EP1343501A1 - Therapie für neurologische infektionen mit dem herpes-virus unter verwendung von 1,4-dihydropyridin-kalziumantagonisten - Google Patents

Therapie für neurologische infektionen mit dem herpes-virus unter verwendung von 1,4-dihydropyridin-kalziumantagonisten

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Publication number
EP1343501A1
EP1343501A1 EP00987986A EP00987986A EP1343501A1 EP 1343501 A1 EP1343501 A1 EP 1343501A1 EP 00987986 A EP00987986 A EP 00987986A EP 00987986 A EP00987986 A EP 00987986A EP 1343501 A1 EP1343501 A1 EP 1343501A1
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European Patent Office
Prior art keywords
felodipine
calcium channel
administered
channel blocker
nifedipine
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EP00987986A
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English (en)
French (fr)
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EP1343501A4 (de
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Howard Zik
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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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • 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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the treatment of certain herpes viral neurological conditions in mammals, principally Bell's Palsy, a palsy of the facial nerves, and to the use of calcium channel blockers coupled preferably with a herpes virus antagonist in a treatment therapy.
  • Other herpes conditions include Ramsay Hunt and other herpes caused neurological conditions such as Herpes Simplex Encephalitis.
  • Bell's Palsy (originally described by Charles Bell, 1812) is recognized as a palsy of the facial nerve, generally the seventh cranial nerve. It most commonly affects one side of the face, may be partial or total, and has a progression time of 7 to 10 days. Regarded in the past as idiopathic, there has recently been convincing evidence that it has its cause in the herpes type virus of the simplex type.
  • Some physicians reassure patients that the disease will most likely remit in a period lasting from 3 weeks up to 6 months, (leading some physicians to advocate a no action policy other than facial management, sometimes referred to as "therapeutic nihilism") but the fact remains that about 24% of the victims with current popular therapies are left with some residual paralysis or other aftereffects such as hemi- facial spasm, synkinesis, or loss of tearing or blinking capacity.
  • steroids particularly prednisone (see US patent 2,897,216) within the first 3 days of onset, where the standard initial prednisone dosage is about 30 mg. and is tapered off over a 5 day period to a 10 mg. level.
  • prednisone see US patent 2,897,216
  • the steroid treatment has taken the form of heavier steroid dosages, mainly cortisone, incorporated within an
  • endothelin is an extremely potent constrictor of blood vessels, particularly smaller ones, and Ikeda maintains that impairment of microcirculation through primary and secondary ischemia in the fallopian aqueduct (and thereby drawing on the earlier work of Hilger and Blunt) is responsible, but what is new here is the role of endothelin in bringing this about.
  • Ramsay Hunt syndrome (also known as "he ⁇ es zoster oticus") is also caused by a he ⁇ es virus, but in this case the he ⁇ es zoster virus, as was maintained (the condition) by J. Ramsay Hunt in 1907.
  • Ramsay Hunt syndrome frequently results in facial paralysis involving the seventh cranial nerve (as with Bell's Palsy) but also commonly affects other cranial nerves including the 5th 9th and 10th and 11th).
  • Ramsay Hunt syndrome as referred to in this invention is Ramsay Hunt Type I, not to be confused with Ramsay Hunt Type II, an entirely different condition which is a rare degenerative neurological disorder characterized by epileptic type fits and myoclonus.
  • Ramsay Hunt is often accompanied at onset by auricular vesicles, sometimes also found on face, neck or scalp and frequently results in hearing loss (48.2 % according to S. Mwaka ⁇ ). (Murakami S.
  • the present invention is directed to the alleviating the effects of Bells Palsy and Ramsay Hunt as well as other he ⁇ es caused neurological conditions by providing a therapy that directly addresses the mechanisms believed to cause the ailment.
  • the invention was realized by an analysis of the existing medical literature on the disease and by developing what the inventor believes to be a novel coherent perspective identifying the most significant causation factors and by determining a pharmacology directed to affecting those factors.
  • the invention has been achieved without experimentation on humans, it represents the results of an analysis of medical and pharmacological considerations not previously reported for the treatment of a very serious and debilitating ailment.
  • the invention is not the result of merely following markers laying out the path to its discovery in the existing literature.
  • Calcium channel blockers that are of the 1,4-dihydropyridine derivative class, especially felodipine but also including nifedidine, nimodipine (See US patent 3,799,934), nisoldipine (See US patent 4,154,839) or alenodipine may be utilized to treat Bell's Palsy and other he ⁇ es causing neurological conditions.
  • the treatment is proposed as continuing up to the tenth day of progression, but to be started as early as possible.
  • the treatment is based on a proposed dynamic for the pathological process underlying Bell's Palsy and the other conditions.
  • the proposed therapy is designed to counter the effects of this pathological process as well as inhibit the very process itself.
  • acyclovir, a he ⁇ es virus antagonist that can stem he ⁇ es viral DNA replication may be used in support of the DHP treatment.
  • the pathological process supported is the pathological process described by
  • DHP calcium channel blockers particularly felodipine, nifedipine, nimodipine, or nisodipine should result in (1) rapid vasodilation of the aqueduct arterioles (2) reduced resistance in the arterioles (3) the blocking of the same channel through which endothelin acts and therefore functionally impairing endothelin's mechanism for generating vasoconstriction. Adequate circulation should then follow with blood and oxygen flow to the seventh cranial nerve. The restoration of adequate microcirculation should then avert further damage and allow immediate blood flow to promote healing. This treatment should compare favorably to current popular steroid approach in that it precisely targets the pathological process, rather than deploying a general anti-inflammatory agent to achieve dilation.
  • Steroid use should only be effective to the extent it counters the effects of a high endothelin level, which it does only indirectly as an anti- inflammatory agent.
  • Felodipine is particularly suited for a more direct and effective role since in comparison studies with other DHP calcium channel blockers in treating hypertension it is more effective in its arterial action.
  • arterioles of the order of size found by arterioles in the fallopian aqueducts has been shown to effect arterioles of the order of size found by arterioles in the fallopian aqueducts.
  • smooth muscle as opposed to cardiac and smooth muscle (nifedipine) which is the main component of the smaller arteries (i.e. arterioles) which comprise the fallopian aqueduct.
  • prednisone as well as other steroids contain various known hazards including hepatic and renal disorders.
  • the steroids are also immunosuppressive agents and inhibit processes needed for combating any he ⁇ es infection.
  • the DHP calcium channel blocker therapy is based on a consideration of a viable understanding of the Bell's Palsy pathological process and its dynamics. Surgery also has various hazards with limited success and has consequently diminished in use over recent years.
  • the same dynamics and treatment regimen involving 1, 4 DHP Dihydo ⁇ yridine calcium channel blockers proposed here for Bell's Palsy would also lend itself to treatment of Ramsay Hunt.
  • Figures 1 is a schematic of process of Bell's Palsy Pathological Progression and may also serve as a model for other he ⁇ es causing neurological conditions e.g. Ramsay Hunt.
  • Figure 2 is a schematic of the proposed therapy of Bell's Palsy with DHP Calcium Channel Blockers, and a model for the other he ⁇ es causing neurological conditions e.g. Ramsay Hunt.
  • the proposed therapy should be administered as soon as possible upon the first diagnosis of Bell's Palsy or other he ⁇ es causing neurological conditions and continue up to the tenth day after first symptoms.
  • Damage as mentioned may be regarded as being brought about by primary and secondary ischemia originating in vasoconstriction of blood vessels in the fallopian aqueduct; consequently, the earlier that microcirculation to the seventh cranial nerve may be restored within the aqueduct, the sooner further damage could be averted as well as natural healing processes activated.
  • the vasoconstriction brought about by endothelin action may involve such arteries and their branches as the petrosal artery branches (Fisch U.
  • DHP calcium channel blockers are preferred for their vasodilatory capacity and in the reduced peripheral resistance that they offer to blood flow, resulting from their blocking action of calcium ions channels, the very channels stimulated by endothelin to produce calcium ions.
  • a preferred embodiment is to use felodipine, which is selective to smooth vascular muscle tissue, the very tissue comprising the arterioles (composed mainly of smooth muscle tissue) the vessels most effected in the vasoconstriction of Bell's
  • felodipine Due to felodipine' s selectivity and other characteristics felodipine is especially suited as a promising Bell's Palsy treatment agent. These characteristics include its effect on smaller arterioles of the magnitude found in the fallopian artery networks, as well as its consistent superior effectiveness (Hagiwara S et al, Effects of Felodipine, Nifedipine and Verapamil on Cystolic Ca2+ on Contraction of
  • Another embodiment of the present invention is to employ nifedipine, which has been proven effective against angina for relief of spasm of arteries or arterioles as well as being selective to both coronary and smooth muscle.
  • Nisodipine another DHP calcium channel blocker acting on the same sites is effective in much lower dosage levels than felodipine and also avoids the coronary areas.
  • Nimodipine a dihydropyridine (DHP) used to treat SAG hemorrhaging is most effective in this latter capacity.
  • tests in countering the effects of endothelin were primarily done with respect to nifedipine (Kiowaski W. et al, Endothelin-induced Vasoconstriction in Man; Variable Modification caused by endothelium-Derived Relaxing Factor, Sau Med
  • Figures 1 and 2 schematically represent the relevant process and therapy.
  • Thrombin Receptor Activation Stimulates Astrocype Proliferation and Reversal ofStellation by Distinct Pathways: involvement of Tyrosine for Phosphorylation, J Neurochem, 64:2: 583- 91, 1995 Feb) and (Stanmirouvic DB, The role of Intercellular Calcium and protein Kinase in Endothelin stimulated Proliferation of rat type I Astrocytes, Glia,
  • protein tyrosine kinase needed for he ⁇ es replication is basically involved in stimulating an immunological reaction for astrocyte cell production.
  • Astrocytes are one of the basic cells found in certain tissues of the peripheral nervous system. Further, proliferation of immunoreactive astrocytes in the brain has been shown to result in endothelin production (ET-1) (K. Ma), and has been traced in 5 out of 9 cases examined by Ma to be stimulated by confirmed he ⁇ es simplex inflammatory infections.
  • Endothelin moreover is a known mitogen, and as such leads to multiple astrocyte cell production. This entails a kind of loop or reciprocal effect whereby endothelin and astrocytes synergistically produce heightened endothelin and astrocyte levels.
  • Endothelin as mentioned, specifically
  • ET-1 is an extremely potent vasoconstricting agent and achieves its vasoconstricting effects by precisely stimulating those calcium channels sites through which DHP calcium channel blockers act. (Hayes, Drimal). Therefore, the DHP calcium channel blockers impair the process of vasoconstriction itself while by appropriate dosage management may even achieve vasodilation beyond simply countering the effects of endothelin.
  • felodipine's effect on reversing the contractile process and replacing it with dilation and reduced blood resistance is selective with respect to vascular smooth muscle with little or no effect on cardiac muscle. Further, felodipine can penetrate the blood brain barrier to the extent that this barrier may be a problem for effective contact with arteries.
  • Nimodipine is also selective and is particularly selective for cerebral arteries, but clinical tests on other aspects of its effectiveness such as dilation and reduced resistance of smaller arteries is not as extensive. Nimodipine may, however, be considered especially relevant to potentially treating he ⁇ es simplex encephalitis insofar as this disease involves he ⁇ es infection of the inner brain regions of the cerebral cortex. The responding endothelin immunoreactivity in this region (Kuo- chun Ma et al, J. of Neurological Sciences 126:184-192, 1994 June) also lends it to the felodipine and nifedipine approaches.
  • Nisodipine is more potent and long lasting per unit dosage than nifedipine and in contrast is selective with respect to countering the contractile effects of vascular smooth muscle as opposed to cardiac muscle. It has, furthermore, been used effectively in treating hypertension
  • Felodipine has been shown in the Lindbom experiments (Lindbom L et. al. J. Cardiacvasec Pharmacol, 14(4): 593-597 ',1990 April) to dilate arterioles of an even smaller magnitude: 10-20 microns of the transverse type and 4-8 microns of the terminal type.
  • Felodipine is known to result in vasodilation of arterioles at oral levels between 2.5 and 20 mg once daily for extended release tablets in treatment of hypertension, and which represents the dosage range proposed in this invention for Bell's Palsy and Ramsay Hunt ; a daily dosage of 10 mg.
  • nifedipine is used, peak levels are reached in 30 minutes at dosage levels of 10 mg. as a preferred level for immediate release tablets and dosage ranges of 10- 20 mg. may be administered 3 times daily for effective treatment for Bell's Palsy and Ramsay Hunt, or once daily for extended release tablets at dosage level of 30 -60 mg. with preferred level at 30 mg.
  • These proposed dosage levels and ranges track with effective treatment of hypertension and angina, and are associated with adequate vasodilation of arterioles.
  • DHP calcium channel blockers Adverse effects for DHP calcium channel blockers are minimal with the most common being headaches (14.7% felodipine, 19 % extended release 30 mg.nifedipine) for the group and mild peripheral edema (17 %) for felodipine and occasional flushing (6.9% felodipine, 4% nifedipine) or dizziness (5.8% felodipine,
  • nifedipine 4% nifedipine.
  • blood pressure may drop where averaging for felodipine at 10 mg. dosage level is 5.3/7.2 systolic and 2.7/2.5 diastolic over a 4 week period for individuals treated.
  • the average reduction over a 6 week period for nifedipine at 30 mg was 5.5/2.9 (systolic/diastolic) and at 60 mg. was 8.0/4.1.
  • Nimodipine as a preferred embodiment is recommended at a dosage of 60 mg. every 4 hours. This dosage tracks the standard dosage for subarachnoid hemorrhaging from ruptured congenital aneurysm, and recommended for effective treatment of that condition.
  • Nisoldipine as an embodiment is an extended release DHP and the recommended daily dosage for treatment of Bell's palsy and Ramsay Hunt is 10 -20 mg.
  • DHP calcium channel blockers Treatment of Bell's Palsy or Ramsay Hunt with 1,4-dihydropyridine (DHP) calcium channel blockers is proposed with recommended administration beginning with the first signs and to continue up to the tenth day. Felodipine is likely to be particularly effective.
  • the administration of DHP calcium channel blockers is based on a disease dynamic that begins with a he ⁇ es (simplex) viral invasion and ultimately leads to primary and secondary ischemia of the seventh cranial nerve in the fallopian aqueduct.
  • the ischemia involves physiological events of a type described by Hilger and Blunt in the 1940's and 1950's, essentially entailing severe vasoconstriction of local arterial branches in the aqueduct area e.g. petrosal arterial branches.
  • a key intermediary event is the production of endothelin (ET-1), unknown in earlier days, as a vasoconstrictive peptide through calcium ion action and generated as an immunoreactive by-product.
  • DHP 1,4-dihydropyridine calcium channel blockers
  • the use of 1,4-dihydropyridine (DHP) calcium channel blockers as one of the 5 classes of calcium channel blockers is proposed here as particularly tailored for treatment of Bell's Palsy as well as the other he ⁇ es causing neurological conditions (e.g. Ramsay Hunt) in light of its vasodilatory and resistance reduction properties, thereby counteracting and inhibiting the vasoconstrictive disease described above.
  • the DHP group is especially suited to effect vascular smooth muscle by calcium channel blockage, where the smooth muscle is the main constituent of the small arteries i.e. the arterioles in the aqueduct region.
  • the use of DHP has been proven effective in treating hypertension and angina.
  • Felodipine would appear to be particularly efficient in treatment of Bell's Palsy because it is selective of smooth vascular muscle (without cardiac selectivity) as well as cerebral arteries, the very arterial elements involved, e.g. petrosal and stylomastoid. Further, it has been proven effective in dilating even smaller arteries than those imputed in Bell's Palsy and it can penetrate rather well the blood brain barrier. Also its consistency in dilation is superior. These facts make felodipine an especially suitable prospect for treatment. Nifedipine, however, is also promising insofar as it is the most experimentally proven in counteracting endothelin. Felodipine also enjoys such support, but to a lesser degree.
  • Nimodipine is promising for its special effectiveness in blood brain barrier penetration and its relation to improved neurological condition by relief from ischemia in patients with subarachnoid hemorrhage from ruptured aneurysms. It has, furthermore, been used on safely for patients without hypertension and does not lower blood pressure significantly .
  • Nisodipine enjoys unique long term unit dosage potency and remains selective to smooth vascular muscle.
  • felodipine in this group appears especially suited to address the appropriate arteriole regions of Bell's Palsy and Ramsay Hunt and even he ⁇ es simplex encephalitus, although nimodipine is also well suited for the latter.
  • Appropriate dosage of felodipine based on treatment of vasoconstriction in hypertension would be of the order of 2.5 gm to 20 gm of extended release tablets daily for the 10 day progression period involved. Nifedipine could involve one 30- 60 extended release tablet daily for a comparable period. Potential adverse effects are generally minimal, the most common being mild edema for felodipine, and dizziness or headaches for felodipine or nifedipine.
  • the conjoint use of acyclovir as an adjunct to control viral replication would be 400 mg., 5 times daily for the 10 day period.
  • the proposed utilization of DHP calcium channel blockers is designed to address the core of the pathological process of Bell's Palsy and thereby to halt and reverse its progression.

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EP00987986A 2000-11-21 2000-11-21 Therapie für neurologische infektionen mit dem herpes-virus unter verwendung von 1,4-dihydropyridin-kalziumantagonisten Withdrawn EP1343501A4 (de)

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PCT/US2000/031994 WO2002041893A1 (en) 2000-11-21 2000-11-21 Therapy for herpes neurological viral conditions utilizing 1,4-dihydropyridine calcium channel blockers

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JP2013526518A (ja) * 2010-05-13 2013-06-24 ザ ユニバーシティ オブ ケンタッキー リサーチ ファウンデーション Ｍｃｉおよびアルツハイマー病の処置
WO2020163815A1 (en) * 2019-02-07 2020-08-13 Innomed Technologies, Inc. Ivig treatments for bell's palsy
CN109820852B (zh) * 2019-03-11 2021-02-19 中国农业科学院兰州兽医研究所 一种尼莫地平在制备预防口蹄疫病毒感染的药物中的应用

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US4849412A (en) * 1986-06-05 1989-07-18 Board Of Regents, The University Of Texas System Methods and compositions for treating viral infections
US5039678A (en) * 1989-03-23 1991-08-13 Wake Forest University Method of increasing cranial vessel proliferation by administering nimodipine
SE9203857D0 (sv) * 1992-12-22 1992-12-22 Astra Ab Use of an enantiomeric dihydropyridine
US5677308A (en) * 1996-12-19 1997-10-14 Lerner; A. Martin Method for alleviating spasmodic torticollis

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WO2002041893A1 (en) 2002-05-30
NO20032276L (no) 2003-06-30
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EP1343501A4 (de) 2004-12-15
AU2001224250A1 (en) 2002-06-03
JP2004513965A (ja) 2004-05-13

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