Anti-Aging Siro Gel

Kojic Acid

Kojic acid is a chelation agent produced by several species of fungi, especially Aspergillus oryzae, which has the Japanese common name koji. Kojic acid is a by-product in the fermentation process of malting rice, for use in the manufacturing of sake, the Japanese rice wine. It is a mild inhibitor of the formation of pigment in plant and animal tissues and is used in food and cosmetics to preserve or change colors of substances.

Niacinamide

In clinical medicine, nicotinic acid is used as an antilipemic, but nicotinamide (niacinamide) is not effective for this purpose. Nicotinic acid was the first hypolipidemic agent shown to decrease the incidence of secondary myocardial infarction (MI) and reduce total mortality in MI patients. However, no incremental benefit of coadministration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for extended-release niacin, simvastatin, or lovastatin monotherapy has been established. In addition, the AIM-HIGH trial demonstrated that the concurrent use of extended-release niacin (1500—2000 mg/day PO) and simvastatin does not result in a greater reduction in the incidence of cardiovascular events than simvastatin alone.^[1]

Sirolimus

Sirolumus or topical rapamycin is a topical anti-aging agent that decreases senescence of the cells by inhibiting the mTOR pathway, allowing more space for healthy tissue to grow and protecting the skin barrier.^[2] It expression of the senescence regulator p16INK4A and reduces signs of photoaging.^[2] Rapamycin has also been used to prevent organ rejection in transplant recipients and is a medication used to treat certain malignancies, lymphoproliferative diseases, and tumors of the immune system. As an immunosuppressant, it works by obstructing the mTOR pathway, which is crucial for cell growth and proliferation. Other indications include psoriasis, rheumatoid arthritis, and acne vulgaris. It resembles sirolimus (rapamune) structurally.^[3][4][5][6]

Kojic Acid

Kojic acid suppresses the formulation of pigment by the melanocyte due to its tyrosinase inhibitory activity. This produces a skin-lightening effect.

Niacinamide

Dietary requirements for niacin can be met by the ingestion of either nicotinic acid or nicotinamide; as vitamins, both have identical biochemical functions. As pharmacologic agents, however, they differ markedly. Nicotinic acid is not directly converted into nicotinamide by the body; nicotinamide is only formed as a result of coenzyme metabolism. Nicotinic acid is incorporated into a coenzyme known as nicotinamide adenine dinucleotide (NAD) in erythrocytes and other tissues. A second coenzyme, nicotinamide adenine dinucleotide phosphate (NADP), is synthesized from NAD. These two coenzymes function in at least 200 different redox reactions in cellular metabolic pathways. Nicotinamide is released from NAD by hydrolysis in the liver and intestines and is transported to other tissues; these tissues use nicotinamide to produce more NAD as needed. Together with riboflavin and other micronutrients, the NAD and NADP coenzymes work to convert fats and proteins to glucose and assist in the oxidation of glucose.

In addition to its role as a vitamin, niacin (nicotinic acid) has other dose-related pharmacologic properties. Nicotinic acid, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic “niacin-flush”. Nicotinic acid-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The flushing effects of nicotinic acid appear to be related to the 3-carboxyl radical on its pyridine ring. Nicotinamide (niacinamide), in contrast to nicotinic acid, does not contain a carboxyl radical in the 3 position on the pyridine ring and does not appear to produce flushing.

Nicotinic acid may be used as an antilipemic agent, but nicotinamide does not exhibit hypolipidemic activity. Niacin reduces total serum cholesterol, LDL, VLDL, and triglycerides, and increases HDL cholesterol. The mechanism of nicotinic acid’s antilipemic effect is unknown but is unrelated to its biochemical role as a vitamin. One of nicotinic acid’s primary actions is decreased hepatic synthesis of VLDL. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin’s inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of Apo A-I and lipoprotein A-I, and a decrease in serum levels of Apo-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids. Clinical trial data suggest that women have a greater hypolipidemic response to niacin therapy than men at equivalent doses.

Sirolimus

During a study, human skin was subjected to a treatment using a formulation containing either 10 μM rapamycin or a control formulation with no active ingredient. This treatment was applied daily at a volume of 0.5 cc for a duration of 6 to 8 months.^[2] At the end of the study, skin biopsies were obtained from a group of 8 participants. These biopsies were processed for immunohistochemistry as outlined in the “Methods” section of the study.^[2] The Leica Aperio software system, utilizing a nuclear stain algorithm, was used to quantify the levels of nuclear p16INK4A in the skin biopsies.By attaching to a particular protein, FK506-binding protein 12 (FKBP12), rapamycin, an immunosuppressive medication, suppresses the activity of a protein known as the mechanistic target of rapamycin (mTOR). This complex reduces the action of mTOR. By regulating protein synthesis, autophagy, and metabolism, mTOR is essential in controlling cell growth, proliferation, and survival. Rapamycin is utilized as an immunosuppressant and an anti-cancer treatment because it inhibits mTOR, which results in a reduction in cell growth and proliferation.^[7]

Niacinamide

Patients who have a known hypersensitivity to niacin or any product component should not be given the drug.

While steady-state plasma concentrations of niacin are generally higher in women than in men, the absorption, metabolism, and excretion of niacin appears to be similar in both genders. Women have been reported to have a greater response to the lipid-lowering effects of nicotinic acid (niacin) when compared to men.

No overall differences in safety and efficacy were observed between geriatric and younger individuals receiving niacin. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity for some older individuals cannot be ruled out.

Niacin is contraindicated in patients who have significant or unexplained hepatic disease. Patients who consume large quantities of ethanol (alcoholism), who have risk factors for hepatic disease, or who have a past-history of gallbladder disease, jaundice, or hepatic dysfunction may receive niacin with close clinical observation. Elevations in liver function tests (LFTs) appear to be dose-related. Some sustained-release nicotinic acid (niacin) formulations have a higher incidence of hepatotoxicity when compared to immediate-release dosage forms. Extended-release nicotinic acid preparations (e.g., Niaspan, Slo-Niacin) should not be substituted for equivalent dosages of immediate-release (crystalline) niacin (e.g., Niacor and others). Follow the manufacturer-recommended initial dosage titration schedules for extended-release products, regardless of previous therapy with other niacin formulations. Monitor LFTs in all patients during therapy at roughly 6-month intervals or when clinically indicated. If transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal, or clinical symptoms of hepatic dysfunction are present, niacin should be discontinued.

Nicotinic acid (niacin) can stimulate histamine release, which, in turn, can stimulate gastric acid output. Niacin is contraindicated in patients with active peptic ulcer disease (PUD) because it can exacerbate PUD symptoms. Use niacin with caution in patients with a past history of peptic ulcer disease or in those on maintenance therapy to prevent PUD recurrence.

Due to its vasodilatory action, nicotinic acid (niacin) should be used with caution in those patients with uncorrected hypotension (or predisposition to orthostatic hypotension), acute myocardial infarction, or unstable angina, particularly when vasodilator medications such as nitrates, calcium channel blockers, or adrenergic blocking agents are coadministered (see Drug Interactions). Because the vasodilatory response to niacin may be more dramatic at the initiation of treatment, activities requiring mental alertness (e.g., driving or operating machinery) should not be undertaken until the response to niacin is known.

Niacin, especially in high doses, can cause hyperuricemia. Niacin should be prescribed cautiously to patients with gout (or predisposed to gout). These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician.

Niacin, especially in high doses, can cause hypophosphatemia. Although the reductions in phosphorus levels are usually transient, clinicians should monitor serum phosphorus periodically in those at risk for this electrolyte imbalance.

Rare cases of rhabdomyolysis have been reported in patients taking lipid-altering dosages of nicotinic acid (niacin) and statin-type agents concurrently (see Drug Interactions). Patients undergoing combined therapy should be carefully monitored for muscle pain, tenderness, or weakness, particularly in the early months of treatment or during periods of upward dose titration of either drug. While periodic CPK and potassium determinations may be considered, there is no evidence that these tests will prevent the occurrence of severe myopathy. If rhabdomyolysis occurs, the offending therapies should be discontinued.

Niacin, especially in high doses, may cause hyperglycemia. Niacin should be prescribed cautiously to patients with diabetes mellitus. These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician. Niacin has also been reported to cause false-positive results in urine glucose tests that contain cupric sulfate solution (e.g., Benedict’s reagent, Clinitest).

Niacin therapy has been used safely in children for the treatment of nutritional niacin deficiency. However, the safety and effectiveness of nicotinic acid for the treatment of dyslipidemias have not been established in neonates, infants and children <= 16 years of age. Nicotinic acid has been used for the treatment of dyslipidemia in pediatric patients under select circumstances. Children may have an increased risk of niacin-induced side effects versus adult populations. At least one pediatric study has concluded that niacin treatment should be reserved for treatment of severe hypercholesterolemia under the close supervision of a lipid specialist.^[8] In general, the National Cholesterol Education Program (NCEP) does not recommend drug therapy for the treatment of children with dyslipidemias until the age of 10 years or older.^[9] Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks since toxicological studies have not been performed.^[1] According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.^[1] Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.^[10] There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. Use niacin with caution in patients with renal disease (renal failure or severe renal impairment) since niacin metabolites are excreted through the kidneys. It appears that no special precautions are needed when administering niacin to meet the recommended nutritional daily allowance (RDA). Use caution when administering higher dosages. Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts or increased prothrombin times and should be used with caution in patients with thrombocytopenia, coagulopathy, or who are receiving anticoagulant therapy. Patients who will be undergoing surgery should have blood counts monitored. Nicotinic acid (niacin) is contraindicated in patients with arterial bleeding. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, glucose and liver function tests should be evaluated regularly because niacin interferes with glucose control, can aggravate diabetes, and can exacerbate active gallbladder disease and gout. Flushing is a common side effect of niacin.^[11]

Sirolimus

Hypersensitivity: Before prescribing rapamycin (sirolimus), there are a few contraindications and safety concerns to take into account.^{[5][12][13][14]}

Active infections: The risk of infections can rise due to immunosuppression brought on by rapamycin. Patients with infections that are still active should not take it.^{[5][12][13][14]}

Pregnancy: Rapamycin should not be used by pregnant women since it may harm the fetus.^{[5][12][13][14]}

Renal impairment: In patients with renal impairment, the dose of rapamycin may need to be changed because it is largely removed through the kidneys.^{[5][12][13][14]}

Hepatic impairment: Since the liver is where rapamycin is metabolized, patients with hepatic impairment may require a dose adjustment.^{[5][12][13][14]}

Hyperlipidemia: Rapamycin use in patients with high cholesterol or triglyceride levels should be closely managed because it can lead to hyperlipidemia.^{[5][12][13][14]}

Diabetes: Diabetes patients should use rapamycin cautiously because it can result in hyperglycemia.^{[5][12][13][14]}

Wound healing: Rapamycin use in individuals undergoing surgery should be closely monitored because it has the potential to impede wound healing.^{[5][12][13][14]}

Elderly patients: Elderly patients might need lower dosages of rapamycin because they might be more sensitive to its negative effects.^{[5][12][13][14]}

Interactions: Other medications, such as immunosuppressants, antifungals, antibiotics, and some anticonvulsants, may interact with rapamycin. Patients taking other medications should have their use of it closely monitored.^{[5][12][13][14]}

Kojic Acid

Melasma patients who had used 1% kojic acid cream were followed for 2 years and no significant side effect or adverse reaction was observed.^[19] Common adverse reactions and disadvantages hsve been associated with kojic acid in cosmetic application. Contact dermatitis (especially for sensitive skins) is the main side effect of kojic acid which is accompanied by irritation, rashes, inflamed skin, itchiness, and pain. These side effects can be observed with a higher concentration more than 1% of kojic acid. Another adverse reaction may appear in long-term use of kojic acid, such as sunburn in sensitive skin.

Niacinamide

Niacin (nicotinic acid), when administered in doses equivalent to the RDA, is generally nontoxic. Niacinamide also rarely causes adverse reactions. Larger doses of nicotinic acid (i.e., >= 1 g/day PO), can cause adverse reactions more frequently. Differences in adverse reaction profiles can be explained by the fact that nicotinic acid has pharmacologic properties that are different from niacinamide.

Peripheral vasodilation is a well-known adverse reaction to niacin. It is characterized by flushing; warmth; and burning or tingling of the skin, especially in the face, neck, and chest. Hypotension can be caused by this vasodilation. Patients should avoid sudden changes in posture to prevent symptomatic or orthostatic hypotension. Dizziness and/or headache, including migraine, can occur. Cutaneous flushing is more likely to occur with immediate-release preparations as opposed to sustained-release ones and also increases in incidence with higher doses.^[20] Following 4-weeks of maintenance therapy of 1500 mg daily, patients receiving immediate release niacin averaged 8.6 flushing events compared to 1.9 events in the Niaspan group. In placebo-controlled studies of Niaspan, flushing occurred in 55—69% of patients compared to 19% of patients receiving placebo. Flushing was described as the reason for discontinuing therapy for 6% of patients receiving Niaspan in pivotal studies.^[1] These reactions usually improve after the initial 2 weeks of therapy. Some patients develop generalized pruritus as a result of peripheral flushing. In placebo controlled trials, pruritus was reported in 0—8% of patients receiving Niaspan compared to 2% of patients taking placebo. Rash (unspecified) was reported in 0—5% of patients in the Niaspan group compared to no patients in the placebo group.^[1] Patients should avoid ethanol or hot drinks that can precipitate flushing. Flushing can be minimized by taking niacin with meals, using low initial doses, and increasing doses gradually. If necessary, taking one aspirin (e.g., 325 mg) 30 minutes before each dose can help prevent or reduce flushing. Spontaneous reports with niacin suggest that flushing may also be accompanied by symptoms of dizziness or syncope, sinus tachycardia, palpitations, atrial fibrillation, dyspnea, diaphoresis, chills, edema, or exacerbations of angina. On rare occasions, cardiac arrhythmias or syncope has occurred. Hypersensitivity or anaphylactoid reactions have been reported rarely during niacin therapy; episodes have included one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, laryngeal edema, face edema, peripheral edema, laryngospasm, maculopapular rash, and vesiculobullous rash (vesicular rash, bullous rash).

Niacin can produce a variety of GI effects, such as nausea/vomiting, abdominal pain, diarrhea, bloating, dyspepsia, or flatulence, when taken in large doses. Eructation and peptic ulcer has been reported with post-marketing experience of Niaspan. Compared to placebo, diarrhea was reported in 7—14% (vs. 13%), nausea in 4—11% (vs. 7%), and vomiting in 0—9% (vs. 4%) of patients receiving Niaspan.^[1] These effects are attributed to increased GI motility and may disappear after the first 2 weeks of therapy. Administering niacin with meals can reduce these adverse reactions.

Jaundice can result from chronic liver damage caused by niacin. It has been shown that elevated hepatic enzymes occur more frequently with some sustained-release niacin than with immediate-release products.^[20] However, in a study of 245 patients receiving Niaspan (doses ranging from 500—3000 mg/day for a mean of 17 weeks) no patients with normal serum transaminases at baseline experienced elevations to > 3x the upper limit of normal. Sustained-release products have been associated with post-marketing reports of hepatitis and jaundice, including Niaspan. Regular liver-function tests should be performed periodically. The changes in liver function induced by niacin are typically reversible with drug discontinuation. However, rare cases of fulminant hepatic necrosis and hepatic failure have been reported. Some cases have occurred after the substitution of sustained-release dosage forms for immediate-release products at directly equivalent doses; these dosage forms are not bioequivalent. Dosage titration schedules must be observed for any patient switched to a sustained-release niacin product, even if the patient was previously taking immediate-release therapy.^[1]

Niacin interferes with glucose metabolism and can result in hyperglycemia.^[1] This effect is dose-related. During clinical anti-lipemic trials, increases in fasting blood glucose above normal occurred frequently (e.g., 50%) during niacin therapy. Some patients have required drug discontinuation due to hyperglycemia or exacerbation of diabetes. In the AIM-HIGH trial of patients with stable cardiovascular disease, the incidence of hyperglycemia (6.4% vs. 4.5%) and diabetes mellitus (3.6% vs. 2.2%) was higher in niacin plus simvastatin-treated patients compared to the simvastatin plus placebo group. Close blood glucose monitoring is advised for diabetic or potentially diabetic patients during treatment with niacin; adjustment of diet and/or antidiabetic therapy may be necessary.^[1]

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.^[1] Therefore, patients predisposed to gout should be treated with caution.

Niacin, especially in high doses (>= 2 g/day PO), can cause hypophosphatemia (mean decrease 13%). Serum phosphorus concentrations should be monitored periodically in patients at risk for hypophosphatemia.^[1]

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts (mean reduction 11%) or increased prothrombin times (mean increase 4%), especially in high doses (>= 2 g/day PO). Rarely do these reactions result in coagulopathy or thrombocytopenia, but clinically significant effects might occur in patients with other risk factors or who are predisposed to these conditions.^[1]

Asthenia, nervousness, insomnia, and paresthesias have been reported during niacin therapy. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in doses >=1 g/day PO and HMG-CoA reductase inhibitors (i.e., ‘statins’) concurrently. In the AIM-HIGH trial, 4 cases (0.2%) of rhabdomyolysis were reported in the niacin; simvastatin group compared with 1 case in the simvastatin plus placebo group. Rhabdomyolysis may present as myopathy (myalgia, myasthenia, muscle cramps, muscle weakness, muscle tenderness, fatigue), elevations in creatinine phosphokinase (CPK), or renal dysfunction (renal tubular obstruction). Toxicity to the skeletal muscle occurs infrequently but can be a serious adverse reaction. This toxicity appears to be reversible after discontinuation of therapy.^[1]

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.^[1]

Although uncommon, niacin may be associated with skin hyperpigmentation or acanthosis nigricans. Dry skin (xerosis) also has been reported during post-marketing surveillance of Niaspan.^[1][21]

During clinical trials, increased cough was reported in <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.^[1]

Sirolimus

Rapamycin (sirolimus) is a medication that can cause various adverse reactions or side effects.^{[5][22][23][24]} Some of the most common side effects of rapamycin include:

Swelling in the legs, ankles, or feet
High blood pressure
Nausea and vomiting
Headache
Difficulty sleeping
Some of the more serious side effects of rapamycin include:

Increased risk of infections
Increased risk of certain types of cancers, such as skin cancer and lymphoma
Kidney damage
Lung problems, such as coughing, shortness of breath, and fluid buildup in the lungs
Liver damage
Hemorrhage (bleeding)
Hyperlipidemia (high cholesterol and triglycerides)
Diabetes or worsening of pre-existing diabetes
Any of these side effects while taking rapamycin should be reported to a healthcare professional. They might need to change the medication’s dosage or keep an eye out for any potential side effects. The likelihood of side effects from rapamycin may be increased if a healthcare provider is aware of any underlying medical issues, such as liver or renal illness.

Kojic Acid

Safe and effective use of kojic acid during pregnancy has not been established. It is also not known whether it can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. Use during pregnancy may not be recommended.

Niacinamide

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.^[1]

Sirolimus

Rapamycin should not be used by pregnant women since it may harm the fetus.^{[5][12][13][14]}

Kojic Acid

It is unknown whether topical kojic acid is absorbed or excreted in human milk and caution is advised when it is used in breastfeeding mothers.

Niacinamide

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.^[1] Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.^[10] There are no safety data regarding the use of nicotinic acid in doses above the RDA during breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Sirolimus

The use of rapamycin (sirolimus) during breastfeeding is not recommended, it is not known whether the drug is excreted in human breast milk or to what effect it may have on the nursing infant. There are no adequate and well-controlled studies in lactating women, and the potential risks to the nursing infant are not known. Therefore, healthcare providers generally advise against the use of rapamycin in breastfeeding mothers.^{[15][16][17][18]}

If rapamycin is required medically for a nursing mother, other choices should be taken into account. The nursing infant should be thoroughly watched for any potential side effects if the medicine is deemed necessary. It is best to decide whether to use rapamycin while nursing in consultation with a medical professional, who will weigh the advantages and disadvantages for the mother and the nursing child.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. Niaspan (niacin extended-release) tablet package insert. North Chicago, IL: Abbott Laboratories; 2015 Apr.
2. Chung, C.L., Lawrence, I., Hoffman, M. et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. GeroScience 41, 861–869 (2019). https://doi.org/10.1007/s11357-019-00113-y - Link Opens in New Tab
3. Zhang, J., & Chung, T. (2010). Old drug, new use: sirolimus in dermatology. International journal of dermatology, 49(8), 947-953.
4. Li, Y., Li, J., & Li, S. (2019). Pharmacokinetics and metabolism of sirolimus. Clinical and experimental pharmacology & physiology, 46(2), 96-107.
5. Pfizer Inc. (2019). Rapamune (sirolimus) prescribing information. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021083s046lbl.pdf - Link Opens in New Tab
6. Smit, J. W., & Stokkel, M. P. (2012). Radiopharmaceuticals in the era of targeted therapy: a clinical review. EJNMMI research, 2(1), 50.
7. Bassleer C, Henrotin Y, Franchimont P. In-vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React 1992;14:231-41.
8. Martel, R. R., & Klicius, J. (1993). Mechanism of action of rapamycin. Journal of Antibiotics, 46(5), 10.1038/ja.1993.113.
9. AbdelFattah W, Hammad T. Chondroitin sulfate and glucosamine: A review of their safety profile. JAMA 2001;3:16-23.
10. Monauni T, Zenti MG, Cretti A et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35.
11. Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-90.
12. Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993;92:78-82.
13. Expert Panel: National Cholesterol Education Program. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89(suppl 2):525-84.
14. Niacinamide. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ, (eds.) 7th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2005:1140-1
15. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
16. Pritchard, S., Szydlo, R. M., Apperley, J. F., & Carreras, E. (Eds.). (2012). The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer Science & Business Media.
17. National Institutes of Health. (2022). Sirolimus. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Sirolimus#section=Effects-During-Pregnancy-and-Lactation - Link Opens in New Tab
18. Davis, M., Williams, G., & Harrison, B. (2014). Sirolimus-associated delayed wound healing: a case report and review of literature. The Annals of pharmacotherapy, 48(3), 393-397.
19. Drugs and Lactation Database (LactMed) – Sirolimus. U.S. National Library of Medicine. (2022). Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK501447/ - Link Opens in New Tab
20. Briggs, G. G., Freeman, R. K., & Yaffe, S. J. (Eds.). (2017). Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Wolters Kluwer. Pfizer Inc. (2019).
21. Rapamune (sirolimus) prescribing information. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021083s046lbl.pdf - Link Opens in New Tab
22. Hale, T. W., & Rowe, H. E. (2019). Medications and Mothers’ Milk. Springer Publishing Company.
23. M. Nakagawa, K. Kawai, K. Kawa Contact allergy to kojic acid in skin care products Contact Derm., 32 (1) (1995), pp. 9-13
24. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-7.
25. Niacor (Niacin tablets) package insert. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2000 Feb.
26. Micromedex Solutions. (2022). Sirolimus. Retrieved from https://www.micromedexsolutions.com/home/dispatch - Link Opens in New Tab
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28. Drugs.com. (2022). Sirolimus Side Effects. Retrieved from https://www.drugs.com/sfx/sirolimus-side-effects.html - Link Opens in New Tab