awakening ( 133). 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

Tacrolimus (previously known as FK506) is a macrolide antibiotic with immunosuppressive properties very similar to cyclosporin. It is more potent than cyclosporin but the side effects are similar. Tacrolimus is a very active immunosuppressive drug both in the prevention and treatment of liver and renal allograft rejection. It is especially valuable for small bowel transplantation. 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

Antibiotics also are active against other protozoans. Tetracycline and erythromycin are alternative therapies for the treatment of intestinal amebiasis. Clindamycin, in combination with other agents, is effective therapy for toxoplasmosis, pneumocystosis, and babesiosis. Spiramycin is a macrolide antibiotic that is used to treat primary toxoplasmosis acquired during pregnancy. Treatment lowers the risk of the development of congenital toxoplasmosis. 

The complex polyene macrolide antibiotics are clinically effective as antifungal agents. Scott Rychnovsky of the University of California at Irvine has reported (Angew. Chem. hit. Ed. 2004,43, 2822) the first synthesis of rimocidinolide methyl ester 4, the aglycone of rimocidin 1. The key step in the synthesis is the condensation of the aldehyde 2 with the phosphonate 3, leading to 4. 

Oleandomycin is a macrolide antibiotic produced by Streptomyces antibi-oticus. Oleandomycin and its triacetylated form, troleandomycin, are less effective than erythromycin against staphylococcal infections. They are usually administered orally or intravenously intramuscular administration is avoided because of the pain and tissue irritation it induces. Oleandomycin is also used in intramammary treatments and as a feed additive for growth promotion purposes. 

However, recent investigations on the effect of the tissue matrix on the detection limits attained by this test have indicated that ceftiofur, sulfonamides, streptomycin, and some macrolide antibiotics cannot be detected in intact meat with the plates and the bacterial strains prescribed in the European four-plate test (81, 82). Two plates of this system were not found suitable for screening sulfamethazine or streptomycin at levels far above the MRL the third plate detected tetracyclines and -lactams up to the MRL levels whereas the fourth was sensitive to -lactams and some but not all macrolides. Detection, on the other hand, of the fluoroquinolones enrofloxacin and ciprofloxacin could only be made possible by an additional Escherichia coli plate not included in the four-plate test. 

For efficient extraction of macrolide and lincosamide residues from edible animal products, bound residues should be rendered soluble, most if not all of the proteins should be removed, and high recoveries for all analytes should be provided. Since tliese antibiotics do not strongly bind to proteins, many effective extraction methods have been reported. Sample extraction/deproteinization is usually accomplished by vortexing liquid samples or homogenizing semisolid samples with acetonitrile (136—139), acidified (136,140-142) orbasified acetonitrile (143), methanol (14, 144, 145), acidified (145-147) or basified methanol (148), chloroform (149-151), or dichloromethane under alkaline conditions (152). However, for extraction of sedecamycin, a neutral macrolide antibiotic, from swine tissues, use of ethyl acetate at acidic conditions has been suggested (153), while for lincomycin analysis in fish tissues, acidic buffer extraction followed by sodium tungstate deproteinization has been proposed (154). 

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