Prostaglandin compositions and methods for the treatment of vasospasm

Inactive Publication Date: 2005-01-13
NEXMED HLDG INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

We have found that administration of prostaglandin compositions comprising a penetration enhancer relieves constriction of a blood vessel in vasospasm and restores blood flow. The method and compositions are useful for the relief of vasospasm in several conditions, including vasospasm occurring during and following replantation surgery.

Problems solved by technology

Vasospasm is a constriction of blood vessels, resulting in ischemia of the tissue supplied by the blood vessels.
Experimental attempts to find roles for modifiers of prostaglandin function, sympatholytics, calcium channel blockers and numerous other drugs have generally not succeeded in producing either clearly applicable models or reproducibly positive results (Buncke, on-line edition, http://buncke.org/book/ch36/ch36—5.html).
If circulation is not re-established in time, tissue damage may result due to reperfusion injury.
Tissue reperfusion injury, seen i

Method used

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  • Prostaglandin compositions and methods for the treatment of vasospasm
  • Prostaglandin compositions and methods for the treatment of vasospasm
  • Prostaglandin compositions and methods for the treatment of vasospasm

Examples

Experimental program
Comparison scheme
Effect test

Example

EXAMPLE 1

Exemplary Compositions

Exemplary Composition A was prepared as follows. Part A was formed by dissolving 0.4 parts prostaglandin E1 (Alprostadil USP) in 5 parts ethyl alcohol. Next, 5 parts dodecyl 2-(N,N-dimethylamino)-propionate were mixed into the alcohol-prostaglandin E1 solution, followed by 5 parts ethyl laurate.

Part B was prepared starting from a pH 5.5 water / buffer solution. The water / buffer solution was prepared by adding sufficient potassium phosphate monohydride to purified water to create a 0.1 M solution. The pH of the water / buffer solution was adjusted to 5.5 with a strong base solution (1 N sodium hydroxide) and a strong acid (1 N phosphoric acid). The buffer solution represented about 80 parts of the total composition. All parts specified herein are parts by weight.

To the buffer solution was added 0.5 parts ethyl laurate. Next, the locust bean gum (in powder form) was dispersed in the buffer solution and homogenized using a homogenizer. Table 1, below,...

Example

EXAMPLE 2

Pharmacodynamic Study of a Topical PGE1 Composition as an Antagonist for Vasospasm

The spasmolysis (reversal of vasospasm) and vasodilation effects of a topical PGE1 composition (Composition H of Example 1 modified as appropriate to contain the indicated amount of PGE1) on vasospasm induced by adrenalin hydrochloride were studied in vivo by monitoring vascular diameter changes in rabbit ears. TABLE 2Drugs UsedDrug NameSizeFunctionBatch No.SupplierSumianxin1.5 ml / General20020425VeterinaryAmpuleAnesthesiaResearchInstitute ofChangchunAgricultural-PastoralUniversityAdrenaline1 mg / 1 mlVasospasm20010625Tianjing People'sHClInductionPharmaceuticalsBlank Sterile0.0% PGE1Blank020401NexMedCreamControlPharmaceuticals0.4% PGE1Positive020401(Zhongshan), Ltd.w / oControlpenetrationenhancersPGE1 Sterile0.1% PGE1Test020401Cream0.2% PGE1Composition0204010.4% PGE10204010.8% PGE1020401

Note: Positive control was 0.4% PGE1 sterile cream without DDAIP penetration enhancer; all other PGE1 cream...

Example

EXAMPLE 3

Laser Doppler Study of Vascular Perfusion Volume Charges in Treatment of Vasospasm Using a Topical PGE1 Composition

The spasmolysis (reversal of vasospasm) and vasodilation effects of a topical PGE1 composition (Composition H of Example 1 modified as appropriate to contain the indicated amount of PGE1) on vasospasm induced by adrenalin hydrochloride were studied by monitoring vascular perfusion volume changes of central arteries of rabbit ears. Rabbits were obtained and anesthetized and vasospasm induced as described in Example 2, above. A total of 60 rabbits were randomly assigned into 6 groups with 10 rabbits per group.

Vascular perfusion volume and skin temperature were measured using the PeriFlux 5000 laser Doppler blood flowmetry system (Perimed AB, Stockholm, Sweden). As in Example 2, above, a single administration of 80 mg topical composition with various PGE1 concentrations was applied onto the skin area, 0.5-2 cm above the ear base, 10 minutes after the appeara...

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Abstract

Compositions and methods for the treatment of vasospasm are provided comprising applying an amount of a semi-solid vasoactive prostaglandin composition to the affected tissue. Also provided are methods of improving microcirculation in a replanted body part.

Description

BACKGROUND OF THE INVENTION Vasospasm is a constriction of blood vessels, resulting in ischemia of the tissue supplied by the blood vessels. Prolonged spasm in arteries, veins, and vein grafts has been described as a physiologic complication in microsurgery for over 20 years (Buncke, H. J, Microsurgery: Transplantation-Replantation, on-line edition, Chapter 36, http: / / buncke.org / textbook.html, accessed Dec. 13, 2002). Vasospasm results from several processes including intrinsic smooth muscle contraction, local noradrenaline metabolism, neurogenic and hormonal processes, and prostaglandin metabolism. Topical agents, such as magnesium sulfate, lidocaine, papaverine and chlorpromazine have been reported to successfully relieve vasospasm. Other described methods for relieving vasospasm include nerve blocks, systemic adrenergic agents and systemic vasodilating agents such as sodium nitroprusside (Buncke, on-line edition, http: / / buncke.org / book / ch36 / ch36—2.html). Experimental attempts to...

Claims

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Application Information

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IPC IPC(8): A61K31/5575A61K47/10A61K47/14A61K47/18A61K47/26A61K47/36A61P9/10
CPCA61K47/36A61K47/14A61K47/18A61K31/5575A61K47/10A61K47/26A61K9/0014A61P43/00A61P7/02A61P9/00A61P9/10A61P9/14A61K31/557
Inventor WEN, TIANLIU, LIULU, MINGQIBAI, JIESHANMO, Y. JOSEPH
Owner NEXMED HLDG INC
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