Title:  Unit dosage forms for the treatment of herpes simplex

United States Patent:  6,231,889

Assignee:  ChronoRX, LLC (Anchorage, AL)

Filed:  September 15, 1999

The components of this invention are chosen because of their complementarity for the prevention or treatment of diseases caused by the herpes simplex virus. L-Lysine favorably increases the physiologic immunomodulation necessary for defense against this virus. Zinc improves and maintains a normal immune response. 2-Deoxy-2-D-glucose and heparin sodium alter the surface interaction between the herpes virus and the cell, preventing fusion and infectivity. N-Acetyl-L-cysteine increases glutathione levels thereby creating a thiol redox barrier to the virus at the cell membrane. Quercetin reduces intracellular replication of the herpes virus and viral infectivity. Ascorbate, in concert with copper and D-.alpha.-tocopherol, provides an antioxidant defense against the herpes virus, which tends to lose latency during period of oxidative, free radical excess. Selenium and quercetin also participate in reducing various oxidative stresses. Together the components of this invention provide the potential for improved resistance to, improved recovery from, and a decreased frequency of recurrence of herpes simplex virus infection.

SUMMARY OF THE INVENTION

Although several in vitro and in vivo studies appear to support the antiviral effectiveness of individual biofactors, almost universally the studies focus upon attempts to measure the effect of the application of single biofactors, i.e., the effectiveness of each biofactor used independently as measured against a single physiological endpoint.

The invention resides in a unique, orchestrated pharmaceutical formulation for use in the treatment of HSV-1 and HSV-2 that takes advantage of the additive and synergistic antiviral complementarity of these biofactors in a variety of applications and makes these specific formulations available in a variety of dosage forms.

The present treatment of HSV infected or exposed patients with cytotoxic drugs is imprecisely effective--i.e., 1) While these drugs may be clinically effective in reducing active epithelial disease they are not effective in treating corneal stromal disease. 2) For a variety of reasons it is not presently practical to treat patients prophylactically between recrudescent episodes of viral activity. Furthermore, current treatment is expensive and involves the use of admittedly cytotoxic agents. In a broader failure, current treatment programs focus almost exclusively upon the topical treatment of acutely infected tissue while ignoring the global, complex, metabolic and immunological cellular environment within which the disease process operates.

This invention takes a different approach entirely. By combining a variety of agents that have been shown individually to have antiviral activity at a variety of the required nodal steps in the invasive interplay between the HSV virion and the host cell, this invention addresses the more expansive physiological stage upon which this pathological activity occurs. Furthermore, the agents used in the invention have not been shown to have any cytotoxicity when used in appropriate dose levels, they are inexpensive and can be used prophylactically without concern for any significant development of viral resistance. Unlike current treatment methods the invention will be effective against stromal HSV infection and will reduce viral rates of recurrence. The invention will not replace current therapy for active HSV infection. It will, however, reduce clinical requirements for present therapies by minimizing therapeutic failure, thus reducing morbidity and recrudescence.

The combined complementary activities of the elements of the invention reduce HSV infection by:

1. Retarding infected host cell clumping by reducing surface glycoprotein. This reduction of cell clumping mechanically interferes with virion-host cell fusion and interferes with cell-to-cell spread. (2-deoxy-D-glucose)

2. Retarding virion-host cell fusion physiologically by reducing levels of glycoprotein gB carbohydrate and, thus, reducing virus infectivity. (2-deoxy-D-glucose)

3. Modifying the host-cell immunomodulation abilities and thus improving existing statistical differences in herpes recurrence rates between patients with dietary L-arginine/L-lysine imbalances. (L-lysine)

4. Improving host-cell defenses by increasing endogenous reduced-GSH levels. Maintenance of GSH levels interferes with late-stage replication of HSV-1. (Se²⁺, NAC)

5. Improving local host-cell antiviral antioxidative effectiveness by reducing local levels of hydroxyl radicals involved in the pathogenesis of ophthalmic herpes. This improves local tissue survival by countering high levels of free radical damage. (Se ²⁺)

6. Increasing host-cell levels of antioxidant thiols and glutathione peroxidase and, in addition, providing synergistic anti-replicative activity in conjunction with acyclovir and deoxyuridine. (quercetin, NAC)

7. Inactivating viral replication and reducing host-cell levels of hydroxyl radicals. (Cu²⁺, ascorbate--alone or, more effectively, in combination)

8. Locally inactivating HSV without creating long-term resistance and concurrently ensuring adequate immune system stability. (Zn²⁺)

9. Inhibiting primary virus fusion by blocking access to the heparan sulfate receptor and improving lesion healing by stimulating bFGF mediated reparative angiogenesis. (heparin sodium)

10. Inhibiting viral DNA synthesis and thus reducing viral replication. (2-deoxy-D-glucose)

In vitro studies or limited clinical evaluations have shown each of these biofactors to have some antiviral activity when used alone. They have not before been united in appropriately designed multi-factor formulations available in a variety of delivery vehicles or modes. The invention is unique in providing this new, safe, effective and inexpensive addition to current therapeutic options, thereby improving the potential for success in treating a worldwide disease with severe morbidity, and in neonates, severe mortality potential.

Claim 1 of 29 Claims

We claim:

1. A unit dosage form for the treatment of herpes simplex and conditions giving rise thereto, said unit dosage form comprising as active ingredients:

(a) a thiol-containing glutathione-increasing agent having the formula

RMX

in which:

R is a member selected from the group consisting of N-acetyl-L-cysteine, L-2-oxothiazolidine-4-carboxylate, N-2(-mercaptopropionyl)-glycine, and L-lysine,

M is a member selected from the group consisting of Mg⁺², Cu⁺², Zn+², and Se+², and

X is a member selected from the group consisting of hydroxide, halide, sulfate, acetate, ascorbate, and bis-ascorbate;

(b) an L-lysine-increasing agent,

(c) a glucosamine-increasing agent, and

(d) magnesium.

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