Minocycline

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Minocycline
Minocycline structure.svg
Minocycline-from-xtal-PDB-2DRD-3D-balls.png
Systematic (IUPAC) name
(2E,4S,4aR,5aS,12aR)- 2-(amino-hydroxy-methylidene)- 4,7-bis(dimethylamino)- 10,11,12a-trihydroxy-4a,5,5a,6- tetrahydro-4H-tetracene- 1,3,12-trione[1]
Clinical data
Trade names Minocin
AHFS/Drugs.com monograph
MedlinePlus a682101
Licence data US Daily Med:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability 100%
Metabolism liver
Half-life 11–22 hours
Excretion mostly fecal, rest renal
Identifiers
CAS number 10118-90-8 YesY
ATC code J01AA08 A01AB23
PubChem CID 24960
DrugBank DB01017
ChemSpider 16735907 YesY
UNII FYY3R43WGO YesY
KEGG D05045 YesY
ChEBI CHEBI:50694 N
ChEMBL CHEMBL1434 YesY
Chemical data
Formula C23H27N3O7 
Mol. mass 457.477
 N (what is this?)  (verify)

Minocycline (INN) is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type. As a result of its long half-life it generally has serum levels 2–4 times that of the simple water-soluble tetracyclines (150 mg giving 16 times the activity levels compared with 250 mg of tetracycline at 24–48 hours).

Minocycline is the most lipid-soluble of the tetracycline-class antibiotics, giving it the greatest penetration into the prostate and brain, but also the greatest amount of central nervous system (CNS)-related side effects, such as vertigo. A common side effect is diarrhea. Uncommon side effects (with prolonged therapy) include skin discolouration and autoimmune disorders that are not seen with other drugs in the class.

Minocycline is a relatively poor tetracycline-class antibiotic choice for urinary pathogens sensitive to this antibiotic class, as its solubility in water and levels in the urine are less than all other tetracyclines. Minocycline is metabolized by the liver and has poor urinary excretion.

Minocycline is not a naturally-occurring antibiotic, but was synthesized semi-synthetically from natural tetracycline antibiotics by Lederle Laboratories in 1966, and marketed by them under the brand name Minocin.[2]

Medical uses[edit]

Minocycline 100 mg Capsules.

Minocycline and doxycycline are frequently used for the treatment of acne vulgaris.[3][4] Both of these closely related antibiotics have similar levels of efficacy, although doxycycline has a slightly lower risk of adverse side effects.[5] Historically, minocycline has been a very effective treatment for acne vulgaris.[6] However, acne that is caused by antibiotic resistant bacteria is a growing problem in many countries.[7] In Europe and North America, a significant number of acne patients no longer respond well to treatment with tetracycline family antibiotics (e.g. tetracycline, doxycycline and minocycline) because their acne symptoms are caused by bacteria (primarily Propionibacterium acnes) that are resistant to these antibiotics.[8]

Minocycline is also used for other skin infections such as MRSA[9] as well as Lyme disease,[10] as the one pill twice daily 100 mg dosage is far easier for patients than the four times a day required with tetracycline or oxytetracycline. Its activity against Lyme disease is enhanced by its superior ability to cross the blood-brain barrier.

Although minocycline's broader spectrum of activity, compared with other members of the group, includes activity against Neisseria meningitidis,[11] its use as a prophylaxis is no longer recommended because of side effects (dizziness and vertigo).

It may be used to treat certain strains of MRSA infection and a disease caused by drug resistant acinetobacter.[12]

Both minocycline and doxycycline have shown effectiveness in asthma due to immune suppressing effects.[13] Minocycline as well as doxycycline have modest effectiveness in treating rheumatoid arthritis.[14] It is recognized as a DMARDS (Disease-Modifying Anti-Rheumatic Drug) by the American College of Rheumatology, which recommends its use as a treatment for rheumatoid arthritis.[citation needed]

A list of indications for which minocycline has been used include;

Cautions[edit]

Contrary to most other tetracycline antibiotics (doxycycline excluded), minocycline may be used in renal impairment, but may aggravate systemic lupus erythematosus.[17] It may also trigger or unmask autoimmune hepatitis.[18]

Also, more so than other tetracyclines, minocycline can cause the rare condition of secondary intracranial hypertension which has initial symptoms of headache, visual disturbances, dizziness, vomiting, and confusion.[citation needed] Cerebral edema, as well as autoimmune rheumatoid arthritis are rare side effects to minocycline in some people.[19]

Minocycline, like most tetracyclines, becomes dangerous past its expiration date.[20] While most prescription drugs lose potency after their expiration dates, tetracyclines are known to become toxic over time. Expired tetracyclines can cause serious damage to the kidney due to the formation of a degradation product, anhydro-4-epitetracycline.[20] Minocycline's absorption is impaired if taken at the same time of day as calcium or iron supplements. Unlike some of the other tetracycline group antibiotics, it can be taken with calcium-rich foods such as milk, although this does reduce the absorption slightly.[21] Minocycline should be taken with plenty of water.[citation needed] If taking this drug, one should avoid prolonged or excessive exposure to direct sunlight.[citation needed]

A study published in 2007, suggested that minocycline harms ALS patients. Patients on minocycline declined more rapidly than those on placebo. The mechanism of this side effect is unknown, although a hypothesis is that the drug exacerbated an autoimmune component of the primary disease. According to the researcher from Columbia University the effect does not seem to be dose-dependent because the patients on high doses did not do worse than those on the low doses.[22]

Side effects[edit]

Minocycline may cause upset stomach, diarrhea, dizziness, unsteadiness, drowsiness, mouth sores, headache and vomiting. Minocycline increases sensitivity to sunlight. Minocycline may affect quality of sleep and rarely cause sleep disorders.[23] It has also been linked to cases of lupus.[24] Prolonged use of minocycline over an extended period of time can lead to blue-gray skin, fingernails and staining of scar tissue. This staining is not permanent but can take a very long time for the skin color to return to normal; on the other hand a muddy brown skin color in sun exposed areas is usually a permanent skin discolouration.[25] Permanent blue discoloration of gums or teeth discoloration may also occur. Rare but serious side effects include fever, yellowing of the eyes or skin, stomach pain, sore throat, vision changes, and mental changes, including depersonalization.[26][27]

Occasionally minocycline therapy may result in autoimmune disorders such as drug related lupus and auto-immune hepatitis; minocycline induced auto-immune hepatitis when it occurs usually occurs in men who also developed minocycline induced lupus, however, women are the most likely to develop minocycline induced lupus. Significant or complete recovery occurs in most people who develop minocycline induced autoimmune problems within a period of a couple of weeks to a year of cessation of minocycline therapy. Autoimmune problems emerge during chronic therapy but can sometimes occur after only short courses of a couple of weeks of therapy.[28][29] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome can occur during the first few weeks of therapy with minocycline.[29]

Minocycline, but not other tetracyclines, can cause vestibular disturbances with dizziness, ataxia, vertigo and tinnitus. These effects are again thought to be related to minocycline's greater penetration into the central nervous system. Vestibular side effects are much more common in women than in men, occurring in 50% to 70% of women receiving minocycline. As a result of the frequency of this bothersome side effect, minocycline is rarely used in female patients.[30]

Symptoms of an allergic reaction include rash, itching, swelling, severe dizziness, and trouble breathing.[26] Minocycline has also been reported to very rarely cause idiopathic intracranial hypertension (pseudotumor cerebri),[31] a side effect also more common in female patients, potentially leading to permanent vision damage.

Thyroid cancer has been reported in the post-marketing setting in association with minocycline products. When minocycline therapy is given over prolonged periods, monitoring for signs of thyroid cancer should be considered.[citation needed]

In 2009, the FDA added minocycline to its Adverse Event Reporting System (AERS); a list of medications under investigation by the FDA for potential safety issues. The AERS cites a potential link between the use of minocycline products and autoimmune disease in pediatric patients.[32]

Anti-inflammatory and neuroprotective[edit]

In various models of neurodegenerative disease, minocycline has demonstrated neurorestorative as well as neuroprotective properties. Neurodegenerative diseases such as Huntington's disease and Parkinson's disease have shown a particularly beneficial response to minocycline in research studies, and an antipsychotic benefit has been found in people with schizophrenia and minocycline is proposed as a possible addon therapy for some schizophrenics.[33][34][35] Current research is examining the possible neuroprotective and anti-inflammatory effects of minocycline against progression of a group of neurodegenerative disorders including multiple sclerosis (MS), rheumatoid arthritis (RA), Huntington's disease, and Parkinson's disease.[36][37][38][39] As mentioned above, minocycline harms ALS patients.

Minocycline is also known to indirectly inhibit inducible nitric oxide synthase (NOS).[40][41][42]

In the Journal of the American Medical Association (JAMA), Chris Zink, Janice Clements, and colleagues from Johns Hopkins University reported that minocycline may exhibit neuroprotective action against AIDS Dementia Complex by inhibiting macrophage inflammation and HIV replication in the brain and cerebrospinal fluid.[43] Minocycline may suppress viral replication by reducing T cell activation.[44][45] The neuroprotective action of minocycline may include its inhibitory effect on 5-lipoxygenase,[46] an inflammatory enzyme associated with brain aging, and the antibiotic is being studied for use in Alzheimer's disease patients.[47] Minocycline may also exert neuroprotective effects independent of its anti-inflammatory properties.[48] Minocycline also has been used as a "last-ditch" treatment for toxoplasmosis in AIDS patients.[49] Minocycline is somewhat neuroprotective in mouse models of Huntington's disease.[50]

As an anti-inflammatory, minocycline inhibits apoptosis (cell death) via attenuation of TNF-alpha, downregulating pro-inflammatory cytokine output. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which results in the decreased ability of T cells to contact microglia which impairs cytokine production in T cell-microglia signal transduction .[51] Minocycline also inhibits microglial activation, through blockade of NF-kappa B nuclear translocation.[citation needed]

A 2007 study reported the impact of the antibiotic minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in 40 MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in the patient group prior to treatment (1.3/year pre-enrollment; 1.2/year during a three-month baseline period), no relapses occurred between months 6 and 24 on minocycline. Also, despite significant MRI disease-activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of interleukin-12 (IL-12), which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1 (VCAM-1). The activity of matrix metalloproteinase-9 was decreased by treatment. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.[52][53][48][54]

A recent study (2007) found that patients taking 200 mg of minocycline for five days within 24 hours of an ischemic stroke showed an improvement in functional state and stroke severity over a period of three months compared with patients receiving placebo.[55]

Trade names and availability[edit]

Minocycline is no longer covered by patent and is therefore marketed under several trade names:

  • Minomycin
  • Minostad (Europe. For the treatment of acne)
  • Akamin
  • Minocin
  • Minoderm
  • Cyclimycin
  • Arestin (1 mg doses administered locally into periodontal pockets, after scaling and root planing, for treatment of periodontal disease.)[56]
  • Aknemin
  • Solodyn (Extended-Release. For the treatment of acne)
  • Dynacin
  • Sebomin
  • Mino-Tabs
  • Acnamino
  • Minopen (In Japan)
  • Maracyn 2 (For treatment of bacterial infections in aquarium fish and amphibians)
  • Quatrocin (In Syria)
  • Minox (In Ireland)
  • Minoz (In India and Romania)
  • Divaine (In India)

Dentomycin (2% minocylcine gel for use in periodontal pockets) StoneBridge Pharma also markets Minocycline as Cleeravue-M in combination with SteriLid eyelid cleanser in the treatment of rosacea blepharitis.

Research[edit]

Early research has found a tentative benefit from minocycline in schizophrenia,[57] with several trials underway.[58] A 2014 systematic review and meta-analysis found minocycline reduced negative and total symptom scores and was well tolerated.[59]

References[edit]

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External links[edit]