US20050176690A1 - Method for treatment of reactive arthritis or bursitis - Google Patents

Method for treatment of reactive arthritis or bursitis Download PDF

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US20050176690A1
US20050176690A1 US11/051,171 US5117105A US2005176690A1 US 20050176690 A1 US20050176690 A1 US 20050176690A1 US 5117105 A US5117105 A US 5117105A US 2005176690 A1 US2005176690 A1 US 2005176690A1
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treatment
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metronidazole
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Ernest Bonner
Robert Hines
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Ficaar Inc
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    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [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

  • This invention relates to an improved method 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, ankle, 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.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • the preferred initial treatment of choice for acute reactive arthritis is indomethacin in divided doses of 75 to 150 milligrams per day.
  • the NSAID of last resort is phenylbutazone, in doses of 100 milligrams twice or three times per day, because of its potentially serious side effects.
  • Patients with debilitating symptoms refractory to NSAID therapy may be treated with cytotoxic agents such as azathioprine or methotrexate, or with sulfasalazine.
  • Tendinitis, other lesions, and uveitis may benefit from corticosteroids.
  • 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 upper thigh, and tenderness over the posterior aspect of the greater trochanter.
  • Retrocalcaneal bursitis involves the bursa located between the calcaneus and the posterior surface of the Achilles tendon.
  • Retrocalcaneal bursitis occurs in association with spondyloarthritities, rheumatoid arthritis, gout, and trauma.
  • 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-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one.
  • Acyclovir is commercially available under the brand name ZOVIRAX® 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 L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride.
  • Valacyclovir hydrochloride is rapidly and nearly completely converted to acyclovir in the body.
  • Acyclovir and valacyclovir hydrochloride are members of the family of synthetic purine nucleoside analog antiviral drugs.
  • 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. Minocycline hydrochloride is a member of the tetracycline family.
  • 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, gynecological, bone and joint, lower respiratory tract and central nervous system infections, bacterial septicemia and endocarditis. Metronidazole is a member of the nitroimidazole family.
  • Ciprofloxacin is a member of the quinolone family of antimicrobial agents. It is a bacteriacidal antibiotic, in the class of antibiotics called fluoroquinolones, which acts to interfere with DNA gyrase, an enzyme needed for the synthesis of bacterial DNA. Quinolones are widely considered to be a medically acceptable alternative to tetracyclines.
  • a combination for treatment of the symptoms in human beings of reactive arthritis or idiopathic bursitis, or both comprises the combination of acyclovir, minocycline hydrochloride, and metronidazole.
  • An alternative combination comprises the substitution of valacyclovir hydrochloride in place of acyclovir.
  • the pharmaceutical dosages of the compounds of the combination may be administered in capsules, tablets, in suspension form, or by injection.
  • the invention provides a method for administration of a pharmaceutical combination that puts the diseases of reactive arthritis and bursitis into remission. 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 method for administration of a treatment for conditions in human beings associated with either or both reactive arthritis or idiopathic bursitis that puts the disease being treated into fill remission.
  • a further object of the invention is to provide a method for administration of a treatment for any constellation of symptoms amenable to treatment using the above combination, including for example, cases of reactive arthritis which have been misdiagnosed as osteoarthritis or psoriatic arthritis.
  • U.S. Pat. No. 6,087,382 to Bonner, Jr., et al. describes a method of treatment involving administration of a combination of L-lysine, minocycline hydrochloride, and metronidazole.
  • An alternate method includes administration of InH 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. Pat. No. 6,465,473 to Bonner, Jr., et al. includes administration of valacyclovir hydrochloride with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole.
  • a third method of treatment includes administration of acyclovir with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole.
  • An embodiment of the treatment described in applicants' U.S. Pat. No. 6,765,000, 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 Like L-lysine, acyclovir inhibits herpes simplex viruses, but by a different mechanism. While L-lysine tends to stop the virus from replicating by inhibiting the initiation of the replication process, acyclovir inhibits effective replication of actively replicating viral particles, e.g., by stopping replication of herpes viral DNA. This is accomplished by either competitive inhibition or inactivation of viral DNA polymerase or incorporation and termination of the growing viral DNA chain. It is believed that acyclovir results in a substantial benefit due to its inhibition of virus replication. In double-blind testing, it has been found that the administration of the combination of acyclovir, minocycline hydrochloride, and metronidazole is an effective treatment for reactive arthritis or bursitis.
  • Acyclovir has never been used in the prior art for treatment of arthritis or bursitis. It does not appear to be effective alone for the treatment of these diseases.
  • the preferred dose of acyclovir is 400 mg twice daily.
  • the daily dose of acyclovir may vary from 200 mg to 4 grams.
  • the preferred dose of valacyclovir hydrochloride is 500 mg twice daily.
  • the total daily dose of valacyclovir hydrochloride may vary from 125 mg to 4 grams.
  • 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 hydrochloride.
  • 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.
  • the preferred embodiment of the present invention comprises the combination of acyclovir, or its prodrug valacyclovir hydrochloride, with minocycline hydrochloride and metronidazole.
  • An alternate embodiment comprises valacyclovir hydrochloride with minocycline hydrochloride and metronidazole.
  • the total combination of medicines in each of these embodiments presents a broad spectrum approach that it is believed effectively addresses the underlying pathogenesis for reactive 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.
  • a 77 year old female presented with complaints of neck, upper back, lower back, bilateral shoulder, bilateral wrist, digits of hands, bilateral hip, and bilateral ankle pains of years duration.
  • the patient complained of associated stiffness in those same joints.
  • Her physical examination was remarkable for tenderness at her neck, right shoulder, elbow bilaterally, wrist bilaterally, the metacarpal phalangeal and the proximal interphalangeal joints of her right hand, hip bilaterally, knee bilaterally, and the Achilles insertion area bilaterally.
  • the Sed rate and rheumatoid factors were normal. This patient was diagnosed with reactive arthritis and was started on a treatment consisting of 125 mg of metronidazole, 250 mg of valacyclovir hydrochloride, and 50 mg of minocycline hydrochloride twice daily.
  • a 52 year old male presented with complaints of bilateral knee and left wrist pain. He also noted associated morning stiffness. He was treated with minocyline hydrochloride 100 mg BID and acyclovir 400 mg BID. This resulted in significan improvement, but not total resolution of his complaints of pain and stiffness in his knees and left wrist.

Abstract

A method for treatment for conditions in human beings associated with either or both reactive arthritis or bursitis comprising administering a combination of member of the family of synthetic purine nucleoside analog antiviral drugs, a member of the tetracycline family, and a member of the nitroimidazole family, or alternatively, administering a combination of a member of the family of synthetic purine nucleoside analog antiviral drugs, a member of the quinolone family, and a member of the nitroimidazole family.

Description

  • This is a continuation of application Ser. No. 10/896,612 filed Jul. 20, 2004, still pending, which was a continuation of application Ser. No. 10/271,117 filed Oct. 15, 2002, now U.S. Pat. No. 6,765,000, which was a continuation of application Ser. No. 09/510,704, filed Feb. 22, 2000, now U.S. Pat. No. 6,465,473, which was a continuation-in-part of application Ser. No. 09/270,962, filed Mar. 17, 1999, now U.S. Pat. No. 6,087,382.
    • BACKGROUND OF THE INVENTION
  • This invention relates to an improved method 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, ankle, 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.
  • Treatment of patients suffering from reactive arthritis with nonsteroidal anti-inflammatory drugs (“NSAIDs”) provides some benefit, although symptoms of reactive arthritis are rarely completely alleviated and some patients fail to respond at all. The preferred initial treatment of choice for acute reactive arthritis is indomethacin in divided doses of 75 to 150 milligrams per day. The NSAID of last resort is phenylbutazone, in doses of 100 milligrams twice or three times per day, because of its potentially serious side effects. Patients with debilitating symptoms refractory to NSAID therapy may be treated with cytotoxic agents such as azathioprine or methotrexate, or with sulfasalazine. Tendinitis, other lesions, and uveitis may benefit from corticosteroids. 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.
  • Long-term follow-up studies have suggested that some joint symptoms persist in many, if not most, patients with reactive arthritis. Recurrences of the more acute symptoms are common and as many as twenty-five percent of patients either become unable to work or are forced to change occupations because of persistent joint problems.
  • 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 upper thigh, and tenderness over the posterior aspect of the greater trochanter. 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 with spondyloarthritities, rheumatoid arthritis, gout, and trauma.
  • Treatment of 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.
  • The long term effects of reactive arthritis and bursitis range from chronic pain to crippling disability. It is also thought that many instances of osteoarthritis and psoriatic arthritis are in actuality reactive arthritis. Unfortunately, current procedures for management treat the symptoms of these diseases rather than their underlying pathogens.
    • SUMMARY OF THE INVENTION
  • Significant benefits can be obtained by treating humans affected with conditions associated with reactive arthritis or bursitis using combinations of acyclovir, minocycline hydrochloride, and metronidazole or, alternatively, valacyclovir hydrochloride, minocycline hydrochloride, and metronidazole.
  • Acyclovir is an anti-viral drug. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one. Acyclovir is commercially available under the brand name ZOVIRAX® 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 L-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. Valacyclovir hydrochloride is rapidly and nearly completely converted to acyclovir in the body.
  • Acyclovir and valacyclovir hydrochloride are members of the family of synthetic purine nucleoside analog antiviral drugs.
  • 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. Minocycline hydrochloride is a member of the tetracycline family.
  • 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, gynecological, bone and joint, lower respiratory tract and central nervous system infections, bacterial septicemia and endocarditis. Metronidazole is a member of the nitroimidazole family.
  • Ciprofloxacin is a member of the quinolone family of antimicrobial agents. It is a bacteriacidal antibiotic, in the class of antibiotics called fluoroquinolones, which acts to interfere with DNA gyrase, an enzyme needed for the synthesis of bacterial DNA. Quinolones are widely considered to be a medically acceptable alternative to tetracyclines.
  • One embodiment of a combination for treatment of the symptoms in human beings of reactive arthritis or idiopathic bursitis, or both, comprises the combination of acyclovir, minocycline hydrochloride, and metronidazole. An alternative combination comprises the substitution of valacyclovir hydrochloride in place of acyclovir. The pharmaceutical dosages of the compounds of the combination may be administered in capsules, tablets, in suspension form, or by injection.
  • The invention provides a method for administration of a pharmaceutical combination that puts the diseases of reactive arthritis and bursitis into remission. Treatment with the combination may effect a cure of reactive arthritis and bursitis, but definitive testing has not been performed to confirm that fact.
  • It is therefore a primary object of the invention to provide a method for administration of a combination for treating conditions in human beings associated with either or both reactive arthritis or idiopathic bursitis.
  • Another object of the invention is to provide a method for administration of a treatment for conditions in human beings associated with either or both reactive arthritis or idiopathic bursitis that puts the disease being treated into fill remission.
  • A further object of the invention is to provide a method for administration of a treatment for any constellation of symptoms amenable to treatment using the above combination, including for example, cases of reactive arthritis which have been misdiagnosed as osteoarthritis or psoriatic arthritis.
    • DETAILED DESCRIPTION OF THE INVENTION
  • U.S. Pat. No. 6,087,382 to Bonner, Jr., et al., describes a method of treatment involving administration of a combination of L-lysine, minocycline hydrochloride, and metronidazole. An alternate method includes administration of InH 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. Pat. No. 6,465,473 to Bonner, Jr., et al., includes administration of valacyclovir hydrochloride with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole. A third method of treatment, described in applicants' U.S. Pat. No. 6,197,776, includes administration of acyclovir with the underlying combination of L-lysine, minocycline hydrochloride, and metronidazole. An embodiment of the treatment, described in applicants' U.S. Pat. No. 6,765,000, comprises a pharmaceutical combination including acyclovir, minocycline hydrochloride, and metronidazole. Alternatively, 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.
  • Like L-lysine, acyclovir inhibits herpes simplex viruses, but by a different mechanism. While L-lysine tends to stop the virus from replicating by inhibiting the initiation of the replication process, acyclovir inhibits effective replication of actively replicating viral particles, e.g., by stopping replication of herpes viral DNA. This is accomplished by either competitive inhibition or inactivation of viral DNA polymerase or incorporation and termination of the growing viral DNA chain. It is believed that acyclovir results in a substantial benefit due to its inhibition of virus replication. In double-blind testing, it has been found that the administration of the combination of acyclovir, minocycline hydrochloride, and metronidazole is an effective treatment for reactive arthritis or bursitis. Acyclovir has never been used in the prior art for treatment of arthritis or bursitis. It does not appear to be effective alone for the treatment of these diseases. The preferred dose of acyclovir is 400 mg twice daily. The daily dose of acyclovir may vary from 200 mg to 4 grams.
  • The preferred dose of valacyclovir hydrochloride is 500 mg twice daily. The total daily dose of valacyclovir hydrochloride may vary from 125 mg to 4 grams.
  • 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 hydrochloride.
  • 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.
  • It is known that the combination of minocycline hydrochloride, InH, and metronidazole inhibits the multiplication of susceptible organisms, including shigella, salmonella, chlamydia, streptococci, and mycobacteria. Applicants have also determined that the combination of L-lysine, minocycline hydrochloride, and metronidazole provides a medically effective treatment for reactive arthritis and bursitis. See U.S. Pat. No. 6,087,382. It has also been shown that the combination of acyclovir, L-lysine, minocycline hydrochloride, and metronidazole provides an effective treatment for these conditions. See U.S. Pat. No. 6,197,776. Individuals with severe symptoms, including joint swelling and joint contractures, who were not thought to be candidates for treatment using the combination of L-lysine, minocycline hydrochloride, and metronidazole only, have also experienced substantial beneficial effects in response to treatment with that combination and valacyclovir hydrochloride.
  • The preferred embodiment of the present invention comprises the combination of acyclovir, or its prodrug valacyclovir hydrochloride, with minocycline hydrochloride and metronidazole. An alternate embodiment comprises valacyclovir hydrochloride with minocycline hydrochloride and metronidazole. These combinations each provide a medically effective treatment for reactive arthritis and bursitis. The total combination of medicines in each of these embodiments presents a broad spectrum approach that it is believed effectively addresses the underlying pathogenesis for reactive 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
  • The following examples serve to illustrate the invention, but is not meant to restrict its effective scope.
    • Example 1
  • A 77 year old female presented with complaints of neck, upper back, lower back, bilateral shoulder, bilateral wrist, digits of hands, bilateral hip, and bilateral ankle pains of years duration. The patient complained of associated stiffness in those same joints. Her physical examination was remarkable for tenderness at her neck, right shoulder, elbow bilaterally, wrist bilaterally, the metacarpal phalangeal and the proximal interphalangeal joints of her right hand, hip bilaterally, knee bilaterally, and the Achilles insertion area bilaterally. The Sed rate and rheumatoid factors were normal. This patient was diagnosed with reactive arthritis and was started on a treatment consisting of 125 mg of metronidazole, 250 mg of valacyclovir hydrochloride, and 50 mg of minocycline hydrochloride twice daily. After 69 days of such treatment, the patient noted pain in the palm of her left hand only. She further denied any stiffness. Physical examination on the 69th day did not reveal any tenderness. Thus, treatment effected resolution of pain, stiffness, and tenderness in this patient.
    • Example 2
  • A 52 year old male presented with complaints of bilateral knee and left wrist pain. He also noted associated morning stiffness. He was treated with minocyline hydrochloride 100 mg BID and acyclovir 400 mg BID. This resulted in significan improvement, but not total resolution of his complaints of pain and stiffness in his knees and left wrist.
  • There have been thus described certain preferred embodiments of a pharmaceutical formulation for treatment of conditions in human beings associated with either or both reactive arthritis or idiopathic bursitis. While preferred embodiments have been described and disclosed, it will be recognized by those with skill in the art that modifications are within the true scope and spirit of the invention. The appended claims are intended to cover all such modifications.

Claims (71)

1. A method for medically treating the symptoms of reactive arthritis or bursitis in humans comprising:
administering to a patient an effective amount of the combination of a member of the family of synthetic purine nucleoside analog antiviral drugs or a pharmaceutically acceptable ester or a metabolite thereof, a member of the tetracycline family or a metabolite thereof, and a member of the nitroimidazole family or a metabolite thereof.
2. The method for treatment of claim 1 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir.
3. The method for treatment of claim 1 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir.
4. The method for treatment of claim 1 wherein:
said member of the tetracycline family comprises minocycline hydrochloride.
5. The method for treatment of claim 1 wherein:
said member of the nitroimidazole family comprises metronidazole.
6. The method for treatment of claim 1 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir or a pharmaceutically acceptable ester thereof, said member of the tetracycline family comprises minocycline hydrochloride, and said member of the nitroimidazole family comprises metronidazole.
7. The treatment of claim 6 wherein:
between approximately 50 to 200 mg of minocycline hydrochloride are administered.
8. The treatment of claim 6 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered.
9. The treatment of claim 6 wherein:
between approximately 100 mg to 1 gm of metronidazole are administered.
10. The treatment of claim 6 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered, between approximately 50 to 200 mg of minocycline hydrochloride are administered, and between approximately 100 mg to 1 gm of metronidazole are administered.
11. The treatment of claim 6 wherein:
approximately 400 mg of acyclovir are administered twice daily.
12. The treatment of claim 6 wherein:
approximately 100 mg of minocycline hydrochloride are administered twice daily.
13. The treatment of claim 6 wherein:
approximately 250 mg of metronidazole are administered twice daily.
14. The treatment of claim 6 wherein:
approximately 400 mg of acyclovir are administered twice daily, approximately 100 mg of minocycline hydrochloride are administered twice daily, and approximately 250 mg of metronidazole are administered twice daily.
15. The method for treatment of claim 1 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir or a pharmaceutically acceptable ester thereof, said member of the tetracycline family comprises minocycline hydrochloride, and said member of the nitroimidazole family comprises metronidazole.
16. The treatment of claim 15 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily.
17. The treatment of claim 15 wherein:
between approximately 50 to 200 mg of minocycline hydrochloride are administered daily.
18. The treatment of claim 15 wherein:
between approximately 100 mg to 1 gm of metronidazole are administered daily.
19. The treatment of claim 15 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily, between approximately 50 to 200 mg of minocycline hydrochloride are administered daily, and between approximately 100 mg to 1 gm of metronidazole are administered daily.
20. The treatment of claim 15 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily.
21. The treatment of claim 15 wherein:
approximately 100 mg of minocycline hydrochloride are administered twice daily.
22. The treatment of claim 15 wherein:
approximately 250 mg of metronidazole are administered twice daily.
23. The treatment of claim 15 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily, approximately 100 mg of minocycline hydrochloride are administered twice daily, and approximately 250 mg of metronidazole are administered twice daily.
24. A method for medically treating the symptoms of reactive arthritis or bursitis in humans comprising:
administering to a patient an effective amount of the combination of a member of the family of synthetic purine nucleoside analog antiviral drugs or a pharmaceutically acceptable ester or a metabolite thereof, a member of the quinolone family or a metabolite thereof, and a member of the nitroimidazole family or a metabolite thereof.
25. The method for treatment of claim 24 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir.
26. The method for treatment of claim 24 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir hydrochloride.
27. The method for treatment of claim 24 wherein:
said member of the quinolone family comprises Ciprofloxacin.
28. The method for treatment of claim 24 wherein:
said member of the nitroimidazole family comprises metronidazole.
29. The method for treatment of claim 1 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir or a pharmaceutically acceptable ester thereof, said member of the quinolone family comprises Ciprofloxacin, and said member of the nitroimidazole family comprises metronidazole.
30. The treatment of claim 29 wherein:
between approximately 50 mg to 2 gm of Ciprofloxacin are administered.
31. The treatment of claim 29 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered.
32. The treatment of claim 29 wherein:
between approximately 100 mg to 1 gm of metronidazole are administered.
33. The treatment of claim 29 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered, between approximately 50 mg to 2 gm of Ciprofloxacin are administered, and between approximately 100 mg to 1 gm of metronidazole are administered.
34. The treatment of claim 29 wherein:
approximately 400 mg of acyclovir are administered twice daily.
35. The treatment of claim 29 wherein:
approximately 500 mg of Ciprofloxacin are administered twice daily.
36. The treatment of claim 29 wherein:
approximately 250 mg of metronidazole are administered twice daily.
37. The treatment of claim 29 wherein:
approximately 400 mg of acyclovir are administered twice daily, approximately 500 mg of Ciprofloxacin are administered twice daily, and approximately 250 mg of metronidazole are administered twice daily.
38. The method for treatment of claim 24 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir or a pharmaceutically acceptable ester thereof, said member of the quinolone family comprises Ciprofloxacin, and said member of the nitroimidazole family comprises metronidazole.
39. The treatment of claim 38 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily.
40. The treatment of claim 38 wherein:
between approximately 50 mg to 2 gm of Ciprofloxacin are administered daily.
41. The treatment of claim 38 wherein:
between approximately 100 mg to 1 gm of metronidazole are administered daily.
42. The treatment of claim 38 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily, between approximately 50 mg to 2 gm of Ciprofloxacin are administered daily, and between approximately 100 mg to 1 gm of metronidazole are administered daily.
43. The treatment of claim 38 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily.
44. The treatment of claim 38 wherein:
approximately 500 mg of Ciprofloxacin are administered twice daily.
45. The treatment of claim 38 wherein:
approximately 250 mg of metronidazole are administered twice daily.
46. The treatment of claim 38 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily, approximately 500 mg of Ciprofloxacin are administered twice daily, and approximately 250 mg of metronidazole are administered twice daily.
47. The method for treatment of claim 24 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir or a pharmaceutically acceptable ester thereof, said member of the quinolone family comprises a fluoroquinolone, and said member of the nitroimidazole family comprises metronidazole.
48. The treatment of claim 29 wherein:
said pharmaceutically acceptable ester of acyclovir is valacyclovir hydrochloride.
49. The treatment of claim 48 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily.
50. The treatment of claim 48 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered, between approximately 50 mg to 2 gm of Ciprofloxacin are administered, and between approximately 100 mg to 1 gm of metronidazole are administered.
51. The treatment of claim 48 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily.
52. A method for medically treating the symptoms of reactive arthritis or bursitis in humans comprising:
administering to a patient an effective amount of the combination of a member of the family of synthetic purine nucleoside analog antiviral drugs or a pharmaceutically acceptable ester or a metabolite thereof, and a member of the tetracycline family or a metabolite thereof.
53. The method for treatment of claim 52 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir.
54. The treatment of claim 53 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered.
55. The treatment of claim 54 wherein:
approximately 400 mg of acyclovir are administered twice daily.
56. The method for treatment of claim 52 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir hydrochloride.
57. The treatment of claim 56 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily.
58. The treatment of claim 57 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily.
59. The method for treatment of claim 52 wherein:
said member of the tetracycline family comprises minocycline hydrochloride.
60. The treatment of claim 59 wherein:
between approximately 50 to 200 mg of minocycline hydrochloride are administered.
61. The treatment of claim 60 wherein:
approximately 100 mg of minocycline hydrochloride are administered twice daily.
62. A method for medically treating the symptoms of reactive arthritis or bursitis in humans comprising:
administering to a patient an effective amount of the combination of a member of the family of synthetic purine nucleoside analog antiviral drugs or a pharmaceutically acceptable ester or a metabolite thereof, and a member of the quinolone family or a metabolite thereof.
63. The method for treatment of claim 62 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises acyclovir.
64. The treatment of claim 63 wherein:
between approximately 100 mg to 4 gm of acyclovir are administered.
65. The treatment of claim 64 wherein:
approximately 400 mg of acyclovir are administered twice daily.
66. The method for treatment of claim 62 wherein:
said member of the family of synthetic purine nucleoside analog antiviral drugs comprises valacyclovir hydrochloride.
67. The treatment of claim 66 wherein:
between approximately 125 mg to 4 gm of valacyclovir hydrochloride are administered daily.
68. The treatment of claim 67 wherein:
approximately 500 mg of valacyclovir hydrochloride are administered twice daily.
69. The method for treatment of claim 62 wherein:
said member of the quinolone family comprises Ciprofloxacin.
70. The treatment of claim 69 wherein:
between approximately 50 mg to 2 gm of Ciprofloxacin are administered.
71. The treatment of claim 70 wherein:
approximately 500 mg of Ciprofloxacin are administered twice daily.
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US10/271,117 US6765000B2 (en) 1999-03-17 2002-10-15 Treatment for reactive arthritis or bursitis
US10/896,612 US7053073B2 (en) 1999-03-17 2004-07-20 Treatment for reactive arthritis or bursitis
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US20050059640A1 (en) 2005-03-17
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