Lyme+Disease

= Disease/Drug of interest: Lyme Disease/Doxycycline  =

Motivation and Background:
[|Lyme Disease] is caused by the bacteria //Borrelia burgdorferi// and is transmitted through blacklegged ticks. Although only 30,000 cases are reported each year to the [|Centers of Disease Control] and Prevention, studies have determined that about 329,000 people in the US, mostly in the Northeast and Midwest, are affected annually, making it the most common vector borne disease. The staggering number of people infected per year is already grounds for further research into the disease to prevent transmission and increase cure efficiency, but the fact that there is such a substantial discrepancy between the number of cases reported and actual number of cases warrants the conception of more reliable and quick methods to detect the disease. However, it is also imperative that occurrences of improper diagnosis and unnecessary treatment are also eliminated. The consequences of such actions are highlighted in a 1999 case in which a woman was given antibiotics through a catheter despite lack of substantial evidence that she actually had Lyme Disease and eventually passed away due to infection by the //Candida parapsilosis// fungus [1]. [|Symptoms] of Lyme Disease include fever, headache, fatigue, a skin rash exclusive to the disease called erythema migrans, arthritis, facial palsy, and inflammation of the brain and spinal cord. A [|vaccine] was available but was discontinued in 2002. Because the efficacy of the vaccine’s protection decreases over time, people who received it prior to its discontinuation are most likely vulnerable to infection at this point. Although treatment through antibiotics is accessible and effective, it would be in society's best interests if investigation into the vaccine was renewed to hopefully restore production, especially to prevent situations in which antibiotic treatment proves unsuccessful, namely PTLDS cases [1]. [|PTLDS], or Post Treatment Lyme Disease Syndrome, is the persistence of symptoms, like fatigue and joint pain, for up to several months after treatment has been administered. In these instances, prolonged treatment does not produce significant benefits.



media type="youtube" key="uarB8H6Bjm8" width="433" height="250" align="center" Video: Even pop stars are not immune to Lyme Disease. In an interview with ABC News, Avril Lavigne discusses the debilitating health conditions and mental hardships she had to face following her diagnosis.

References:
[1] Patel, R.; Grogg, K. L.; Edwards, W. D.; Wright, A. J.; Schwenk, N. M., Death from Inappropriate Therapy for Lyme Disease. Clinical Infectious Diseases 2000, 31, (4), 1107-9. [2] Heilpern, A. J.; Wertheim, W.; He, J.; Perides, G.; Bronson, R. T.; Hu, L. T., Matrix Metalloproteinase 9 Plays a Key Role in Lyme Arthritis but Not in Dissemination of Borrelia burgdorferi. Infection and Immunity 2009, 77, (7), 2643-9 [3] Buisson, A. C. C. A.; Zahm, J.-M.; Polette, M.; Pierrot, D.; Bellon, G.; Puchelle, E.; Birembaut, P.; Tournier, J.-M., Gelatinase B Is Involved in the In Vitro Wound Repair of Human Respiratory Epithelium. Journal of Cellular Physiology 1996, 166, (2), 413–426. [4] Arkell, J; Jackson, C. J., Constitutive secretion of MMP9 by early-passage cultured humanendothelial cells. Cell Biochem Funct 2003, 21, (4), 381-6. [5] Lindeman, J. H. N.; Abdul-Hussein, H.; Bockel, J. H. V.; Wolterbeek, R.; Kleemann, R., Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm. Vascular Medicine 2009, 119, (16), 2209-16.

External links:
[] [] [] [] [|https://www.cdc.gov/lyme/postlds/index.html#] []

Target Information: Matrix Metallopeptidase 9 (MMP-9)
One of the key contributors to the symptoms of Lyme Disease is MMP-9, or matrix metallopeptidase 9, a 92 kDa protease enzyme that utilizes zinc ions to break down extracellular proteins such as decorin, laminin, gelatin, and elastin [2]. When a person is bitten by a tick carrying the Borrelia burgdorferi bacteria, he/she will begin to develop the erythema migrans rash, and areas of the body inflicted with the rash will experience upregulated MMP-9 levels in an attempt to repair the skin [2]. However, such an increase in MMP-9 action actually degrades bone and cartilage, causing the arthritis that many Lyme Disease patients experience [3].

** Size: **
92 kDa

Location:
To achieve its function, it is secreted by cells and is therefore localized in the extracellular matrix (ECM). Within the body, it is mostly expressed in the bone marrow, albeit not constitutively as it must be induced by phorbol myrstate acetate [4]. It is also present in small amounts in human surface respiratory epithelial cells, and it is expressed constitutively in this case [3].

Function in a normal cell:
It plays major roles in processes such as migration of neutrophils, a type of white blood cell, embryonic development, and repair of wounds [2, 3]. For example, when epithelial damage is suffered, MMP-9 remodels the extracellular space to allow cells to more efficiently move towards the wound and repair it [3]. It also displays anti-inflammatory effects by releasing soluble mediators that are in the ECM and thereby drawing in effector cells that reduce inflammation at the infection site [2].

Drug Information: Doxycycline
Doxycycline is a tetracycline based drug that is used to treat Lyme Disease. MMP-9 requires a Zn 2+ cofactor to function, and by binding to this, doxycycline is able to inhibit the protein’s function. However, in addition to this, the drug can also decrease the production of MMP-9 by blocking the pathways that lead to the creation of TGF- β1, a growth factor that increases expression of MMP-9 mRNA [5]. By both stopping the production and inhibiting the function of the metalloprotease, the drug alleviates the arthritis and tissue injury that are characteristic of Lyme Disease [5].

Formula:
C 22 H 24 N 2 O 8

Molecular weight:
444.43 g/mol

CAS Number:
564-25-0

Delivery method:
Tablet, capsule, powder, or syrup, in two doses of 100 mg daily

Side effects:
Taking doxycycline may cause intracranial hypertension, which is an increase of pressure within the skull. Other side effects include diarrhea, increased skin sensitivity, and darkened skin, nails, or eyes.

Other names:
Doryx, Doxyhexal, Doxylin

Maker or company:
Adoxa, Adoxa CK, Adoxa Pak, Adoxa TT, Alodox, Doryx, Monodox, Oracea, Periostat, Vibramycin Calcium, Vibramycin Hyclate, Vibramycin Monohydrate, Vibra-Tabs

Is it patented?
Doxycycline is patented under Class 552 (Organic Compounds) and Subclass 203 (Nitrogen and carbonyl or cyano bonded directly to the tetracyclo ring system)

Clinical Trials Info:
There are 18 clinical trials involving doxycycline and Lyme Disease, with 9 having already been completed

Origin:
Doxycycline is made synthetically through modifications of tetracycline

Alternatives to this drug:
Amoxicillin, cefuroxime axetil, ceftriaxone, and penicillin are also used to treat Lyme Disease.

Other uses:
It can be used to treat acne caused by rosacea and anthrax infection, as well as prevent malaria. It also has anti-tumor capabilities which aid in treating cancer.