The present invention is directed to a method of increasing the time period between outbreaks of genital herpes comprising providing an imidazoquinolinamine formulation, disposing an amount of the imidazoquinolinamine formulation into a first nare of an individual infected with Herpes Simplex Virus type 2, covering at least a portion of the internal surface of the individual's first nare with a portion of the amount of the imidazoquinolinamine in the nare, massaging the portion of the amount of the imidazoquinolinamine into the internal surface of the first nare, disposing the amount of the imidazoquinolinamine formulation into a second nare of the individual, covering at least a portion of the internal surface of the second nare with a portion of the amount of the imidazoquinolinamine in said nare and massaging the portion of the amount of the imidazoquinolinamine into the internal surface of said nare.

Description of the Invention

TECHNICAL FIELD

The present invention generally relates to methods of stimulating an immune response in certain individuals. Methods to stimulate a host immune system against viral infections associated with common colds are disclosed. Methods to stimulate immune response of a virally infected individual through an immunomodifier such as a non-nucleoside imidazoquinolinamine (heterocyclic amine) are disclosed. Methods to stimulate immune response of an individual infected with influenza are also disclosed. Methods to stimulate immune response of individuals having various cancers, such as lung cancer, bronchogenic carcinoma, bronchoalveolar carcinoma and nasal type natural killer T cell lymphoma are disclosed. Methods to stimulate immune response of individuals having herpes simplex virus type 2 ("HSV-2"), the most common cause of recurrent genital herpes are disclosed.

BACKGROUND OF THE INVENTION

Uncomplicated cases of viral infections usually produce mild symptoms such as nasal discharge, obstruction of nasal breathing, swelling of the sinus membranes, sneezing, sore throat, cough, and headache. These symptoms generally last between one and two weeks. A mild infection is generally associated with the rhinoviruses and the coronaviruses. The uncomplicated infection is most often referred to as the "common cold."

At present, only symptomatic treatment is available for uncomplicated viral infections, "common colds." The treatments include the use of over-the-counter decongestants, cough suppressants, cough expectorants, aspirin, and acetaminophen. The treatments, however, do not cure or even shorten the duration of the illness. Moreover, many of the treatments have side effects such as drowsiness, dizziness, insomnia, or upset stomach. Because of the diversity of the viruses, vaccines may not be effective in preventing the onset of colds.

It has been estimated that in the course of a year, individuals in the United States suffer one billion colds. Colds thus have a tremendous societal cost in lost work days and lost school days. People suffer symptomatic discomfort. Even people receiving symptomatic treatment still suffer from some discomfort and additionally suffer side effects of treatment. Moreover, influenza affects many people, typically causing more serious symptoms than a cold.

Aldara.TM. (imiquimod; manufactured by 3M Corporation, St. Paul, Minn.) cream, is a prescribed patient-applied topical cream for treating external genital and perianal warts. The Aldara.TM. product label does not recommend using it for any other purposes.

Genital herpes is a significant health problem worldwide and continues to increase in prevalence in the United States. In individuals in the United States over 12 years old, HSV-2 seroprevalence has increased from 16.4% in 1976 to 21.8% in 1994 and is still rising. Thus, the current incidence of genital herpes caused by HSV-2 in the United States is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year.

HSV-2 causes periods of active disease--presenting as painful blisters containing infectious virus particles--that last 2-21 days and are followed by remission when the sores disappear. Most cases of genital herpes are asymptomatic, although viral shedding may still occur. HSV-2 is transmitted by direct contact with a sore or body fluid of an infected individual. After initial infection, the virus moves to sensory nerves, where it resides as a life-long, latent virus. The virus lies dormant in lumbrosacral that supply sensation to the genitals, perineum and upper legs.

Occasionally, these viruses reactivate and return to the area of skin infected during the primary infection. Intermittent reactivation of viral replication can result in both symptomatic and subclinical recurrences because HSV-2 can reside latently in the sensory ganglion. The reactivation rate is highly variable and very difficult to predict from individual to individual. Many believe cell-mediated immunity plays a major role in restricting reactivation yet this role is not currently well understood.

Treatments are available to reduce the symptoms and speed up the healing process of herpes infections but there is currently no cure. Antiviral drugs, such as aciclovir and valaciclovir, taken orally, reduce viral reproduction and shedding, and some topical creams, such as Docosanol and Tromantadine prevent the virus from entering the skin. Some other drugs reduce herpetic symptoms by synergising with oral antiviral medication. Cimetidine and probenecid can reduce aciclovir clearance and aspirin can reduce inflammation associated with viral infection.

While the above listed treatment methods are effective, they require constant daily dosing of medications which can be expensive. Additionally, once discontinued, the medications have no posttreatment effect and the patient immediately reverts back to pre-treatment reactivation levels. Therefore, it would be advantageous to develop a treatment for HSV-2 that would be effective in treating viral outbreaks when they occur and would reduce the rate of outbreak recurrences after the treatment is discontinued.

In 2002, Timothy W. Schacker et al. hypothesized that long term HSV-2 treatment could be achieved through enhancing the host's ability to control the virus and that topical application of imiquimod in the form of Aldara.TM. to herpes lesions could achieve this result. Timothy W. Schacker et al., Imiquimod 5-Percent Cream Does Not Alter the Natural History of Recurrent Herpes Genitalis: a Phase II, Randomized, Double-Blind, Placebo-Controlled Study, Antimicrobial Agents and Chemotherapy, October 2002, pp. 3243-48. Schacker et al.'s hypothesis was based on the knowledge that imiquimod produces a localized immunological response in the area of skin to which it is applied as explained above and successful results in studies where imiquimod was applied to herpes lesions in Guinea Pigs. To test their hypothesis, Schacker et al. performed a phase II, randomized, double-blind, placebo-controlled study on 235 human patients. The results of the study showed that there was no statistically significant difference in outbreak recurrence times between those patients treated with imiquimod and those treated with placebo. Therefore, Schacker et al. concluded that imiquimod was not effective in reducing the rate of herpes outbreaks in humans.

SUMMARY OF THE INVENTION

Methods to reduce the duration of symptoms associated with the common cold, viral rhinitis or influenza, without producing any substantial side effects generally associated with symptomatic treatment are disclosed. To reduce the duration of symptoms associated with the common cold or influenza, methods relate to applying an imidazoquinolinamine formulation, such as, for example, an imiquimod salve within a person's nostrils, also referred to as nares. Any suitable imidazoquinolinamine formulation can be used to reduce the duration of symptoms associated with the common cold, viral rhinitis or influenza. Further, in another embodiment, the method can be used to treat various cancers including lung cancer, bronchogenic carcinoma, bronchoalveolar carcinoma and nasal type natural killer T cell lymphoma.

Application of imiquimod to the inside of the nostrils and in particular to the mucosal membrane of an infected individual stimulates host cells to secrete chemical substances such as interleukins and interferons that promote the individual's immune response.

A method to reduce the duration of symptoms associated with the common cold or viral rhinitis includes application of 1/2 packet of Aldara.TM. (imiquimod formulation; 0.25 g of 5% active ingredient) into both nostrils (nares) every 12 hours for a total of 4 applications. The formulation may be applied by way of an applicator or any other suitable means. The formulation is applied into both nares at the onset of the cold. The onset is the day when the first cold symptoms appear. If the formulation is not applied on the first day the symptoms appear, it should be applied by the next day. The formulation is applied twice daily for two consecutive days. The formulation can be massaged into the internal surface of each naris. The treatment of the second naris is after the treatment of the person's first naris.

An imiquimod formulation is applied as described above at the onset of first cold symptoms such as nasal irritation, watery eyes, nasal drip or other early cold symptoms. The earlier the imiquimod formulation is applied after the onset of the cold, the shorter the recovery from the cold. An imiquimod formulation may also be applied the next day after the onset of the cold.

A method to reduce the duration of symptoms associated with the common cold or viral rhinitis includes application of a coating of the mucosal membrane within each naris with Neosynepherine.RTM. (phenylephrine) prior to applying the Aldara.TM. formulation within each naris. The Neosynepherine.RTM. (phenylephrine) may be applied in the form of an over-the-counter liquid formulation by means of a spray bottle. The Neosynepherine.RTM. (phenylephrine) is preferably applied 15 minutes before applying the imiquimod formulation.

Another aspect of the present invention is directed to a method of increasing the time period between outbreaks of genital herpes comprising providing an imidazoquinolinamine formulation, disposing an amount of the imidazoquinolinamine formulation into a first nare of an individual infected with Herpes Simplex Virus type 2, covering at least a portion of the internal surface of the individual's first nare with a portion of the amount of the imidazoquinolinamine in the nare, massaging the portion of the amount of the imidazoquinolinamine into the internal surface of the first nare, disposing the amount of the imidazoquinolinamine formulation into a second nare of the individual, covering at least a portion of the internal surface of the second nare with a portion of the amount of the imidazoquinolinamine in said nare and massaging the portion of the amount of the imidazoquinolinamine into the internal surface of said nare. The imidazoquinolinamine formulation is first applied within 12 hours after an appearance of first symptoms and is reapplied every 12 hours thereafter until it has been applied four times to each nare.


DETAILED DESCRIPTION

While the concepts of the present disclosure are illustrated and described in detail in the drawings and the description below, such an illustration and description is to be considered as exemplary and not restrictive in character, it being understood that only the illustrative embodiment is shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

FIG. 1 (see Original Patent) generally describes how some cells in the human body operate as part of the host immune system to combat infection. In FIG. 1, a lymphocyte (monocytic dendritic cell) 10 takes in an antigen 11 and displays part of the digested antigen 13 with a marker molecule 12 to a mature T cell 13. The T cell secretes cytokines 14 which help stimulate the B cell to mature into a plasma cell 15 which produces antibodies 16. The foreign antigen in the present diagram is viral. This is known as T-helper 2 mode.

This figure is a schematic representation of the adapted immune system which works much more slowly than the innate immune system. As part of the innate immune system, the skin and mucous membranes have been shown to be able to produce and secrete cytokines such as TNF-a, and the like. FIG. 2 (see Original Patent) discloses a macrophage 20 digesting a foreign antigen 21. The macrophage 20 displays antigen fragments 21a on its marker 22 to an immature T cell 23. Cytokines 24 are produced and help the T cell mature. Further cytokines 24 actually produced by the maturing T cell help the maturing T cell evolve into killer cells 25 and helper T cells 26. Cytokines 24 also help attract additional macrophages 27, granulocytes 28, and other lymphocytes to the area of infection thereby promoting an attack on infected cells 29 (this is now known as T-helper 1 mode).

Imiquimod enhances both the innate and adapted cell-mediated immune pathways to stimulate the production of various cytokines. For example, imiquimod stimulates the innate immune response by inducing the synthesis and release of cytokines, including IFN-a and TNF-a in both humans and animal studies. Inhalation of imiquimod results in even larger amounts of IFN-a and TNF-a, to the point of creating flu-like symptoms. Production of various cytokines by the activated innate immune system results in the strengthening of the cell-cell interaction. For example, monocytes, macrophages, B cells, and dendritic cells (including Langerhan cells; LC) are targeted by imiquimod.

A proposed mechanism by which imiquimod may activate the above-mentioned target cells is via the activation of Toll-like receptors (TLRs), a family of pathogen recognition receptors located on the cell surface of various innate immune cells such as dendritic cells. Activation of TLRs, such as, for example, TLR7 results in the downstream activation of a signal cascade mediated by MyD88 and various effector cytokines such as IFN-a, IL-12, and IL-18 are produced (FIG. 4 (see Original Patent)).

A proposed mechanism of action for imiquimod to activate the cell-mediated immune response is through an indirect stimulation of T cells by producing Th-1 cytokine IFN-y. Imiquimod also enhances the migration of LCs to the regional lymph nodes to enhance antigen presentation to T cells. In vitro assays have established that exposure of LCs to imiquimod results in increased gene expression for TF-a, IL-1.beta., and IL-12, and also secretion of IFN-.gamma. by imiquimod-treated T cells compared to untreated cells.

Studies have shown that immune response modifiers such as imiquimod and resiquimod are TLR7 agonists and induce type 1 interferon in numerous species including humans. Imiquimod and resiquimod induce IFN-a from purified plasmacytoid dendritic cells.

Thus imiquimod and resiquimod stimulate the local production of various cytokines such as IL-12, IL-18, IL-1.beta., IFN-a, and IFN-.gamma. to promote both innate as well as cell-mediated immunity.

The common cold causes a group of symptoms that usually are easily recognized by patients and doctors. About 50 percent of patients will develop a sore throat, which is often the first symptom to appear since it can occur as early as 10 hours after infection. This is followed rapidly by the most common symptoms of the common cold--congested nasal and sinus passages, a runny nose and sneezing. Hoarseness and cough are less likely to occur, but they may last longer than other symptoms, sometimes for several weeks.

Most patients diagnose the common cold by the typical symptoms of runny nose, congestion and sneezing, and rarely consult medical attention. Symptoms typically peak on the second, third or fourth days of infection and last about one week to 10 days. Up to 25 percent of people may have persistent symptoms, such as a nagging cough that can last for several weeks.

The methods disclosed herein stimulate the immune system response as described in FIGS. 1, 2, and 4 (see Original Patent). The methods disclosed herein promote host cells to secrete chemicals and cytokines such as interferons and interleukins, which impact the host cellular immune response at least partially as shown in FIGS. 1, 2, and 4.

Low molecular weight heterocyclic non-nucleoside imidazoquinolinamines can be used to treat viral rhinitis. One such imidazoquinolinamine is imiquimod whose IUPAC nomenclature is (1-(2-methylpropyl)-1H-imidazo)[4,5-c]quinolin-2-amine. Imiquimod may also be referred to as R-837. Another imidazoquinolinamine is resiquimod, whose IUPAC nomenclature is 4-amino-2-ethoxymethyl-a,a-dimethyl-1H-imidazol [4,5-c]quinoline-lethanol. Resiquimod may also be referred to as R-848. (see FIG. 5).

To provide effective treatment, a formulation of imiquimod commonly used to treat warts can be used. For example, the formulation sold in salve format under the brand name Aldara.TM. is effective. It is believed that other imiquimod formulations such as imiquimod in a fluid formulation or in a fine powder formulation might be effective.

A method to reduce the duration of symptoms associated with the common cold or viral rhinitis includes application of 1/2 packet of Aldara.TM. (imiquimod formulation; 0.25 g of 5% active ingredient) into both nostrils (nares) every 12 hours for a total of 4 applications. Each gram of 5% Aldara.TM. cream contains 50 mg of imiquimod as active ingredient.

In an embodiment, an applicator is used to disperse the imiquimod within each naris. The applicator used can be a cotton swab. See FIG. 3a. The swab should be of suitable size to fit internally within each naris such that the exterior of the swab can move freely within each naris and make substantial contact with the naris' mucosal membrane. In an embodiment, the imiquimod salve is combined with the swab shown in FIG. 3a by applying a 4 mm.sup.3 dab of the imiquimod salve on the head of the swab. The swab is then inserted in a naris and moved around within the naris so as to spread the salve over the naris' mucosal membrane.

In another embodiment, the foregoing methods utilizing imiquimod may also be used to treat influenza. The applicator is used to disperse the imiquimod within each naris. The applicator used can be a cotton swab. See FIG. 3a. The swab should be of suitable size to fit internally within each naris such that the exterior of the swab can move freely within each naris and make substantial contact with the naris' mucosal membrane. In an embodiment, the imiquimod salve is combined with the swab shown in FIG. 3a by applying a 4 mm.sup.3 dab of the imiquimod salve on the head of the swab. The swab is then inserted in a naris and moved around within the naris so as to spread the salve over the naris' mucosal membrane. For treating influenza, the imiquimod may be applied once a day for two days. The nares are then squeezed against the septum to improve absorption.

In a further embodiment, the foregoing methods utilizing imiquimod may also be used to treat various cancers such as lung cancer, bronchogenic carcinoma, bronchoalveolar carcinoma and nasal type natural killer T cell lymphoma. The applicator is used to disperse the imiquimod within each naris. The applicator used can be a cotton swab. See FIG. 3a. The swab should be of suitable size to fit internally within each naris such that the exterior of the swab can move freely within each naris and make substantial contact with the naris' mucosal membrane. In an embodiment, the imiquimod salve is combined with the swab shown in FIG. 3a by applying a 4 mm.sup.3 dab of the imiquimod salve on the head of the swab. The swab is then inserted in a naris and moved around within the naris so as to spread the salve over the naris' mucosal membrane. The nares are then squeezed against the septum to improve absorption.

The swab shown in FIG. 3a is not the only type of applicator which can be used to apply an amount of imiquimod salve to a naris. Many other types of applicators can be used. For instance, an applicator with a hollow swab head fluidly connected with an injection tube would work. See FIG. 3c. The hollow swab head 30 would have a series of tiny apertures 31 through which the salve could be extruded. Extrusion through the tiny holes would occur by way of actuating an amount of salve in the injection tube 33 to flow into the hollow swab head 30. Actuation could occur by a plunger 34. Once the salve is extruded, the hollow swab head is moved around within the naris so as to spread the salve within the naris. The swab head could have many configurations. Additionally, it is feasible that one could use an injection tube alone to dispense the salve in the naris. The salve could then be spread by a cotton swab, a finger or some other means.

Instead of using imiquimod in a salve formulation, one may also use imiquimod in a liquid formulation. If an imiquimod liquid formulation is used, the applicator can be a spray nozzle 40a, FIG. 3b, or a dropper nozzle 40b, FIG. 3d. The nozzles 40a, 40b could be interfaced to vessels such as bottles 41a or squeeze bulbs 41b. The vessels 41a, 41b and nozzles 40a and 40b would be configured so that a predetermined actuation sequence would emit an effective dosage of imiquimod from the nozzle into the naris. For instance, to emit imiquimod from the spray nozzle 40a, an operator would simply depress pump 42 interfaced with the spray nozzle. In addition to the above, the applicator could simply be a finger or any other member which would fit within a naris and allow dispersion of the imiquimod formulation within the naris.

It is preferable after first applying the imiquimod formulation to the internal surface of a naris or nares, i.e., within the naris, to massage the formulation into the naris' mucosal membrane.

Each of a person's two nares is treated in the same fashion. Treatment of the second naris is immediately after the first naris. Massaging of the salve into at least a portion of the internal surface of each naris can occur after the salve has been applied to both nares.

Prior to treating each naris with the imiquimod formulation, each naris can be precoated with Neo-Synephrine.RTM. (a solution of about 10% phenylephrine hydrochloride) at least 15 minutes before applying the imiquimod formulation. Prepping the nares with the formulation facilitates prolonged contact of the imiquimod to the nares' internal surfaces by helping to prevent wash-off due to nasal secretion. Phenylephrine is a decongestant that works by constricting (shrinking) blood vessels (veins and arteries). Constriction of blood vessels in the sinuses, nose, and chest allows drainage of these areas, which decreases congestion. Any other suitable alpha-adrenergics or other decongestants may also be used.

The utility of the above-described method for treating persons with viral infections can also be seen by reference to the below in vivo experiments.

In each of the tests, an imiquimod salve was used. The formulation was that commonly used to treat warts and sold under the brand name Aldara.TM.. The salve was applied to each naris of the test subject by use of a common cotton swab. Either a 4 mm.sup.3 dab of salve or 1/2 pack of 5% Aldara.TM. was placed on the swab head. The swab head was inserted into a naris. The swab was moved around inside the naris to distribute the salve over the mucosal membrane of the naris. Immediately, after application of the Aldara.TM. to the subject's first naris, a swab was used to apply the Aldara.TM. to the subject's second naris. Immediately after application to each naris, the salve was massaged into the mucosal membrane of each naris.

Application of an immunomodifier such as imiquimod to the internal surface of the nostrils stimulates innate immunity locally and thus helps to shorten the duration of cold symptoms.
 

Claim 1 of 13 Claims

1. A method of increasing the time period between outbreaks of genital herpes consisting essentially of: providing an imidazoquinolinamine formulation; disposing an amount of the imidazoquinolinamine formulation into a first nare of an individual infected with Herpes Simplex Virus type 2; covering at least a portion of the internal surface of the individual's first nare with a portion of the amount of the imidazoquinolinamine in the first nare; massaging the portion of the amount of the imidazoquinolinamine into the internal surface of the first nare; disposing the amount of the imidazoquinolinamine formulation into a second nare of the individual; covering at least a portion of the internal surface of the second nare with a portion of the amount of the imidazoquinolinamine in said the second nare; and massaging the portion of the amount of the imidazoquinolinamine into the internal surface of said the second nare.

 

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