Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/65—Tetracyclines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• TECHNICAL FIELD This invention relates to an improved pharmaceutical formulation for treatment of symptoms associated in humans with reactive arthritis or idiopathic bursitis.
• Reactive arthritis refers to a spondyloarthritity which usually arises as a complication of an infection elsewhere in the body. Reactive arthritis can be caused by species of Shigella bacteria (most notably Shigella flexneri), Yersinia enterocolitica, Campylobacter jejuni, several species of Salmonella, genitourinary pathogens, Chlamydia trachomatis, Neisseria gonorrhea, Ureaplasma urealyticum, Streptococcus pyogenes, and other yet unidentified infectious agents. Reactive arthritis commonly occurs in young men and women, but can occur at any age.
• Sufferers experience joint pain, stiffness, redness or swelling. Common symptoms may include fatigue, malaise, fever, and weight loss.
• the joints of the lower extremities, including the knee, anlde, and joints of the foot, are the most common sites of involvement, but symptoms can also occur in the wrists, fingers, elbows, shoulders, neck, and lower back. Other symptoms may include urethritis and prostatitis in males, and cervicitis or salpingitis in females.
• Ocular disease is common ranging from transient, asymptomatic conjunctivitis to aggressive anterior uveitis that occasionally results in blindness. Mucocutaneous lesions and nail changes are frequent. On less frequent or rare occasions manifestations of reactive arthritis include cardiac conduction defects, aortic insufficiency, central or peripheral nervous system lesions, and pleuropulmonary infiltrates.
• NSATD nonsteroidal anti- inflammatory drugs
• debilitating symptoms refractory to NSAID therapy may be treated with cytotoxic agents such
• Minocycline hydrochloride a semisynthetic derivative of tetracycline, is indicated for infections caused by at least Shigella microorganisms,
• Streptococcus pyogenes and Neisserie gonorrhoeae. It is therefore an accepted treatment in incidents of reactive arthritis triggered by these biological entities.
• Bursitis is inflammation of a bursa, a thin-walled sac lined with synovial tissue.
• the function of the bursa is to facilitate movement of tendons and muscles over bony prominences. Bursitis may be caused by excessive frictional forces, trauma, systemic disease such as rheumatoid arthritis or gout, or infection.
• the most common form of bursitis is subacromial. Trochanteric bursitis causes patients to experience pain over the lateral aspect of the hip and
• Retrocalcaneal bursitis involves the bursa located between the calcaneus and the posterior surface of the Achilles tendon. Pain is experienced at the back of the heel, and swelling appears on either or both of the medial and lateral sides of the tendon. Retrocalcaneal bursitis occurs in association
• bursitis generally consists of prevention of the aggravating condition, rest of the involved part, an NSAID, and local steroid injection. In the long term, bursitis can result in loss of use of a joint and chronic pain syndrome.
• Acyclovir is an anti-viral drug.
• the chemical name of acyclovir is 2-amino-l,9- dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one.
• Acyclovir is commercially available under the brand name ZOVLRAX® in capsules, tablets, or suspension.
• Acyclovir has demonstrated anti-viral activity against herpes simplex virus types I and II, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus, both in vitro and in vivo.
• Valacyclovir hydrochloride (sold under the brand name Valtrex®) is the hydrochloride salt of L-valyl ester of acyclovir.
• the chemical name of valacyclovir hydrochloride is Z-valine 2-[(2-amino- l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester, monohydrochloride.
• Valacyclovir hydrochloride is rapidly and nearly completely converted to acyclovir in the body.
• Minocycline hydrochloride is a bacteriostatic antibiotic which exerts its antimicrobial effect by inhibition of bacterial protein synthesis. It has been shown to be effective against gram-negative bacteria, some gram-positive bacteria and other microorganisms.
• Metronidazole is an oral synthetic antiprotozoal and antibacterial agent. Heretofore it has been indicated for treatment of symptomatic trichomoniasis, intestinal amebiasis, and a wide range of intra-abdominal, skin, and gynecological, bone and joint, and lower respiratory
• acyclovir beings of reactive arthritis or idiopathic bursitis, or both
• An alternative formulation comprises the substitution of valacyclovir hydrochloride in place of acyclovir.
• the pharmaceutical dosages of the compounds of the combination may be administered in capsules,
• the invention provides a pharmaceutical combination that puts the diseases of reactive
• Treatment with the combination may effect a cure of reactive arthritis and bursitis, but definitive testing has not been performed to confirm that fact.
• Another object of the invention is to provide a treatment for conditions in human beings associated with either or both reactive arthritis or idiopathic bursitis that puts the disease being treated into full remission.
• a further object of the invention is to provide a treatment for any constellation of
• a still further object of the invention is to provide a combination comprising a
• An alternate method includes administration of IxiH for those individuals who have tested positively for mycobacterial exposure, along with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole.
• Another method described in U.S. Patent No. 6,465,473 Bl to Bonner, et al. includes administration of valacyclovir hydrochloride with the
• a third method of treatment described in U.S. Patent No. 6,197,776 Bl to Bonner, et al. includes administration of acyclovir with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole.
• the preferred embodiment of the present treatment includes administration of acyclovir with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole.
• the treatment comprises a pharmaceutical combination including acyclovir, minocycline hydrochloride, and metronidazole.
• the treatment may include valacyclovir hydrochloride,
• minocycline hydrochloride and metronidazole. Either of these embodiments may be supplemented with administration of pyridoxine hydrochloride, glucosamine, manganese, vitamin C, and desalinated seawater, such as Essence of Life.
• Administration will generally be accomplished orally via capsules, tablets, or in suspension form, but delivery could be accomplished by injection, or any other method commonly used for administration of internal medicines.
• acyclovir inhibits herpes simplex viruses, but by a different mechanism.
• acyclovir inhibits effective replication of actively replicating viral particles by stopping replication of herpes viral DNA. This is accomplished by either competitive
• the daily dose of acyclovir may vary from 200 mg to 4 grams.
• the preferred dose of acyclovir is 400 mg twice daily.
• the preferred dose of minocycline hydrochloride is an initial dosage of 200 mg followed by doses of 100 mg twice per day. Daily doses of minocycline hydrochloride following the initial administration of 200 mg may vary from 50 mg to 200 mg. Based upon their similar properties, it is expected that other members of the tetracycline family such as doxycycline can be effectively substituted, in the combination, for minocycline hydrochrloride.
• the preferred dose of metronidazole is 250-500 mg twice per day.
• the total dose per day of metronidazole may vary from 100 mg to 1,000 mg.
• lysine, minocycline hydrochloride, and metronidazole provides a medically effective treatment for reactive arthritis and bursitis. See U.S. Patent No. 6,087,382. It has also been shown that
• the preferred embodiment of the present invention comprises the combination of acyclovir or its prodrug, valacyclovir, with minocycline hydrochloride and metronidazole. It is believed that acyclovir results in a substantial benefit due to its inhibition of virus replication.
• arthritis and what has previously been referred to as idiopathic bursitis, and further is a beneficial treatment for reactive arthritis in particular cases wherein the symptom complex has been misdiagnosed as osteoarthritis or psoriatic arthritis, or in any other similar cases of misdiagnosis.
• Example 1 A 54 year old male presented with joint pain in his neck, upper back, lower back, both shoulders, both elbows, both wrists, both hands, both hips, both ankles, both knees, and both
• hydrochloride 100 mg BID, and metronidazole, 250 mg BID, for 8 weeks.
• the patient experienced resolution of joint tenderness at all mentioned joints, excepting the PIP joint of the third digit of his right hand and his left knee, though such tenderness had decreased in severity in both those joints; and resolution of knee effusions.
• the patient experienced stiffness in all aforementioned joints lasting for up to 18 hours daily. After treatment stiffness remained in only four joints for about 10 minutes daily.
• Example 2 A female, 79 years old presented with tenderness in her left shoulder, right elbow, both hands, both knees, her right hip, both ankles, the Achilles insertion of both feet, her lower back, and both wrists. She also experienced effusio in both knees, and pretibial edema
• tenderness remained in only the right ankle with a decrease in severity at that joint. Tenderness decreased in severity in each joint from "moderate to severe” before treatment, to "slight" post-treatment. The effusions and pretibial edema had resolved. The patient went from a semi-sedentary state to being able to walk around daily for 20 minutes at a time and was able to resume her shopping activities and performing household chores.

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• Animal Behavior & Ethology (AREA)
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• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Urology & Nephrology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Immunology (AREA)
• Ophthalmology & Optometry (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2002
  • 2002-10-15 US US10/271,117 patent/US6765000B2/en not_active Expired - Fee Related
• 2003
  • 2003-10-14 WO PCT/US2003/032653 patent/WO2004034987A2/en not_active Ceased
  • 2003-10-14 KR KR1020057006451A patent/KR20050083762A/ko not_active Ceased
  • 2003-10-14 EP EP03776410A patent/EP1558266A4/en not_active Withdrawn
  • 2003-10-14 MX MXPA05003930A patent/MXPA05003930A/es active IP Right Grant
  • 2003-10-14 JP JP2004545314A patent/JP2006503095A/ja active Pending
  • 2003-10-14 CN CN200380103653A patent/CN100584335C/zh not_active Expired - Fee Related
  • 2003-10-14 AU AU2003284231A patent/AU2003284231A1/en not_active Abandoned
  • 2003-10-14 CA CA002502397A patent/CA2502397A1/en not_active Abandoned
  • 2003-10-14 CH CH00998/04A patent/CH696629A5/de not_active IP Right Cessation
• 2004
  • 2004-07-20 US US10/896,612 patent/US7053073B2/en not_active Expired - Fee Related
• 2005
  • 2005-02-04 US US11/051,171 patent/US20050176690A1/en not_active Abandoned
• 2009
  • 2009-11-18 AU AU2009238327A patent/AU2009238327A1/en not_active Abandoned

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