Method for treating vaso occlusive crises associated with sickle cell disease

Abstract

The present invention relates to a treatment of vaso-occlusive crisis (VOC) associated with Sickle cell disease by administering a therapeutically effective amount of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate.

Claims

1. A method for treating a vaso-occlusive crisis comprising administering to a Sickle cell anemia patient a pharmaceutical composition having, as sole active agent, a therapeutically effective amount of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate.

2. The method according to claim 1 wherein the pharmaceutical composition is administered at the onset of the prodromal phase and during the vaso-occlusive crisis.

3. The method according to claim 1 wherein the method comprises reducing the severity or duration of the vaso-occlusive crisis.

4. The method according to claim 1 wherein the method comprises treating pain associated with the vaso-occlusive crisis.

5. The method according to claim 1 wherein the method comprises reducing or preventing organ and tissue damages caused by the vaso-occlusive crisis.

6. The method according to claim 1 wherein the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers.

7. The method according to claim 6 wherein the pharmaceutical composition is suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal or parenteral administration.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: is a graph showing Nitrite blood concentrations (concentration-time) after intravenous administration of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) or naproxen in homozygous Sickle Cell transgenic mice.

(2) FIG. 2: is a graph showing cGMP concentrations (concentration-time) after intravenous administration of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) or naproxen in homozygous Sickle Cell transgenic mice.

DETAILED DESCRIPTTION OF THE INVENTION

(3) A method is provided for the treatment of the acute pain crisis in a Sickle cell anemia patient. The method includes administering a therapeutically effective amount of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod).

(4) The following description provides specific details in order to provide a thorough understanding of the invention. The skilled artisan, however, would understand that the invention can be practiced without employing these specific details. For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

(5) “Treatment” as defined herein means any reduction of the severity or duration of the vaso-occlusive events, to abort a crisis, or any reduction of the pain associated with Sickle cell anemia. The reduction in pain can include the reduction in frequency, duration or intensity of the pain. The intensity of the pain can be measured by standard means, for example, a dolorimeter, a palpometer, 10 points pain scale, etc.

(6) “Prodromal signs and symptoms of the vaso-occlusive crisis” as defined herein includes: tiredness, dizziness, weakness, yellowing of the eyes, pallor, gastrointestinal symptoms such as nausea, vomiting, and change in appetite, musculosketal symptoms such as swelling of hands/feet, tenderness, or stiffness in joints as well as respiratory such as sniffling, coughing, and changes in breathing.

(7) As used herein, the term “therapeutically effective amount” of the compound is that amount necessary or sufficient to treat or prevent a disease, disorder, and/or a condition as described herein. The effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compound of the invention without undue experimentation.

(8) Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

(9) The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

(10) A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

(11) In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

(12) If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

(13) While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.

(14) For use in the present treatment 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate is administered orally; the dosage for adults ranges from 100 mg/day to 3000 mg/day or from 100 mg/day to 2000 mg/day, preferably from 375 mg/day to 1500 mg/day, most preferably from 750 mg/day to 1500 mg/day; the dosage for children (over 2 years old and under 16 years old) ranges from 15 to 22.5 mg per Kg per day.

(15) The exact dosage and schedule of administration will vary depending on the amount needed to provide relief in each particular instance.

(16) For use in the present treatment, 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate is preferably administered to a patient from the onset of the early prodromal signs and symptoms of the vaso-occlusive crisis until the crisis is managed. The treatment can be also used for maintenance therapy after management of the vaso-occlusive crisis.

(17) The regimen of administration can affect what constitutes an effective amount. Several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

(18) The term “pharmaceutical composition” as used herein includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

(19) The term “pharmaceutically acceptable carrier” as used herein is recognized in the art and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compound of the present invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

(20) Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

(21) Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

(22) Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

(23) Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

(24) Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

(25) Regardless of the route of administration selected, the compounds of the present invention and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

EXAMPLE 1

Effect of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) on Nitric Oxide Blood and cGMP Levels in Sickle Cell Mouse Model

(26) This trial was conducted to assess the efficacy of 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) to increase Nitrite (a precursor to NO), and cGMP in Homozygous Townes Sickle Cell transgenic mice.

(27) Experimental Design

(28) Homozygous Sickle Cell transgenic mice were treated with either 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) (15 mg/kg) or naproxen (15 mg/kg—as a control) or saline (as a vehicle control) by intravenous injection. After one hour, the mice were injected with thrombin (1 u/20 g) to induce platelet activation. Blood was drawn at 15, 30 and 1 hour after thrombin administration. Plasma nitrite levels were measured as a marker of nitric oxide bioavailability. cGMP levels were measured after addition of IBMX (3-Isobutyl-1-methylxanthine) (100 uM) to prevent cGMP degradation. Platelets were isolated and activation measured by surface expression of p-selectin.

(29) Results

(30) At one-hour nitrite concentration was statistically greater with naproxcinod compared to thrombin alone or naproxen administration (FIG. 1). At 30 minutes and 60 minutes, cGMP levels were significantly increased (p<0.01) by naproxcinod compared to thrombin alone or naproxen administration (FIG. 2).

(31) The data support the assertion that 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate (naproxcinod) can be useful and helpful, in treating the recurrent ischemic crises in patients suffering from Sickle cell anemia, indeed 4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) is able to increase the cGMP level that mitigates the depletion of nitric oxide in Sickle cell disease and subsequently the vasculopathy, which are factors that contribute to the vaso-occlusive, in addition the anti-inflammatory component of the compound reduces inflammation and pain.

(32) Thus while there have been described what are presently believed to be preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as fall within the true scope of the invention.