Low dose oral dipyridamole compositions and uses thereof

Abstract

A composition comprising about 10 mg or less of dipyridamole formulated for oral administration and a physiologically acceptable carrier.

Claims

1-13. (canceled)

14. A method of treating a disorder selected from the group consisting of dry eye disease, sleep disorders, nonspecific recurrent sore throat, erectile dysfunction, viral disease, pain, xerostomia and Graft-versus-Host Disease (GvHD) comprising: and administering a pharmaceutical composition comprising 10 mg or less of dipyridamole and wherein said pharmaceutical composition is an oral dosage form.

15. A method according to claim 14, wherein the oral dosage form comprises 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg or 10 mg of dipyridamole.

16. A method according to claim 14, wherein the oral dosage forms comprises 1 mg, 2 mg, 3 mg or 5 mg of dipyridamole.

17. A method according to claim 14, wherein the disorder is dry eye disease.

18. A method according to claim 14, wherein the disorder is a sleep disorder.

19. A method according to claim 18, wherein the sleep disorder is insomnia.

20. A method according to claim 19, wherein the insomnia is treatment-refractory insomnia.

21. A method according to claim 14, wherein the disorder is a nonspecific recurrent sore throat.

22. A method according to claim 14, wherein the disorder is erectile dysfunction.

23. A method according to claim 14, wherein the disorder is viral disease.

24. A method according to claim 14, wherein the disorder is xerostomia.

25. A method according to claim 14, wherein the disorder is pain.

26. A method according to claim 14, wherein the pain is rheumatic or fibromyalgia pain.

27. A method according to claim 14, wherein the pain is angina pectoris.

28. A method according to claim 14, wherein the pain is cancer-related bone pain.

29. A method according to claim 14, wherein the daily dose of dipyridamole is 10 mg or less.

30. A method according to claim 14, wherein the oral dosage form further comprises melatonin.

31. A method according to claim 30, wherein the oral dosage form comprises between 0.25 mg and 10 mg of melatonin.

32. A method according to claim 30, wherein the disorder is a sleep disorder.

33-42. (canceled)

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0059] Embodiments of the invention relate to therapeutic compositions for oral administration containing about 10 mg or less per dosage unit dipyridamole and treatment packs including such compositions and methods for producing such treatment packs and/or compositions.

[0060] Specifically, some embodiments of the invention can be used to treat various ailments while reducing the likelihood of undesirable side effects.

[0061] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

Exemplary Compositions

[0062] Some embodiments of the invention relate to pharmaceutical composition. According to various exemplary embodiments of the invention the pharmaceutical composition includes 10 mg, 7.5 mg, 5 mg, 2.5 mg, 1 mg, 0.5 mg or 0.25 mg, or lesser or intermediate amounts of dipyridamole formulated for oral administration and a physiologically acceptable carrier. In some embodiments the pharmaceutical composition is formulated as a liquid dosage form dissolved with propylene glycol. In some embodiments propylene glycol is the primary inactive ingredient in the composition. Alternatively or additionally, in some embodiments the liquid dosage form has a concentration of 2 mg/ml or less. In some embodiments the composition is formulated as a solid dosage form (e.g. pill, tablet or capsule). In some embodiments the composition is provided as a liquid filled capsule.

Exemplary Treatment Methods

[0063] According to various exemplary embodiments of the invention, compositions described above are administered to a subject in need thereof 1 or 2 or 3 or 4 or 5 or more times daily to achieve a total daily dose of 1, 5, 10, 15 or 20 mg/day or lesser or intermediate total daily dose. In some embodiments the compositions described above are administered once every other day. Subjects in need thereof suffer from viral infections and/or erectile dysfunction and/or sleep disorders and/or anxiety and/or pain and/or xerostomia and/or hair loss and/or dry eye and/or cancer, and/or dry eye.

Exemplary Treatment Packs

[0064] Some exemplary embodiments of the invention relate to a treatment pack including multiple oral dosage forms of a composition containing dipyridamole as an active ingredient. In some embodiments each oral dosage form contains 10 mg, 7.5 mg, 5.0 mg, 2.5 mg. 1.0 mg or 0.5 mg or intermediate or smaller amounts of dipyridamole. The treatment pack also includes packaging material and instructions for oral administration of the composition with a total daily dose of 20 mg/day, 10 mg/day, 5 mg/day, 2.5 mg/day, 1.0 mg/day, 0.5 mg/day, 0.25 mg/day or intermediate or lower daily dosages. According to various exemplary embodiments of the invention instructions included in the kit indicate that the product is useful in treatment of viral infections and/or erectile dysfunction and/or sleep disorders and/or anxiety and/or pain and/or xerostomia and/or hair loss and/or dry eye and/or prostate cancer and/or chronic lymphocytic leukemia. According to various exemplary embodiments of the invention the composition in the kit is formulated as described hereinabove under Exemplary Compositions. Alternatively or additionally, in some embodiments the instructions in the kit specify a dosing regimen of one or two dosage forms per day or every other day. In some embodiments the kit includes a single container for the multiple doses (e.g. a bottle of syrup or elixir or a single bottle containing multiple solid oral dosage forms). In other exemplary embodiments of the invention, the kit includes multiple containers, each of the multiple containers containing a single dose of the multiple doses (e.g. individual containers with pre-measured liquid doses or individual solid dosage forms in bubble packs, blister packs or foil pack wrapping).

Exemplary Dosages

[0065] According to various exemplary embodiments of the invention the total daily dose of dipyridamole is 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg or 20 mg/day or intermediate or lesser amounts. According to various exemplary embodiments of the invention the daily dose is given in 1, 2, 3, 4 or 5 doses at least every other day. According to various exemplary embodiments of the invention oral dosage forms such as tablets, capsules, gel-caps, dragees, solutions and suspensions are employed.

[0066] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0067] Specifically, a variety of numerical indicators have been utilized. It should be understood that these numerical indicators could vary even further based upon a variety of engineering principles, materials, intended use and designs incorporated into the various embodiments of the invention. Additionally, components and/or actions ascribed to exemplary embodiments of the invention and depicted as a single unit may be divided into subunits. Conversely, components and/or actions ascribed to exemplary embodiments of the invention and depicted as sub-units/individual actions may be combined into a single unit/action with the described/depicted function.

[0068] Alternatively, or additionally, features used to describe a method can be used to characterize an apparatus and features used to describe an apparatus can be used to characterize a method.

[0069] It should be further understood that the individual features described hereinabove can be combined in all possible combinations and sub-combinations to produce additional embodiments of the invention. The examples given above are exemplary in nature and are not intended to limit the scope of the invention which is defined solely by the following claims.

[0070] Each recitation of an embodiment of the invention that includes a specific feature, part, component, module or process is an explicit statement that additional embodiments of the invention not including the recited feature, part, component, module or process exist.

[0071] All publications, references, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

[0072] The terms include, and have and their conjugates as used herein mean including but not necessarily limited to.

Exemplary Physiologic Considerations

[0073] Dipyridamole absorption is believed to be dependent on physiologic conditions (e.g. pH levels i.e. increased absorption at more acidic levels) and/or patient's age and/or fasting status. It is therefore anticipated dosage forms which increase absorption efficiency and/or absorption rate will lead to efficacy of lower doses.

[0074] Additional objects, advantages, and novel features of various embodiments of the invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0075] Despite the fact that dipyridamole is difficult to dissolve in water, it was surprisingly found to be soluble in propylene glycol, at a concentration of 5 mg or 10 mg or more per ml.

EXAMPLES

[0076] Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non-limiting fashion.

Example 1

Preparation of Solid Oral Dosage Forms

[0077] Dipyridamole capsules were prepared as follows. Fish or beef gelatin capsules with 200 mg capacity were used. Dipyridamole powder was mixed into dextrose monohydrate powder as follows:

[0078] 190 mg dextrose monohydrate+10 mg dipyridamole

[0079] 195 mg dextrose monohydrate+5 mg dipyridamole

[0080] 198 mg dextrose monohydrate+2 mg dipyridamole

[0081] 199 mg dextrose monohydrate+1 mg dipyridamole

[0082] 199.5 mg dextrose monohydrate+0.5 mg dipyridamole

[0083] 199.75 mg dextrose monohydrate+0.25 mg dipyridamole

[0084] After this, capsules were filled and closed, and provided to users.

[0085] In other exemplary embodiments of the invention, rice powder or microcrystalline cellulose powder or Avicel or leucine is substituted for dextrose monohydrate.

Example 2

Preparation of Liquid Oral Dosage Forms

[0086] For some users who preferred a liquid formulation, dipyridamole was dissolved in pure propylene glycol to provide concentrations of 0.25 mg per drop (5 mg/mL), 0.5 mg per drop (10 mg/mL), and 1 mg per drop (20 mg/mL). Dipyridamole was surprisingly soluble in propylene glycol and maintained its potency even after 1 year of storage at room temperature. Solubility of a compound is known to increase absorption and efficacy. In other exemplary embodiments of the invention, liquid formulations are provided in gel-caps.

Example 3

Insomnia Treatment

[0087] In order to determine the effect of low dose oral dipyridamole for treating insomnia, 4 human subjects with intractable insomnia (who had failed numerous other treatments with different types of sleeping pills) were treated with low dose oral dipyridamole prepared as in example 1 as the sole treatment.

[0088] Subject 1 (48 y/o [year old] male), Subject 2 (22 y/o female), Subject 3 (13 y/o female) and Subject 4 (38 y/o female) were treated with varying doses (0.25, 0.5, 1, 2, 4, 5, 7 and 10 mg) taken before sleep, for periods of 2 weeks or more for each dose and followed for up to 7 months in total.

[0089] Subject 1: 2 mg was found to be the optimal dose for ensuring an excellent night's sleep. Additional effects included intense dreams, especially pleasant ones, dreams involving remote events and increased incidence of nocturnal penile tumescence which had been very rarely experienced in the past. Subject tried half a dozen sleep meds prior to this with either poor effect or unbearable side effects. Dipyridamole 10 mg had negligible benefit compared to lower doses.

[0090] Subject 2: 2 mg was found to be the optimal dose for ensuring an excellent, undisturbed sleep lasting approximately 6-8 hours per night. An additional effect included good dream recall. She previously used melatonin both regular and timed release without clear benefit.

[0091] Subject 3: 1 mg was found to be the optimal dose for ensuring an excellent, deep sleep. An additional effect included frightening dreams. The subject weighed 37 kg. Hence, a lower dose was used. She needed to take it by mid-evening in order to fall asleep easily.

[0092] Subject 4: 5 mg was found to be the optimal dose for ensuring ease in falling asleep and having deep restorative sleep. Additional effects included better dream recall and better mood. The subject had a diminishing effect with increasing dose.

[0093] This example illustrates that low dose oral dipyridamole is effective for the treatment of insomnia, even in patients that do not respond to conventional sleeping medications. This example also illustrates that the benefits are lost with increasing dosage, especially 10 mg or more which has little or no effect.

Example 4

Keratoconjunctivitis Sicca Treatment

[0094] In order to determine the effect of low dose oral dipyridamole for treating keratoconjunctivitis sicca, three subjects with keratoconjunctivitis sicca with duration between 3 & 12 years were treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment. Each of the three subjects was unresponsive to cyclosporine eye drops or to lubricating drops which are the conventional treatments.

[0095] Subject 1 (58 y/o female), Subject 2 (40 y/o male) and Subject 3 (40 y/o male) were treated with varying doses (2, 5 and 10 mg) taken before sleep or in the afternoon/evening hours, for initial periods of up to 2 weeks for each dose to establish optimal dosing, and followed for up to 12 months in total.

[0096] Subject 1: 2 mg was found to be the optimal dose for relieving the effects of keratoconjunctivitis sicca. She reported complete relief of dry eye symptoms (grittiness, graininess, itching), cessation of eye discharge, and was finally able to use a computer screen for a full day's work without symptoms. She was able to cease the copious use of lubricating drops. Additional effects included significantly improved quality of sleep and a great improvement in arthritis symptoms. For a period of 1 month, dipyridamole was prepared as in Example 2.

[0097] Subject 2: 2 mg was found to be the optimal dose which resulted in complete resolution of previous symptoms of burning, itching, grittiness and discomfort, and copious eye discharge. He no longer required lubricating eye drops or artificial tears. For a period of 1 month, dipyridamole was prepared as in Example 2. Additional effects included improved memory and sleep quality.

[0098] Subject 3: 2 mg was found to be the optimal dose for the resolution of symptoms and, normalization of tear osmolality and Schirmer's test which no longer showed evidence of dry eye. He was able to stop the use of lubricating eye drops, and artificial tears. The 10 mg dose was not effective and the 2 mg worked better than 5 mg. Additional effects included improved sleep and mood.

[0099] This example illustrates that low dose oral dipyridamole is effective for the treatment of keratoconjunctivitis sicca. The results also suggest that 2 mg/day is an effective dose.

Example 5

Angina Pectoris Treatment

[0100] In order to determine the effect of low dose oral dipyridamole for treating angina pectoris, 2 subjects with chronic treatment-resistant angina were treated with low dose oral dipyridamole as the sole treatment.

[0101] Subject 1 (74 y/o male) and Subject 2 (58 y/o male) were treated with varying doses of oral dipyridamole prepared as in Example 1 (1, 2, 3, 5 and 10 mg) taken in the morning or evening, for periods of up to 2 weeks for each dose and followed for up to 7 months in total.

[0102] Subject 1: 3 mg was found to be the optimal dose for complete resolution of angina. The 10 mg dose was ineffective. Additional effects included improved hair growth including eyelashes and eyebrows, and improved sleep.

[0103] Subject 2: 2 mg was found to be the optimal dose for complete resolution of angina symptoms (chest pain, shortness of breath). For a period of 1 month, dipyridamole was prepared as in Example 2. Additional effects included improved sleep and vivid dreams.

[0104] This example illustrates that low dose oral dipyridamole is effective for the treatment of angina pectoris, even in patients that do not respond to conventional treatments.

Example 6

Treatment of Non-specific Recurrent Sore Throat

[0105] In order to determine the effect of low dose oral dipyridamole for treating recurrent sore throat, one subject with recurrent, non-streptococcal, non-specific, sore throat occurring every 4-8 weeks and lasting 7-10 days was treated with low dose oral dipyridamole prepared as in example 1 as the sole treatment.

[0106] A 10 y/o female was treated with 1 mg taken before sleep and followed for 11 months in total. A dose of 1 mg/day resulted in complete resolution of recurrent sore throat. One mg dose was given based on a weight of 29 kg. An additional effect was the resolution of post nasal drip.

[0107] This example illustrates that low dose oral dipyridamole is effective for the treatment of recurrent sore throat.

Example 7

Erectile Dysfunction Treatment

[0108] In order to determine the effect of low dose oral dipyridamole for treating erectile dysfunction, 5 subjects with erectile dysfunction were treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment. Some subjects had either failed or could not tolerate conventional treatments.

[0109] Subject 1 (41 y/o male), Subject 2 (27 y/o male), Subject 3 (67 y/o male), Subject 4 (70 y/o male) and subject 5 (48 y/or male) were treated with varying doses (2, 3, 5 and 10 mg) taken in the evening or before sleep, for periods 2 weeks or more for each dose and followed for up to 15 months of use in total.

[0110] Subject 1: 2 mg was found to be the optimal dose for complete restoration of erectile function that had not been present for 6 years including absence of nocturnal penile tumescence for 12 years. The subject could not take sildenafil or similar agents due to adverse side effects. A consistent daily dose of dipyridamole was taken at night on a continuous basis. Nocturnal penile tumescence effect was experienced sooner (noticed if waking up in middle of the night) if taken on empty stomach, but always upon awakening in the morning. Additional effects included excellent dream recall, vivid dreams and improved sleep.

[0111] Subject 2: 3 mg was found to be the optimal dose for obtaining satisfactory erectile function. Subject 2 had not been able to achieve an erection for 3 years without the use of sildenafil, tadalafil or vardenafil. An additional effect included improved sleep.

[0112] Subject 3: Erectile function was restored to user's satisfaction within 10 days of starting dipyridamole at 2 mg. For a period of time, the subject increased dose to twice daily, still with satisfactory outcome. When the subject increased dose to 10 mg daily, the beneficial effect was lost.

[0113] Subject 4: Resolution of erectile dysfunction was achieved within 5 days of starting low dose oral dipyridamole at 2 mg. As the subject was satisfied with the result, no dose adjustment was attempted. The subject noticed increased resistance to upper respiratory viral infections (or colds) which now rarely occurred, as opposed to previous incidence of every 2-3 months.

[0114] Subject 5: Erectile dysfunction resolved within 2 weeks of starting low dose oral dipyridamole at 2 mg. The subject found that when taken with food, 2 mg was not that effective but 5 mg was. However 10 mg did not produce the same benefit as 5 mg. The subject also found that use of low dose oral dipyridamole alleviated his long-standing depression. The subject was no longer using SSRI's due to their risk of causing erectile dysfunction.

[0115] This example illustrates that low dose oral dipyridamole is effective for the treatment of erectile dysfunction and suggests that it is a viable substitute for drugs currently approved for erectile dysfunction.

Example 8

Treatment of Chronic Lymphocytic Leukemia

[0116] In order to determine the effect of low dose oral dipyridamole for treating chronic lymphocytic leukemia (CLL), 2 subjects with CLL were treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment.

[0117] Subject 1 (75 y/o female) and Subject 2 (74 y/o male) were treated with varying doses (2 or 3 mg) taken in the morning, afternoon or evening, for periods of up to 2 weeks for each dose and followed for up to 6 months in total.

[0118] Subject 1: 2 mg was found to be the optimal dose for lowering of the white blood cell count from 25,000 (which was rising by 10%/month on observation only) to 18,000 in a one month period. Additional effects included significantly improved energy and memory recall.

[0119] Subject 2: 3 mg was found to be the optimal dose for lowering of the white blood cell count from 30,000 to 18,000 over 6 months. Additional effects included renewed growth of eyebrows and eyelashes.

[0120] This example illustrates that low dose oral dipyridamole is effective for the treatment of CLL. The possibility of low dose oral dipyridamole in conjunction with standard treatments for CLL remains to be investigated.

Example 9

Prevention and Treatment of Viral Disease

[0121] In order to determine the effect of low dose oral dipyridamole for preventing and treating viral disease, 4 subjects with frequent viral infections (with upper respiratory symptoms) were treated with low dose oral dipyridamole prepared as in Example 1 or example 2 as the sole treatment.

[0122] Subject 1 (45 y/o male), Subject 2 (15 y/o male), Subject 3 (20 y/o female), and Subject 4 (33 y/o male) were treated with varying doses (2, 5 and 10 mg) taken at any time during the day, for periods of 2 weeks for each dose, and thereafter continuously for up to 2 years.

[0123] Subject 1: 2 mg was found to be the optimal dose for decreasing the frequency and duration of viral infections from 6 times yearly, lasting up to 10 days to one episode of influenza once in 2 years, lasting only 2 days and two episodes of upper respiratory tract infection yearly for 2 years, lasting only 1 day. An additional effect included vivid dreams.

[0124] Subject 2: 2 mg was found to be the optimal dose for decreasing the duration of cold symptoms from 5-7 days to 12-24 hours. An additional effect included vivid dreams.

[0125] Subject 3: 2 mg taken once daily was found to be the optimal dose for reducing incidence of viral infections from 5-6 times yearly to 1-2 times yearly. When an infection did occur, accompanied by symptoms such as sore throat, watery eyes, headache and sometimes fever, a dose of 2 mg twice daily resolved the symptoms very quicklywithin 1-2 days, whereas previously these episodes would last 7-10 days. On one occasion the subject tried a 10 mg dose but this failed to deliver the same benefit as the 2 mg dose. Vast improvement in chronic depressive symptoms was also observed.

[0126] Subject 4: 2 mg was taken twice daily for a severe viral infection (upper respiratory symptoms plus viral conjunctivitis) with rapid complete relief of symptoms (in 1-2 days). Thereafter the subject continued taking 2 mg daily for 10 months without any recurrence of infections, which previously would occur every 3-4 months. Improved deep sleep and alleviation of anxiety was also reported.

[0127] This example illustrates that low dose oral dipyridamole is effective for the prevention and treatment of viral infections.

Example 10

Treatment of Cancer-Related Bone Pain

[0128] In order to determine the effect of low dose oral dipyridamole for treating cancer-related bone pain, a single subject with cancer-related bone pain was treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment.

[0129] A 70 y/o male was treated with 2 mg taken in the early evening hours. The subject reported resolution of bone pain related to metastatic prostate cancer to the cervical spine within 4 days. The subject was previously dependent on the daily use of opiate pain medications for the past 6 months. An additional effect observed was improved energy.

[0130] This example illustrates that low dose oral dipyridamole is effective for the treatment of cancer-related bone pain.

Example 11

Treatment of Chronic Rheumatic or Fibromyalgia Pain

[0131] In order to determine the effect of low dose oral dipyridamole for treating chronic rheumatic or fibromyalgia pain, 3 subjects with chronic rheumatic pain were treated with the addition of low dose oral dipyridamole prepared according to Example 1 to their present pain regimen.

[0132] Subject 1 (39 y/o female) was treated with 2 mg taken once daily with the first daily dose of oxycodone. Subject 2 (40 y/o male) was treated with 2 mg or 5 mg taken once daily, in conjunction with oxycodone. Subject 3 (45 y/o female) was treated with 2 mg, 5 mg or 10 mg taken once daily with PERCOCET.

[0133] Subject 1: After adding dipyridamole 2 mg the subject had complete relief of pain related to chronic fibromyalgia. She had previously been dependent on oxycodone 10 mg twice daily with incomplete pain relief.

[0134] Subject 2: After adding dipyridamole 2 mg the subject had complete relief of pain related to chronic rheumatic pain in the joints. When trying 10 mg instead, there was negligible pain relief 2 mg was continued for 12 months. Within 3 months of use, this subject was able to completely wean off oxycodone while maintaining pain relief.

[0135] Subject 3: After adding dipyridamole 2 mg the subject had complete relief of pain related to chronic fibromyalgia and rheumatoid arthritis. At a 5 mg dose, she experienced less pain relief, so she resumed 2 mg. She had previously been dependent on Percocet with incomplete pain relief. Percocet was slowly weaned off after 2 months of low dose dipyridamole use.

[0136] This example illustrates that low dose oral dipyridamole is effective for the treatment of chronic rheumatic and fibromyalgia pain. It also suggest that low dose oral dipyridamole can serve as a substitute for opiates in some patients.

Example 12

Xerostomia Treatment

[0137] In order to determine the effect of low dose oral dipyridamole for treating xerostomia, 2 subjects with xerostomia were treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment.

[0138] Subject 1 (40 y/o male) and Subject 2 (67 y/o female) were treated with varying doses (1, 2, 3, 4, 5 and 10 mg) taken in the morning or evening, for periods of 2 weeks for each dose then continued on optimal dose for 15 months in total.

[0139] Subject 1: 2 mg was found to be the optimal dose for complete resolution of xerostomia. Occasionally (once every few weeks) symptoms recurred, but only lasted 2-3 hours and were 70% less severe than before. An additional effect included improved sleep.

[0140] Subject 2: 3 mg was found to be the optimal dose for complete resolution of xerostomia (and dry eye symptoms) related to Sjogren's syndrome of 12 years duration. An additional effect included deep sleep.

[0141] This example illustrates that low dose oral dipyridamole is effective for the treatment of xerostomia.

Example 13

Treatment of Androgenetic Alopecia

[0142] In order to determine the effect of low dose oral dipyridamole for treating androgenetic alopecia, a single subject with androgenetic alopecia was treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment.

[0143] A 35 y/o male was treated with varying doses (2 and 4 mg) taken in the morning or evening, for periods of 2 weeks for each dose and continued with the optimal dose for 14 months in total.

[0144] A dose of 4 mg was found to be the optimal dose for expansion of hairline, thicker hair, and decreased hair loss in addition to increased hair growth of chest and abdominal hair in a subject with previously accelerated hair loss and thinning body hair which had been unresponsive to standard treatment.

[0145] This example illustrates that low dose oral dipyridamole is effective for the treatment of androgenetic alopecia. Results of this example are consistent with reports of increased hair growth in example 5.

Example 14

Prostate Cancer Treatment

[0146] In order to determine the effect of low dose oral dipyridamole for treating prostate cancer, a single subject with prostate cancer was treated with low dose oral dipyridamole prepared as in Example 1 as the sole treatment.

[0147] A 74 y/o male was treated with 2 mg taken in the afternoon or evening and followed for 3 months.

[0148] A daily dose of 2 mg decreased PSA (Prostate Specific Antigen) from 19.1 to 14 in a 3 month period. Additional effects included improved sleep and cognition.

[0149] This example illustrates that low dose oral dipyridamole is effective for the treatment of prostate cancer.

[0150] Examples 3-14 illustrate the surprising benefits of low dose oral dipyridamole. Contrary to expectation, the benefits are dependent on low dose and dissipate or disappear when dosing is increased above 10 mg daily.

[0151] Spontaneous patient reports of effects on dreams, dream recall, sleep, memory and cognition suggest that low dose oral dipyridamole (below 10 mg/day) operates via a different physiologic mechanism than conventional high dose oral dipyridamole therapy.

[0152] Due to the dependence of dipyridamole on stomach acidity for optimal absorption, in certain cases of drug induced or age related gastric hypo-activity, doses of 10 mg up to 20 mg may conceivably be needed to achieve the same benefit as most subjects would have with doses of 2 to 5 mg daily.

Example 15

Dipyridamole in Combination with Melatonin

[0153] In order to examine the sleep inducing effects of dipyridamole combined with melatonin, six subjects with treatment-refractory insomnia, unresponsive to melatonin and somewhat responsive to low dose dipyridamole (1 or 2 mg daily) were treated with a combination of dipyridamole and melatonin. The dipyridamole dose ranged between 0.5 mg and 5 mg per pill. The melatonin dose ranged between 0.25 mg and 10 mg per pill. Melatonin and dipyridamole were combined in a single oral dosage form. In all cases, subjects reported complete restoration of normal sleep after the first dose. The dose had to sometimes be reduced as the subjects felt that they were over-sleeping. The synergy between dipyridamole and melatonin is surprising and not yet understood.