Originally developed as an immunosuppressant for organ transplant patients, it has found new life as a potential anti-aging drug. Rapamycin has not been approved for this use in humans, but many gerontologists consider it—or similar agents—the best hope for pharmacologically slowing the aging process.
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Composition and release form
Capsules - 1 capsule:
- active substance: azithromycin dihydrate - 262.03 mg, equivalent to azithromycin - 250.00 mg;
- excipients: lactose - 132.3 mg, corn starch - 33.0 mg, sodium lauryl sulfate - 2.0 mg, magnesium stearate - 8.0 mg;
- hard gelatin capsules No. 0, body and cap: quinoline yellow dye, sunset yellow dye, titanium dioxide, gelatin, purified water, sodium lauryl sulfate, propyl parahydroxybenzoate (propylparaben), methyl parahydroxybenzoate (methylparaben);
- black ink: (shellac, anhydrous ethanol, isopropanol, isobutanol, propylene glycol, ammonium sulfate concentrated solution, black iron oxide dye, sodium hydroxide, purified water).
Capsules 250 mg.
6 capsules in an aluminum/PVC blister, 1 blister along with instructions for use in a cardboard box.
pharmachologic effect
Antibiotic - azalide.
Pharmacokinetics
Absorption - high, acid-resistant, lipophilic. Bioavailability after a single dose of 0.5 g is 37% (the “first pass” effect through the liver), maximum concentration after oral administration of 0.5 g is 0.4 mg/l, time to reach maximum concentration is 2.5-2.9 hours; in tissues and cells the concentration is 10-50 times higher than in blood plasma, the volume of distribution is 31.1 l/kg. Easily passes through histohematic barriers.
Penetrates well into the respiratory tract, genitourinary organs and tissues, incl. prostate gland, skin and soft tissues.
Penetrates through cell membranes and creates high concentrations in them, accumulates in lysosomes (which is especially important for the eradication of intracellular pathogens). It is also transported by phagocytes: polymorphonuclear leukocytes and macrophages.
The concentration in foci of infection is significantly higher (24-34%) than in healthy tissues, and correlates with the severity of inflammatory edema. Remains in effective concentrations for 5-7 days after taking the last dose. Plasma protein binding is 7-50% (inversely proportional to blood concentration).
It is demethylated in the liver and inactive metabolites are formed. The metabolism of the drug involves isoenzymes CYP3A4, CYP3A5, CYP3A7, of which it is an inhibitor.
Plasma clearance - 630 ml/min. The half-life between 8 and 24 hours after administration is 14-20 hours, the half-life between 24 and 72 hours is 41 hours.
50% is excreted unchanged in bile, 6% by the kidneys.
Food intake significantly changes the pharmacokinetics: maximum concentration and area under the “conspiracy” curve, lowering blood pressure, ventricular tachycardia, increasing the QT interval, bidirectional ventricular tachycardia, “flushing” of blood in the face.
From the digestive system: gastritis, bloating, pancreatitis, nausea, vomiting, diarrhea, abdominal pain/cramps, flatulence, belching, indigestion, anorexia, constipation, discoloration of the tongue, pseudomembrane colitis, cholestatic jaundice, fulminant hepatitis, impaired liver function , liver failure, liver necrosis (possibly fatal), gastroenteritis, dysphagia. dryness of the oral mucosa, ulcers of the oral mucosa. increased secretion of the salivary glands.
Allergic reactions: itching, skin rashes, angioedema, urticaria, eosinophilia, anaphylactic reaction, including angioedema (in rare cases fatal), erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, hypersensitivity reaction.
From the musculoskeletal system: arthralgia, osteoarthritis, myalgia, back pain, neck pain.
From the genitourinary system: interstitial nephritis, acute renal failure, pain in the kidneys, metrorrhagia, testicular dysfunction, dysuria.
From the respiratory system: pneumonia, pharyngitis, respiratory diseases, rhinitis, shortness of breath, nosebleeds.
From the skin: dermatitis. dry skin, sweating.
Other: vaginitis, candidiasis, photosensitivity, malaise, feeling of fatigue, chest pain, peripheral edema, facial edema, fever.
Laboratory indicators: decreased number of lymphocytes, increased activity of aspartate aminotransferase, alanine aminotransferase; in blood plasma: increased number of basophils, monocytes, neutrophils, decreased or increased bicarbonate concentration, increased alkaline phosphatase activity, increased chlorine content, increased glucose concentration, increased platelet count, increased hematocrit, change in sodium content, increased bilirubin concentration, increased urea concentration, change in potassium content.
Competition "bio/mol/text"-2018
This work was published in the “Biopharmaceutics” category of the “bio/mol/text” competition 2018.
The general sponsor of the competition is: the largest supplier of equipment, reagents and consumables for biological research and production.
The audience award was sponsored by the medical genetics center Genotek.
"Book" sponsor of the competition - "Alpina Non-Fiction"
A famous saying goes that with age comes wisdom. However, looking around, you realize that age often comes in a completely different company: it is accompanied by diseases of various etiologies, slowly progressing over the course of a person’s life. Heart disease, diabetes and dementia are among the top five causes of death worldwide, and the healthcare industry is investing heavily in preventing their progression. But if these diseases in the overwhelming majority of cases are associated with a person’s age, with his aging, isn’t it worth massively concentrating some of these resources on the study of aging as a biological phenomenon and the molecular mechanisms that underlie it? Isn't it worth looking for “pills and vaccines for old age” on a global scale? Below we will talk about the strategy for searching for them, as well as about substances that partly claim to be this “pill”. In conclusion, we will touch upon the pitfalls and benefits of classifying such a natural process as aging as pathological conditions and diseases.
Drug interactions
Antacids do not affect the bioavailability of azithromycin. but reduce the maximum concentration in the blood by 30%, so the drug should be taken one hour before or two hours after taking these drugs and eating.
Azithromycin does not affect the concentration of carbamazepine, didanosine, rifabutin and methylprednisolone in the blood when used together.
In pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were detected when cimetidine was used 2 hours before azithromycin.
Concomitant use of azithromycin (600 mg/day once) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.
Concomitant use of azithromycin (1200 mg once) did not change the pharmacokinetics of fluconazole (800 mg once). The total exposure and half-life of azithromycin were not affected by concomitant use of fluconazole. however, a decrease in Cmax of azithromycin was observed (by 18%). which had no clinical significance.
Concomitant use of azithromycin (1200 mg once) did not cause a statistically significant effect on the pharmacokinetics of indinavir (800 mg three times a day for 5 days).
Concomitant use of azithromycin with cetirizine (20 mg) for 5 days in healthy volunteers did not lead to pharmacokinetic interaction or a significant change in the QT interval.
When used in healthy volunteers, there was no evidence of the effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Cmax of sildenafil or its main circulating metabolite.
Azithromycin does not affect the bioavailability of co-trimoxazole.
No significant changes in pharmacokinetic parameters were detected with simultaneous use of azithromycin with triazolam or midazolam in therapeutic doses.
Neutropenia has occasionally been observed with concomitant use of azithromycin and rifabutin, although neutropenia has been associated with the use of rifabutin; a causal relationship between the use of the combination of azithromycin and rifabutin and neutropenia has not been established.
Azithromycin does not affect the pharmacokinetics of theophylline; however, when taken together with other macrolides, the concentration of theophylline in the blood plasma may increase.
If combined use with cyclosporine is necessary, it is recommended to monitor the concentration of cyclosporine in the blood plasma and adjust the dose accordingly.
When taking digoxin and azithromycin together, it is necessary to monitor the concentration of digoxin in the blood, because simultaneous use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates, such as digoxin. leads to an increase in the concentration of the substrate P-glycoprotein in the blood plasma.
If co-administration with warfarin is necessary, careful monitoring of prothrombin time is recommended.
It was found that the simultaneous use of terfenadine and macrolide antibiotics causes arrhythmia and prolongation of the QT interval. Based on this, the above complications cannot be excluded when terfenadine and azithromycin are used together.
Since there is a possibility of inhibition of the CYP3A4 isoenzyme by azithromycin in parenteral form when used together with cyclosporine, terfenadine, ergot alkaloids, cisapride, pimozide, quinidine, astemizole and other drugs whose metabolism occurs with the participation of this enzyme, the possibility of such interaction should be taken into account when prescribing azithromycin for administration inside.
Given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot alkaloid derivatives (ergotamine and dihydroergotamine) is not recommended.
When used concomitantly with zidovudine, azithromycin has little effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite.
Azithromycin weakly interacts with cytochrome P450 isoenzymes. It has not been revealed that azithromycin is involved in pharmacokinetic interactions similar to erythromycin and other macrolides; azithromycin is not an inducer or inhibitor of cytochrome P450 isoenzymes.
The simultaneous use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times a day) causes an increase in the equilibrium concentration of azithromycin in the blood plasma; no clinically significant side effects were observed and no dose adjustment of azithromycin is required when used simultaneously with nelfinavir.
There have been isolated case reports of rhabdomyolysis in patients taking azithromycin and statins concomitantly.
special instructions
If you miss one dose, the missed dose should be taken as soon as possible, and subsequent doses should be taken at intervals of 24 hours.
The drug should be taken at least one hour before or two hours after taking anatacid medications.
The drug should be used with caution in patients with mild to moderate liver dysfunction due to the possibility of developing fulminant hepatitis and severe liver failure.
If there are symptoms of liver dysfunction, such as rapidly increasing asthenia, jaundice, darkening of urine, tendency to bleeding, hepatic encephalopathy, drug therapy should be stopped and a study of the functional state of the liver should be performed.
In case of mild to moderate renal dysfunction (creatinine clearance more than 40 ml/min), azithromycin therapy should be carried out with caution under monitoring the state of renal function.
As with the use of other antibacterial drugs, during therapy with azithromycin, patients should be regularly examined for the presence of non-susceptible microorganisms and signs of the development of superinfections, including fungal ones.
The drug should not be used for longer courses than indicated in the instructions, because The pharmacokinetic properties of azithromycin allow us to recommend a short and simple dosage regimen.
There is no data on a possible interaction between azithromycin and ergotamine and dihydroergotamine derivatives, but due to the development of ergotism with the simultaneous use of macrolides with ergotamine and dihydroergotamine derivatives, this combination is not recommended.
With long-term use of azithromycin, the development of pseudomembranous colitis caused by Clostridium difficile, both in the form of mild diarrhea and severe colitis, is possible. If antibiotic-associated diarrhea develops while taking the drug, as well as 2 months after the end of therapy, clostridial pseudomembranous colitis should be excluded.
When treated with macrolides, incl. azithromycin, prolongation of cardiac repolarization and QT interval was observed, increasing the risk of developing cardiac arrhythmias, incl. ari.
Caution should be exercised when using the drug in patients with the presence of proarrhythmogenic factors (especially in elderly patients): with congenital or acquired prolongation of the QT interval, in patients taking antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with fluid and electrolyte imbalance, especially in the case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia or severe heart failure.
The use of azithromycin may provoke the development of myasthenic syndrome or cause an exacerbation of myasthenia gravis.
Azithromycin dosage
Adults and children over 12 years of age weighing more than 45 kg: orally, 1 hour before or 2 hours after meals, 1 time per day: for infections of the upper and lower respiratory tract, ENT organs, skin and soft tissues - 0.5 g/ day for 1 dose for 3 days (course dose - 1.5g); for acne vulgaris - 0.5 g/day in one dose for 3 days, then 0.5 g/day once a week for 9 weeks. The course dose is 6 g. The first weekly capsule should be taken 7 days after taking the first daily capsule (8th day from the start of treatment), the next 8 weekly capsules should be taken at an interval of 7 days.
For urinary tract infections caused by Chlamydia trachomatis (urethritis, cervicitis) - 1 g once.
For Lyme disease - for the treatment of stage I. (erythema migrans) - 1 g on the first day and 0.5 g daily from days 2 to 5 (course dose - 3 g). When used in patients with mild to moderate renal impairment (creatinine clearance more than 40 ml/min), no dose adjustment is required; When used in patients with mild to moderate liver dysfunction, no dose adjustment is required in elderly patients.
Brief conclusions
- The immunosuppressant rapamycin appears to have antiaging properties;
- In experiments on mice, the drug showed an increase in their life expectancy;
- Rapamycin has also demonstrated anti-aging effects on human skin;
- However, in order to start using it as an anti-age drug, additional observations are necessary to exclude and minimize possible risks.
