WO2011001258A1

WO2011001258A1 - Compositions, methods, and kits for treating viral and bacterial infections by tocotrienols, tocomonoenols, tocodienols, tocopherols, and their derivates

Info

Publication number: WO2011001258A1
Application number: PCT/IB2010/001589
Authority: WO
Inventors: Ralf Altmeyer; Ralf Lange
Original assignee: Evita Life Science Pte. Ltd
Priority date: 2009-07-01
Filing date: 2010-06-29
Publication date: 2011-01-06

Abstract

The invention relates to the treatment and prevention of viral and bacterial infections using vitamin E, including all isoforms of tocopherol, tocomonoenol, tocodienol, tocotrienol, and their derivates.

Description

COMPOSITIONS, METHODS, AND KITS FOR TREATING VIRAL

AND BACTERIAL INFECTIONS BY TOCOTRIENOLS,

TOCOMONOENOLS, TOCODIENOLS, TOCOPHEROLS, AND THEIR

DERIVATES

BACKGROUND OF THE INVENTION

This application claims benefit of U.S. Provisional Application Serial No. 61/222,269, filed July 1, 2009, which is hereby incorporated by reference.

Viral and bacterial infections are major public health concerns worldwide. Viral and bacterial infections can lead to severe morbidity and mortality, especially in high risks groups such as immunocompromised patients and children, and are often accompanied by considerable economic losses.

Safe and efficacious treatment for many viral infections is currently lacking. For example, adenovirus is the causative agent of multiple diseases, including respiratory and ocular infections. Adenoviral-associated ocular disease is fairly common worldwide and endemic in certain parts of Asia.

Although the infection is usually mild and self-limiting, adenovirus can result in severe clinical manifestations, particularly in immuno-compromised patients. Moreover, ocular infection can lead to long-term visual impairment. Currently, there is no treatment against ocular adenovirus infections.

In another example, influenza virus affects 5-15% of the population during epidemics and causes upper respiratory tract infections. Hospitalizations and deaths can occur, especially in high-risk groups (elderly, chronically ill, and immuno-compromised). Between three and five million cases of severe influenza and between 250,000 and 500,000 deaths worldwide are recorded every year, including more than 35,000 deaths in the United States alone. Currently, the standard of care for influenza infections are the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza). However, resistance to neuraminidase inhibitors has recently been described for more than 95% of HlNl viruses, raising the concerns that the current Influenza A HlNl virus (swine flu) or other influenza viruses with pandemic potential could become drug-resistant._

Finally, pathogenic bacteria also cause a multitide of diseases in humans. While antibacterial agents (i.e. antibiotics) have been effectively used to treat many bacterial infections, their widespread use has led to antibiotic resistance in many pathogenic bacterial strains. For example, a methicillin-resistant strain of Staphylococcus aureus (MRSA) containing drug-resistance genes arose in response to the introduction of the synthetic penicillin-related drug methicillin. Thus, the use antibacterial agents to treat bacterial infection must be limited or avoided where possible.

Accordingly, there exists a need to identify novel antiviral and

antibacterial compounds that could complement existing therapeutics.

Tocepherols were identified in the early twenties of last century as an essential nutrient in humans. Tocopherols and tocotrienols, which occur naturally as components of Vitamin E, are fat-soluble compounds that are synthesized exclusively by photosynthetic organisms. In particular, eight substances with anti-oxidant activity have been identified as components of Vitamin E: α-tocopherol, β-tocopherol, δ-tocopherol, γ-tocopherol, α- tocotrienol, β- tocotrienol, δ-tocotrienol, and γ-tocotrienol.

Tocopherols are mainly found in vegetable oils (wheat germ oil), nuts (almonds, peanut) and seeds (sunflower seeds), while high levels of

tocotrienols can be found in palm oil, coconut oil and cereal grains. Natural tocopherol and tocotrienol extracts have been widely and safely used in nutraceutical and cosmeceutical formulations. Pure isomers of tocotrienol (alpha, beta, gamma, and delta isoforms of greater than 97% purity) can be used in pharmaceutical applications. While tocopherols and tocotrienols are similar in structure, they differ in many characteristics. Tocotrienols possess potent neuroprotective, antioxidant, anti-cancer and cholesterol-lowering properties that differ from those of tocopherols. For example, micromolar amounts of tocotrienol suppress the activity of HMG-CoA reductase, a primary enzyme in the cholesterol synthetic pathway. Because tocotrienols have an unsaturated aliphatic side chain, they more easily penetrate into tissues containing saturated fatty acids such as the brain and the liver. Furthermore, tocotrienols are better distributed into the fatty acids of the cell membrane. On the other hand, the bioavailability of orally administered tocopherols is greater than that of tocotrienols.

SUMMARY OF THE INVENTION

We have identified that vitamin E and its components, including tocopherols, tocomonoenols, tocodienols, tocotrienols, and isoforms and analogs thereof, are potent antiviral and antibacterial compounds, both alone and in combination with additional therapeutics.

In a first aspect, the invention features a composition comprising (a) one or more vitamin E compounds (defined below); and (b) an antiviral agent or an antibacterial agent. In one embodiment, the vitamin E compounds may be α- tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β- tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ- tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ- tocotrienol, desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl- tocodienol, or desmethyl-tocotrienol. In a particular embodiment, the vitamin E compounds may be a d-stereoisomer thereof. In one embodiment, the vitamin E compounds may be naturally occurring. In another embodiments, the vitamin E compounds may be synthetic.

The vitamin E compounds and antiviral agent may be present in amounts that together are effective to treat or prevent a viral infection. The viral infection may be caused by an adenovirus or an influenza virus. In a particular embodiment, the influenza virus may be of type A, B, or C. In another embodiment, the influenza virus may be of subtype HlNl. In one embodiment, the antiviral agent may be oseltamivir, zanamivir, peramivir, or an analog thereof.

In yet another embodiment, the composition may further comprise an additional antiviral agent. The third compound may be amantadine,

rimantadine, T-705, or an analog thereof. In yet another embodiment, the composition may further comprise one or more additional antiviral agents.

In another embodiment, the vitamin E compound(s) and antibacterial agent may be present in amounts that together are effective to treat or prevent a bacterial infection. In certain embodiments, the bacterial infection is an infection of Wolbachia, and the antibacterial agent is doxycycline.

The composition may be formulated for administration by any route known in the art such as oral, parenteral (e.g., intravenously or

intramuscularly), rectal, determatological, cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, intrathecal, and intracranial. In certain embodiments, the composition includes, consists of, or consists essentially of (a) a combination of active ingredients and (b) one or more pharmaceutically acceptable excipients.

Another aspect of the invention is a vitamin E compound that does not occur naturally. Yet another aspect is a vitamin E compound that is extracted from a natural source.

In an additional aspect, the invention features a method for treating or preventing a viral or bacterial infection in a patient by administering one or more vitamin E compounds to the patient. In one embodiment, the vitamin E compounds may be chosen from α-tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β-tocomonoenol, β-tocodienol, β-tocotrienol, γ- tocopherol, γ-tocomonoenol, γ-tocodienol, γ-tocotrienol, δ-tocopherol, δ- tocomonoenol, δ-tocodienol, δ-tocotrienol, desmethyl-tocopherol, desmethyl- tocomonoenol, desmethyl-tocodienol, and desmethyl-tocotrienol. In a particular embodiment, the vitamin E compounds may be a d-stereoisomer thereof. In one embodiment, the vitamin E compounds may be naturally occurring. In another embodiment, the vitamin E compounds may be synthetic.

In another embodiment, the method further comprises administering to the patient an antiviral agent or an antibacterial agent. The antiviral agent may be, for example, oseltamivir, zanamivir, peramivir, or an analog thereof. The antibacterial agent may be doxycycline or an analog thereof. The viral infection may be caused, for example, by an adenovirus or an influenza virus. In a particular embodiment, the influenza virus may be of type A, B, or C. In another embodiment, the influenza virus may be of subtype HlNl . In another embodiment, the infection may be caused by Wolbachia.

In another embodiment the method further comprises administering to the patient an additional antiviral agent or an antibacterial agent. The antiviral agent may be amantadine, rimantadine, T-705, or an analog thereof.

In certain embodiments, the vitamin E compound(s) and (if present) additional antiviral or antibacterial compounds are administered within 7 days, 1 day, or 1 hour of each other or substantially simultaneously.

In certain embodiments, the compounds and methods herein will be useful against a disease caused by an adenovirus. These include acute respiratory disease (ARD), pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, follicular conjunctivitis, pneumonia, pertussis-like syndrome, acute hemorrhagic cystitis, acute infantile gastroenteritis, adenoviral infections in immunocompromised hosts, intussusception, meningitis, obesity, adenovirus hepatitis, and encephalitis. In other embodiments, the compounds and methods will be useful against a disease caused by an influenza virus such as influenza-like illness, pneumonia, and multi-organ infections in

immunocompromised transplant, chronic obstructive pulmonary disease (COPD) or asthma patients.

The invention also features kits. One kits includes (a) one or more vitamin E compounds and (b) instructions for administering (a) to a patient for treating or preventing a viral or bacterial infection. Another kit includes (a) one or more vitamin E compounds and (b) instructions for administering (a) with at least one antiviral agent to a patient for treating or preventing a viral infection. Yet another kit includes (a) one or more vitamin E compounds and (b) instructions for administering (a) with at least one antibacterial agent to a patient for treating or preventing a bacterial infection. Yet another kit includes (a) one or more vitamin E compounds, (b) an antiviral or antibacterial agent, and (c) instructions for administering (a) and (b) to a patient for treating or preventing a viral or bacterial infection. Yet another kit includes (a) one or more vitamin E compounds, (b) an antiviral agent, (c) amantadine, rimantadine, or T-705, and (d) instructions for administering (a), (b), and (c) to a patient for treating or preventing a viral infection. Yet another kit includes (a) one or more vitamin E compounds, (b) an antiviral agent, and (c) instructions for

administering (a) and (b) with amantadine, rimantadine, or T-705 to a patient for treating or preventing a viral infection.

To "treat" is meant to administer one or more agents to measurably slow or stop the replication of a virus or bacteria in vitro or in vivo, to measurably decrease the load of a virus or bacteria in a cell in vitro or in vivo, or to reduce at least one symptom (e.g., inflammation) associated with having a viral or bacterial infection in a patient. Desirably, the slowing in replication, the decrease in viral load, or reduction in the symptom is at least 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 99%, as determined using a suitable assay (e.g., a inflammation assay described herein) as compared to in the absence of the agent.

To "prevent" a disease is meant to reduce the frequency of appearance of the disease in a population of patients, the likelihood of an individual patient developing the disease, or to reduce the symptoms or severity of a disease upon its appearance by administering one or more agents to a patient prior to diagnosis of the disease or manifestation of disease symptoms.

By "an effective amount" is meant the amount of an agent, alone or in combination with another therapeutic regimen, required to treat a patient with a viral or bacterial infection in a clinically relevant manner. A sufficient amount of an agent used to practice the present invention for therapeutic treatment of conditions caused by a virus or bacteria varies depending upon the manner of administration, the age, body weight, and general health of the patient.

Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of an agent in a combination of the invention that is safe and efficacious in the treatment of a patient having a viral or bacterial infection over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug

Administration).

By "more effective" is meant that a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given

indication.

By a "low dosage" is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular agent formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that treats a viral infection and that is formulated for administration by intravenous injection will differ from a low dosage of the same agent formulated for oral administration.

By a "high dosage" is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, 300%, 500%, 1,000%, 2,000%, 5,000%, or 10,000%) more than the highest standard recommended dosage of a particular agent for treatment of any human disease or condition.

By a "vitamin E compound" is meant any compound having a structure shown in (I).

By "antiviral agent" is meant any of the compounds listed in Table 1. Table 1: Antiviral agents

The term "pharmaceutically acceptable salt" represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the agents of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate,

cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium,

methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may also be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl). Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically- labeled reagent in place of a non-isotopically-labeled reagent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows typical layouts of 96- well microtiter plates used for antiviral assays.

Figure 2 is shows the percentage inhibition of Wolbachia bacteria treated with vitamin E compounds. Activity was assayed in C6/36 cells stably infected with Wolbachia. The results of two repeats of the experiment are shown in panels A and B.

DETAILED DESCRIPTION OF THE INVENTION

The invention features methods, compositions, and kits for the administration of an effective amount of a vitamin E, alone or in combination with additional therapeutics, to treat a viral or bacterial infection. The invention is described in greater detail below.

Viruses

The invention relates to the treatment of viral disease, which can be caused by viruses from the families orthomyxoviridae, adenoviridae and flaviridaeviridae. Viruses of the orthomyxoviridae family include the influenza A virus, influenza B virus, influenza C virus, the infectious salmon anemia virus (isavirus), Thogoto Virus, and Dhori Virus. Members of the adenoviridae family include human adenovirus A, B, C, D, E, and F; bovine adenovirus A, B, and C; canine adenovirus; equine adenovirus A and B; murine adenovirus A; ovine adenovirus A and B; porcine adenovirus A, B, and C; and tree shrew adenovirus. Members of the Flaviviridae family include Dengue fever

Japanese encephalitis virus, Kyasanur Forest disease virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Tick-borne encephalitis virus, West Nile encephalitis virus, Yellow fever virus, Hepatitis C Virus.

Adenovirus

In certain embodiments, the virus refers to an adenovirus. Adenoviruses are DNA viruses of the family Adenoviridae. The viruses are non-enveloped icosahedral infectious particle of around 60-90 nm that enter the nucleus a target cell to replicate. Currently, 51 distinct human adenovirus serotypes (Adl-Ad51) are identified, which are subdivided into 6 PCR-distinguishable species (group A-F) based on DNA homology, RPPL analyses,

haemagglutination grouping, pathogenesis in rodents and differential ability to transform murine primary cells. The group classification is as follows: group A: Adl2, Adl 8, Ad31 ; group B: Ad3, Ad7, AdI l, Ad 14, Adlό, Ad34, Ad35, Ad50; group C: AdI, Ad2, Ad5, Ad6; group D: Ad8, Ad9, AdIO, Adl3, AdI 5, Adl7, Ad 19, Ad20, Ad22, Ad23, Ad24, Ad25, Ad26, Ad27, Ad28, Ad29, Ad30, Ad32, Ad33, Ad36, Ad37, Ad38, Ad39, Ad42, Ad43, Ad44, Ad45, Ad46, Ad47, Ad48, Ad49, Ad51; group E: Ad4; group F: Ad40, Ad41.

The different groups are characterized by different clinical

manifestations, which include respiratory diseases, conjunctivitis and gastroenteritis.

Clinical manifestations of adenovirus infections

Although many adenovirus infections pass without clinical

manifestations, adenoviruses are associated with a range of clinical symptoms, including respiratory disease (mainly species HAdV-B and C), conjunctivitis (HAdV-B and D) and gastroenteritis (HAdV-F serotypes 40 and 41). Usually, the infection is self-limiting and short in duration. Infection induces a strong adaptive and protective immunity that limits disease by the same or closely related serotypes. In contrast, in immunocompromised individuals (i.e.

transplant patients) and children, adenovirus can disseminate into multiple organs and induce substantial morbidity and mortality. In

immunocompromised individuals, adenoviruses can be associated with adenoviral hepatitis, encephalitis, acute hemorrhagic cystitis, and meningitis. Also, adenovirus has been found in 41% of children with intussusception.

Many adenovirus infections are associated with Acute Respiratory Disease (ARD), which sometimes cause very severe consequences. It is estimated that about 5% of acute respiratory illnesses in children under 5 are due to adenovirus infection, while a study in Argentina showed that 14.3 % of hospitalized children with acute lower respiratory infection were confirmed to be infected with adenovirus. The fatality rate among these patients reached 16.7 %. A recent outbreak of Ad 14, which started in February 2007 in a military camp in the USA, caused 140 severe illnesses and 10 deaths, including those among healthy and young individuals. Symptoms associated with an adenoviral respiratory infection include pneumonia, pharyngitis, tonsilitis, and Pertussis-like syndrome. Adenoviruses associated with ARD are Ad3, Ad4, Ad7, AdI 1, AdH, and Ad21.

Another important clinical manifestation of adenovirus infection are diseases of the ocular surface. Adenovirus-associated conjunctivitis is estimated to be the main cause of conjunctivitis and is common worldwide. In Japan, over 1 million cases have been reported at the National Epidemiological Surveillances of Infectious Agents Registry. There are three clinical

presentations of ocular disease: follicular conjunctivitis, which is a relatively mild conjunctivitis lasting 3-5 days; pharyngoconjunctival fever, which is associated with cold-like symptoms and fever and conjunctivitis lasting 5-7 days (mostly associated with Ad3, Ad4, Ad7); and epidemic

keratoconjunctivitis (EKC), a severe condition of the cornea and conjunctiva which may lead to long-term visual impairment (commonly caused by Ad8, Adl9 and Ad37). Over half of the 51 serotypes have been shown to cause ocular diseases.

In addition, adenoviruses are a major cause of acute infantile

gastroenteritis, which is believed to be a major contributor to childhood diarrhea in underdeveloped and high population density areas.

Finally, the presence of certain adenoviruses is also associated with increased body mass index (BMI), leading to obesity. In vitro experiments have shown that Ad36 and Ad37 have the potential to induce obesity.

Influenza virus

In certain embodiments, the virus is an influenza virus. Influenza viruses are RNA viruses of the family Orthomyxoviridae. Three types of influenza viruses (types A, B, and C) have been identified. Subtypes of type A are based on variations in the hemagglutinin (HA) polypeptide and the neuraminidase (N) polypeptide. Fifteen (Hl, H2, H3, H4, H5, H6, H7, H8, H9, HlO, HI l, H 12, H 13, H 14, and H 15) different HA subtypes have been identified, and nine (Nl , N2, N3, N4, N5, N6, N7, N8, and N9) N subtypes have been identified. Strains including these subtypes can occur in various combinations (e.g., HlNl, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7). One serotype of influenza B has been identified, and influenza type C is generally less virulent than types A or B.

Clinical manifestations of influenza virus infections

Influenza is characterized by fever, headache, tiredness, cough, sore throat, runny or stuffy nose, body aches, and diarrhea and vomiting.

Complications which can develop from an influenza infection include bacterial pneumonia, dehydration, and worsening of chronic medical conditions, such as congestive heart failure, asthma or diabetes. Sinus problems and ear infections can also develop. Influenza infections can spread to multiple organs, especially in immunocompromised transplant patients and patients with chronic

obstructive pulmonary disease (COPD) asthma.

Mortality due to influenza infection is often associated with lung inflammation, which can be severe. Influenza virus can induce cytokines including interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor- alpha in the serum and nasopharyngeal fluid (Laurent et al., J. Med. Virol.

64:262-268, 2001; Hayden et al., J. Clin. Investig. 101 :643-649, 1998).

Mortality associated with influenza infection is often due to the ability of the influenza A virus to infect the entire lung and induce high levels of

macrophage-derived chemokines and cytokines, which results in infiltration of inflammatory cells and severe haemorrhage (Kobasa et al., Nature 431 :703- 707, 2004).

Bacteria

Bacterial are a diverse group single-celled prokaryotic organisms that include Proteobacteria, Firmicutes, Bacteroidetes, Actinomycetes,

Mycobacteria, Corynebacteria, Spirochetes, Chlamydiae, and Cyanobacteria. Bacteria may be classified as aerobic or anaerobic, or as Gram-positive or Gram-negative. Bacteria may also be classified by shape, such as bacilli (rod- shaped), cocci (spherical), or spirilla (curved). Certain bacteria, such as Wolbachia and Chlamydia trachomatis, are obligate intracellular parasites. Genera of bacteria which can cause infections in humans include

Staphylococcus, Streptococcus, Gonorrhea, Meningitis, Salmonella,

Escherichia, Yersinia, Clostridium, Mycobacteria, Mycoplasma, Legionella, Lysteria, Pseudomonas, and Bacillus.

Diseases caused by bacterial infections include Lyme disease, granuloma inguinale, gonorrhea, syphilis, melioidosis, whooping cough, leprosy, tetanus, bubonic plague, scarlet fever, invasive group A Streptococcal disease, toxic shock syndrome, meningoccal disease, bacteremia, strep throat, cholera, dysentery, amebic dysentery, shigellosis, diphtheria, Legionnaire's disease, tuberculosis, typhoid fever, Rocky Mountain spotted fever, vibrio, Whipple's Disease, bacterial digestive infections, acute appendicitis, meningitis, encephalitis, impetigo, cellulitis, carbuncle, acne, sepsis, septicemia,

pneumonia, food poisoning, rheumatic fever, brucellosis, ehrichiosis, psittacosis, acanthamoeba, granulomatous amebic encephalitis, relapsing fever, naegleria, listeriosis, trachoma, Chlamydia, Q fever, yaws, actinomysis, and lymphogranuloma venereum.

Obligate intracellular parasites

Obligate intracellular parasites depend on entry, growth, and replication within the cytoplasm of eukaryotic host cells. They cannot live in artificial nutrient environments and must be grown either in tissue or in embryo cultures. Taxonomically, obligate intracellular parasites are positioned between viruses and true bacteria. Obligate intracellular parasites include parasitic

microorganisms which cannot reproduce outside of their host cells, and which force the hosts to assist in the parasites' reproduction.

Obligate intracellular parasites of humans include viruses, bacteria, and protozoa. Bacterial parasites include Chlamydia, Rickettsia, Coxiella, and certain species of Mycobacteria. Protozoan parasites include Plasmodia, Leishmania spp., Toxoplasma gondii, and Trypanosoma cruzi.

Rickettsia are thought to be the nearest extant relatives of the bacterial ancestors of eukaryotic mitochondria. Rickettsia are carried by ticks, fleas, and lice, and cause diseases such as typhus, rickettsialpox, Boutonneuse fever, African Tick Bite Fever, Rocky Mountain spotted fever, Australian Tick Typhus, Flinders Island Spotted Fever, and Queensland Tick Typhus in humans. They have also been associated with a wide range of plant diseases. Like viruses, they only grow inside living cells. The majority of Rickettsia bacteria are susceptible to antibiotics of the tetracycline group.

Chlamydia is a genus of bacteria which cause sexually transmitted infections in humans and are the leading cause of infectious blindness worldwide.

Wolbachia

Wolbachia is a genus of bacteria which infects predominantly arthropod species, including a high proportion of insects. Wolbachia also infects a variety of isopod species, spiders, mites, and many species of filarial nematodes, including those causing onchocerciasis ("river blindness") and elephantiasis in humans as well as heartworms in dogs. The pathogenicity of filarial nematodes is mostly due to host immune response toward Wolbachia, which live symbiotically in the filarial worms' reproductive tracts. A current strategy for controlling filarial nematode diseases is the elimination of Wolbachia via the antibiotic doxycycline. It has been shown that filarial worms become sterile after the symbiotic Wolbachia is eliminated, thus reducing transmission of the diseases.

Clinical manifestations of Wolbachia infection

Onchocerciasis, also known as river blindness, is the world's third leading infectious cause of blindness. It is caused by Onchocerca volvulus, a nematode that can spread throughout the human body live for up to fifteen years. When the worms die, they cause intense itching and a strong immune response that can destroy nearby tissue, such as the eye. The immune responses are triggered by Wolbachia-derived antigens. Thus, Wolbachia are thought to be the main determinant of the disease's severity. About 18 million people are currently infected with this parasite; approximately 300,000 have been permanently blinded. Onchoceriasis currently occurs endemically in 30 African countries, Yemen, and isolated regions of South America.

Elephantiasis is a disease that is characterized by the thickening of the skin and underlying tissues, especially in the legs, male genitals and female breasts. Elephantiasis occurs in the presence of microscopic, thread-like parasitic worms transmitted by mosquitoes. The disease is a result of interactions between the worm, the symbiotic Wolbachia within the worm, the host's immune response, and the opportunistic infections and that consequently arise. Elephantiasis is common in tropical regions and in Africa, and is one of the most common causes of disability in the world.

Additional ocular disorders

Additional infectious and non-infections disorders of the eye may be caused by viruses, bacteria, protozoa, and fungi, and include conjunctivitis, blepharoconjunctivitis, scleritis, keratitis, corneal ulcer, corneal abrasion, snow blindness, arc eye, Thygeson's superficial punctate keratopathy, corneal neovascularization, Fuchs' dystrophy, keratoconus, keratoconjunctivitis sicca, iritis, uveitis, cataract, retinal detachment, retinoschisis, hypertensive retinopathy, retinopathy of prematurity, macular degeneration, retinitis pigmentosa, macular edema, glaucoma, floaters, Leber's hereditary optic neuropathy, strabismus, ophthalmoparesis, progressive external

ophthalmoplegia, esotropia, exotropia, hypermetropia, myopia, astigmatism, anisometropia, presbyopia, internal ophthalmoplegia, amblyopia, Leber's congenital amaurosis, scotoma, achromatopsia/maskun, hyctalopia

(nightblindness), micro-ophthalmia/coloboma, Arhyll Roberson pupil, xerophthalmia and aniridia. Additional ocular disorders and their associated pathogens are described in Table 2.

Table 2

Compounds

Certain compounds that may be employed as agents in the methods, compositions, and kits of the present invention are discussed in greater detail below. It will be understood that analogs of any of these compound can be used in the methods, compositions, and kits of the present invention.

Vitamin £ compounds

The methods, compositions, and kits of the invention can include one or more vitamin E compound. A "vitamin E compound" is represented by the following structures:

wherein

the compound contains 40 or fewer carbon atoms;

R₁ - R₁₀ are independently:

H; CH3; (CH₂)_nCH₃ wherein n is any integer from 1 to 20; X; OH; NH₂; NH₃ ⁺X^"; COOH; COO M⁺ wherein M⁺ is any alkali metal cation;

wherein any of the positions indicated with a dashed line (— ) may contain a carbon-carbon double bond;

, wherein the alkyl chain is fully saturated;

, wherein n may be any integer from 1 to

20, and wherein any of the positions indicated with a dashed line (— ) may contain a carbon-carbon double bond;

O (CH₂CH₂O)_nH, wherein n can be any integer from 1 to 100; O (CH(CH₃)CH₂O)_nH, wherein n can be any integer from 1 to 100; or

OC(O)R₁₂;

X is F, Cl, Br, or I;

Y is O, NR₁,, or S;

R₁₁ is H or a linear or branched alkyl or aryl group containing 1 to 10 carbon atoms that is saturated or unsaturated; and

R₁₂ is:

a linear or branched alkyl or aryl group containing 1 to 20 carbon atoms that is saturated or unsaturated;

COOH or (CH₂)_^COOH, where n is any integer from 1 to 10, or any salt or alkoxy derivative thereof, including CH₂CH₂C(O)O(CH₂CH₂O)_mH wherein m is any integer from 1 to 100; CH₂CH₂C(O)O(CH(CH₃)CH₂O)_OTH wherein m is any integer from 1 to 100; or any amino ester derivative or a salt thereof, including CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NH₃ ⁺X^",

CH₂NH₂CH₃ ⁺X-, CH₂NH(CH₃)₂ ⁺X-, and CH₂N(CH₃)₃ ⁺X\

Suitable vitamin E compounds include isoforms (e.g. α-, β-, γ-, or δ-) of tocopherol, tocomonoenol, tocodienol, and tocotrienol. These include α- tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β- tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ- tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ- tocotrienol, and any stereoisomer thereof. Suitable vitamin E compounds of the present invention also include desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl-tocodienol, desmethyl-tocotrienol, and any stereoisomer thereof. Suitable vitamin E compounds may contain a carbon-carbon double bond at any of the positions indicated with a dashed line (— ) as shown above.

The structures of exemplary vitamin E compounds are provided in Table 3.

Table 3

When a compound disclosed herein contains one or more chiral atoms where stereochemistry is unspecified, it will be understood that each stereoisomer of the compound is invidually disclosed as if the structure of each stereoisomer were explicitly drawn. For example, α-tocopherol may represent any of the structures shown in (II):

In certain embodiments of the invention, the vitamin E compound may be a naturally-occuring d-stereoisomer of vitamin E, the structures of which are given in (III):

The vitamin E compounds of the present invention may be naturally occurring or synthetic. Certain embodiments of the invention include a naturally occurring vitamin E compound such as an extract from a food source. For example, α-tocopherol, α-tocotrienol, β-tocopherol, β-tocotrienol, γ- tocopherol, γ-tocotrienol, δ-tocopherol, and δ-tocotrienol are available naturally from fortified cereals, green vegetables, nuts, seeds, and vegetable oils.

Methods of extracting vitamin E compounds from natural sources have been described, for example, in U.S. Patent Nos. 6,743,450, 6,838,104, 7,161,055 and 7,544,822, which are hereby incorporated by reference.

Other embodiments of the invention include a synthetic vitamin E compound or a mixture of synthetic vitamin E compounds. There are many known methods of chemically synthetizing vitamin E compounds. An exemplary method for making α-tocopherol is the reaction of

trimethylhydroquinone (TMHQ) with iso-phytol (3,7,11,15- tetramethylhexadec-l-en-3-ol) in a condensation reaction with a catalyst. It will be apparent to one skilled in the art that other tocopherol, tocomonoenol, tocodienol, and tocotrienol isoforms and their derivates can also be prepared using a similar strategy starting from appropriate precursors. For example, the starting compounds may be TMHQ and 3,7,1 l,15-tetramethylhexadec-2-en-l- ol. An additional method of making vitamin E with isophytol under relatively mild rnnHUinnς haς hpe.n deςr.rihe.H hv Wehrli et al in T OrP C!he.m 36"?Q10- 2912. Methods for synthesizing unsaturated side chains of vitamin E are described in U.S. Patent No. 4,168,271, which is hereby incorporated by reference. Additional methods of synthesizing vitamin E side chains have been reviewed by Stalla-Bourdillon, Ind. Chim. BeIg. 35, 13 (1970). Additional methods of synthesizing tocopherols are described in U.S. Patent Nos.

5,523,420, 6,005,122, which are hereby incorporated by reference. Additional methods of synthesizing tocotrienols are described in U.S. Patent No.

7,038,067, which is hereby incorporated by reference.

Additional antiviral agents

One or more (e.g., two, three, four, five, or six) additional antiviral agents can be used in the compositions, methods, and kits of the invention. Exemplary antiviral agents are those shown in Table 1. Agents useful in treating viral infections such as influenza include neuraminidase inhibitors (e.g., oseltamivir, zanamivir, and peramivir) and M2 ion channel inhibitors (e.g., amantadine and rimantadine). Other agents which, for example, inhibit viral replication, transcription, reverse transcription, or viral particle production may also be used in the compositions, methods and kits of the invention.

Neuraminidase inhibitors

The compositions, methods, and kits of the invention can include a neuraminidase inhibitor or an analog thereof. Neuraminidase inhibitors are a class of compounds which block viral neuraminidase peptide, preventing viral replication from the host cell. Neuraminidase inhibors act against both influenza type A and type B. Suitable neuraminidase inhibitors include oseltamivir, zanamivir, and peramivir. Oseltamivir

In certain embodiments, oseltamivir ((3R,4R,5S)-4-acetylamino-5- amino-3(l-ethylpropoxy)-l-cyclohexene-l-carboxylic acid, ethyl ester; e.g. oseltamivir phosphate) or its structural analogs may be used in the compositions, methods, and kits of the invention. Oseltamivir has the following structure:

Oseltamivir

Oseltamivir is a prodrug, which is hydrolyzed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071), which has the following structure:

GS4071

Oseltamivir and GS4071 are described in U.S. Patent No. 5,763,483.

Oseltamivir can be administered as an oral tablet. The standard recommended dosage of oseltamivir for the treatment or prevention of influenza is 75 mg twice daily for 5 days. Dosages for children and patients with renal impairment are decreased and vary by body weight. Structural analogs of oseltamivir include those having the formula:

wherein R₁ is an alkyl group or a substituted alkyl group, R₂ is an alkyl group, and R₃ and R₄ are, independently, H or a substituent of an amino group, wherein R₃ and R₄ are not both H. Additional information information regarding these oseltamivir analogs can be found in U.S. Patent No. 6,437,171.

Additional structural analogs of oseltamivir include those having the formula:

wherein R₁ and R₂ are described below:

and R₃ is H or CH₂CH₃. Additional information information regarding these oseltamivir analogs can be found in U.S. Patent No. 6,111,132.

Additional oseltamivir analogs, synthetic intermediates, and methods of synthesis can be found in U.S. Patent Nos. 6,057,459, 6,204,398, 6,225,341, 6,376,674, 6,455,571, 6,518,305, 6,518,438,6,593,314, and 7,122,684, each of which is incorporated by reference.

Zanamivir

In certain embodiments, zanamivir ((2R,3R,4S)-4-

[(diaminomethylidene)amino]-3-acetamido-2-[( 1R,2R)- 1 ,2,3-trihydroxypropyl]- 3,4-dihydro-2H-pyran-6-carboxylic acid) or its structural analogs may be used in the compositions, methods, and kits of the invention. Zanamivir has the following structure:

Zanamivir

Zanamivir can be administered through oral inhalation using a breath- activated plastic device called a Diskhaler. The standard recommended dosage of zanamivir for the treatment of influenza is 10 mg (2 inhalations) twice daily for 5 days in patients 7 years and older. Zanamivir can also be used to prevent influenza infection for patients 5 years and older with a standard recommended dosage of 1 inhalation per day for 10 to 28 days. Zanamivir is not

recommended for people with underlying respiratory disease such as asthma or chronic obstructive pulmonary disease. Zanamivir has not been shown to shorten the duration of influenza in people with these diseases, and some people have had serious side effects of bronchospasm (wheezing) and worsening lung function.

Structural analogs of zanamivir includes compounds having the formula:

wherein ( ) indicates lack of a specified stereochemistry; and R) is

(3Ik)_xNR₃R₄, CN or N₃; where alk is an unsubstituted or substituted methylene; x is 0 or 1 ; R₃ is H, C_1-6 alkyl, aryl, aralkyl, amidine, NR₄R₅ or an unsaturated or saturated ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R₄ is H, Ci_-6 alkyl, or allyl; R₅ is H or C]_-6 alkyl; and R₂ is NNHCOR₆ where R₆ is H, substituted or unsubstituted Cj_-4 alkyl or aryl or a pharmaceutically acceptable salt thereof. The compound may have the following stereochemistry:

R₂ (VI)

Additional information information regarding these zanamivir analogs can be found in U.S. Patent No. 5,360,817. Additional zanamivir analogs, synthetic intermediates, and methods of synthesis are described in U.S. Patent Nos. 5,859,284, 5,866,601, 5,886,213, 5,958,973, 5,985,859, 5,944,377, 6,114,386, 6,225,341, 6,340,702, and 6,451 ,766, each of which is incorporated by reference. Peramivir

In certain embodiments, peramivir ((75,2S,3S,4R)-3-[(7.S)-l-Acetamido- 2-ethyl-butyl] -4-(diaminomethylideneamino)-2-hydroxy-cyclopentane - 1- carboxylic acid), its structural analogs, or pharmaceutically acceptable salts thereof, may be used in the compositions, methods, and kits of the invention. Peramivir has the following structure:

Peramivir

Structural analogs of peramivir includes compounds having the formula:

wherein R, is H or OH and R₂ are both CH₂CH₃ or both CH₂CH₂CH₃.

Additional information information regarding these peramivir analogs can be found in WO2007/095218. Additional peramivir analogs are described in WO2007/087056.

Amantadine and rimantadine

The compositions, methods, and kits of the invention can include amantadine (e.g. amantadine hydrochloride), rimantadine (e.g. rimantadine hydrochloride), or analogs thereof. The structures of amantadine and rimantadine are given below:

Amantadine Rimantadine

Amantadine (adamantan-1 -amine) and rimantadine (l-(adamantan-l- yl)ethan-l -amine) are substituted adamantane compounds which can be used singly for the treatment or prevention of influenza A. Currently the mechanism of viral inhibition by amantadine and rimantadine is not well understood.

These compounds are believed to inhibit influenza's viral replication by binding to the viral M2 ion channel.

The recommended dose for amantadine or rimantadine is 100 mg taken twice daily. If the patient does not respond to this dosage, then the dosage may be increased to 200 mg, or to a maximum of 300 mg. A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance less than 10 mL/min. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day or rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary.

In certain embodiments, amantadine, rimantadine, and analogs thereof can be used in combination with a neuraminidase inhibitor and a PDE inhibitor in the compositions, methods and kits of the invention. Amantadine analogs include compounds having the formula (XIV):

Rq Rr (XIV) wherein R* is -(A)_n-(CR₁R₂)_H1-NR₃R₄, n+m=0, 1, or 2, A is selected from the group consisting of linear or branched C]-C₆ alkyl, linear or branched C₂-C₆ alkenyl, and linear or branched C₂-C₆ alkynyl, R₁ and R₂ are independently selected from the group consisting of hydrogen, linear or branched C₁-C₆ alkyl, linear or branched C₂-C₆ alkenyl, linear or branched C₂-C₆ alkynyl, aryl, substituted aryl, and arylalkyl, R₃ and R₄ are independently selected from the group consisting of hydrogen, linear or branched CpC₆ alkyl, linear or branched C₂-C₆ alkenyl, and linear or branched C₂-C₆ alkynyl, or together form C₂-C]₀ alkylene or C₂-C₆ alkenylene or together with the N form a 3-7- membered azacycloalkane or azacycloalkene, including substituted (C₁-C₆ alkyl, C₂-C₆ alkenyl) 3-7-membered azacycloalkane or azacycloalkene; or independently R₃ or R₄ may join with R_p, R₄,, R₁-, or R₅ to form an alkylene chain -CH(R₆)-(CH₂)_t-, wherein t=0 or 1 and the left side of the alkylene chain is attached to U or Y, the right side of the alkylene chain is attached to N, and R₆ is selected from the group consisting of hydrogen, linear or branched C₁-C₆ alkyl, linear or branched C₂-C₆ alkenyl, linear or branched C₂-C₆ alkynyl, aryl, substituted aryl and arylalkyl; or independently R₃ or R₄ may join with R₅ to form an alkylene chain represented by the formula -CH₂-CH₂-CH₂-(CH₂)_t-, or an alkenylene chain represented by the formulae -CH=CH-CH₂- (CH₂)_t-, - CH=C=CH-(CH₂)_t- or -CH₂-CH=CH-(CH₂)_t-, wherein t=0 or 1, and the left side of the alkylene or alkenylene chain is attached to W and the right side of the alkylene ring is attached to N; R₅ is selected from the group consisting of hydrogen, linear or branched C]-C₆ alkyl (C]-C₆), linear or branched C₂-C₆ alkenyl, and linear or branched C₂-C₆ alkynyl, or R₅ combines with the carbon to which it is attached and the next adjacent ring carbon to form a double bond, R_p, R_q, R₁-, and R₅, are independently selected from the group consisting of hydrogen, linear or branched C]-C₆ alkyl, linear or branched C₂-C₆ alkenyl, linear or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, substituted aryl, and arylaklyl, or R_p, R_q, R_r, or R_s independently may form a double bond with U or with Y or to which it is attached, or R_p, R_q, R₁-, or R_s may combine together to represent a lower alkylene -(CH₂)_X- or a lower alkenylene bridge wherein x is 2-5, inclusive, which alkylene bridge may, in turn, combine with K_$ to form an additional lower alkylene - (CH₂)_y- or a lower alkenylene bridge, wherein y is 1-3, inclusive, U, V, W, X, Y, Z represent carbon atoms, and include optical isomers, diastereomers, polymorphs, enantiomers, hydrates, pharmaceutically acceptable salts, and mixtures of compounds within formula (I).

The ring defined by U-V-W-X-Y-Z is preferably selected from the group consisting of cyclohexane, cyclohex-2-ene, cyclohex-3-ene, cyclohex-1,4- diene, cyclohex-l,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene.

Examples of amantadine analogs that can be employed in the methods, compositions, and kits of the invention include the amantadine analogs selected from the group consisting of l-amino-l,3,5-trimethylcyclohexane, 1-amino- l(trans),3(trans),5-trimethylcyclohexane, l-amino-l(cis),3(cis),5- trimethylcyclohexane, 1 -amino- 1 ,3,3,5-tetramethylcyclohexane, 1 -amino- 1 ,3,3,5,5-pentamethylcyclohexane(neramexane), 1 -amino- 1 ,3,5,5-tetramethyl- 3-ethylcyclohexane, l-amino-l,5,5-trimethyl-3,3-diethylcyclohexane, 1-amino- l,5,5-trimethyl-cis-3-ethylcyclohexane, l-amino-(lS,5S)cis-3-ethyl- 1,5,5- trimethylcyclohexane, 1 -amino- 1 ,5,5-trimethyl-trans-3-ethylcyclohexane, 1 - amino-( lR,5S)trans-3-ethyl- 1 ,5,5-trimethylcyclohexane, 1 -amino- 1-ethyl- 3,3,5,5-tetramethylcyclohexane, l-amino-l-propyl-3,3,5,5- tetramethy Icy clohexane, N-methy 1- 1 -amino- 1,3,3, 5 ,5 -pentamethy lcyclohexane, N-ethyl-l-amino-l,3,3,5,5-pentamethyl-cyclohexane, N-( 1,3,3, 5,5- pentamethylcyclohexyl) pyrrolidine, 3,3,5,5- tetramethylcyclohexylmethylamine, l-amino-l-propyl-3,3,5,5- tetramethylcyclohexane, 1 amino-l,3,3,5(trans)-tetramethylcyclohexane (axial amino group), 3-propyl-l,3,5,5-tetramethylcyclohexylamine semihydrate, 1 -amino- 1 ,3,5,5-tetramethyl-3-ethylcyclohexane, 1 -amino- 1 ,3,5- trimethylcyclohexane, 1 -amino- 1 ,3-dimethyl-3-propylcyclohexane, 1 -amino- 1 ,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane, 1 -amino- 1 ,3-dimethyl- 3-ethylcyclohexane, l-amino-l,3,3-trimethylcyclohexane, cis-3-ethyl-l (trans)- 3(trans)-5-trimethylcyclohexamine, 1-amino- 1 ,3(trans)-dimethylcyclohexane, 1 ^^-trimethyl-S^-dipropylcyclohexylamine, 1 -amino- 1 -methyl-3(trans)- propy lcyclohexane, 1 -methyl-3 (cis)-propylcyclohexy lamine, 1 -amino- 1 -methyl - 3(trans)-ethylcyclohexane, 1 -amino- 1 ,3,3-trimethyl-5(cis)-ethylcyclohexane, 1 - amino- 1,3,3 -trimethy 1-5 (trans)-ethy Icy clohexane, ci s-3 -propyl- 1,5,5- trimethylcyclohexylamine, trans-3-propyl- 1 ,5,5-trimethylcyclohexylamine, N- ethyl-l,3,3,5,5-pentamethylcyclohexylamine, N-methyl-l-amino-1,3,3,5,5- pentamethylcyclohexane, 1 -amino- 1 -methylcyclohexane, N,N-dimethyl- 1 - amino- 1,3,3, 5, 5-pentamethylcyclohexane, 2-(3, 3,5,5- tetramethylcyclohexyl)ethylamine, 2-methyl-l-(3,3,5,5- tetramethylcyclohexyl)propyl-2-amine, 2-(l,3,3,5,5-pentamethylcyclohexyl-l)- ethylamine semihydrate, N-(l,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine, 1- amino- 1 ,3(trans),5(trans)-trimethylcyclohexane, 1 -amino- 1 ,3(cis),5(cis)- trimethylcyclohexane, 1 -amino-( 1 R,5 S)trans-5-ethyl- 1,3,3- trimethylcyclohexane, l-amino-(lS,5S)cis-5-ethyl-l,3,3-trimethylcyclohexane, 1 -amino- 1 ,5,5-trimethyl-3(cis)-isopropyl-cyclohexane, 1 -amino- 1 ,5,5- trimethyl-3(trans)-isopropyl-cyclohexane, 1 -amino- 1 -methyl-3 (cis)-ethyl- cyclohexane, 1 -amino- 1 -methyl-3 (cis)-methyl-cy clohexane, 1 -amino-5 ,5 - diethyl- 1 ,3,3-trimethyl-cyclohexane, 1-amino- 1 ,3,3,5,5- pentamethy Icy clohexane, 1 -amino- 1 ,5, 5 -trimethy 1-3, 3 -diethy Icy clohexane, 1 - amino-l-ethyl-3,3,5,5-tetramethylcyclohexane, N-ethyl- 1-amino- 1,3,3, 5, 5- pentamethylcyclohexane, N-(l,3,5-trimethylcyclohexyl)pyrrolidine or piperidine, N-[l,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or piperidine, N-[l,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine, N-(1, 3,3,5- tetramethylcyclohexyl)pyrrolidine or piperidine, N-(1, 3, 3,5,5- pentamethylcyclohexyl)pyrrolidine or piperidine, N-(1, 3,5, 5-tetramethyl-3- ethylcyclohexyl)pyrrolidine or piperidine, N-(l,5,5-trimethyl-3,3- diethylcyclohexyl)pyrrolidine or piperidine, N-(1, 3, 3 -trimethy l-cis-5- ethylcyclohexyl)pyrrolidine or piperidine, N-[(l S,5S)cis-5-ethyl- 1,3,3- trimethylcyclohexyljpyrrolidine or piperidine, N-(l,3,3-trimethyl-trans-5- ethylcyclohexyl)pyrrolidine or piperidine, N-[(lR,5S)trans-5-ethyl,3,3- trimethylcyclohexyl]pyrrolidine or piperidine, N-(l-ethyl-3,3,5,5- tetramethylyclohexyl)pyrrolidine or piperidine, N-(l-propyl-3,3,5,5- tetramethylcyclohexyl)pyrrolidine or piperidine, N-(1, 3,3, 5, 5- pentamethylcyclohexyl)pyrrolidine, their optical isomers, diastereomers, enantiomers, hydrates, their pharmaceutically acceptable salts, and mixtures thereof. One amantadine analog is neramexane (l-amino-1,3,3,5,5- pentamethylcyclohexane), which is described, e.g., in U.S. Patent No.

6,034,134.

Certain amantadine analogs of general formula (XIV) include the case where three axial alkyl substituent, e.g., R_p, R₁. and R₅ all together form a bridgehead to yield compounds (so called 1-aminoadamantanes) illustrated by the formulae XVb-XVd below:

Certain amantadine analogs of formula (XIV) wherein n+m=0, U, V, W, X, Y and Z form a cyclohexane ring, and one or both of R₃ and R₄ are independently joined to the cyclohexane ring via alkylene bridges formed through R_p, R_q, R_r, R₈ or R₅ are represented by the following formulas XVIa- XVIc:

where R_q, R_r, R₅, R₁. and R₅ are as defined above for formula (XIV), R₆ is hydrogen, linear or branched C] -C₆ alkyl, linear or branched C₂-C₆ alkenyl, linear or branched C₂-C₆ alkynyl, aryl, substituted aryl or arylalkyl Y is saturated or may combine with R₆ to form a carbon-hydrogen bond with the ring carbon to which it is attached, 1=0 or 1 and k=0, 1 or 2 and

represents a single or double bond.

Other amantadine analogs include 1 -amino adamantane and its derivatives selected from the group consisting of l-amino-3 -phenyl

adamantane, 1-amino-methyl adamantane, l-amino-3-ethyl adamantane, 1- aminr>-3-iςr>nrnnvl aHamantanp 1 -amino-3-n-hntvl aHamantanp l -amino-3 S- diethyl adamantane, l-amino-3,5-diisopropyl adamantane, l-amino-3,5-di-n- butyl adamantane, l-amino-3-methyl-5-ethyl adamantane, 1-N-methylamino- 3,5-dimethyl adamantane, l-N-ethylamino-3,5-dimethyl adamantane, 1-N- isopropyl-amino-3,5-dimethyl adamantane, 1 -N,N-dimethyl-amino-3,5- dimethyl adamantane, 1 -N-methyl-N-isopropyl-amino-3-methyl-5-ethyl adamantane, l-amino-3-butyl-5-phenyl adamantane, l-amino-3-pentyl adamantane, l-amino-3,5-dipentyl adamantane, l-amino-3-pentyl-5-hexyl adamantane, l-amino-3-pentyl-5-cyclohexyl adamantane, l-amino-3-pentyl-5- phenyl adamantane, l-amino-3-hexyl adamantane, l-amino-3,5-dihexyl adamantane, l-amino-3-hexyl-5-cyclohexyl adamantane, l-amino-3-hexyl-5- phenyl adamantane, l-amino-3-cyclohexyl adamantane, l-amino-3,5- dicyclohexyl adamantane, l-amino-3-cyclohexy 1-5 -phenyl adamantane, 1- amino-3,5-diphenyl adamantane, l-amino-3,5,7-trimethyl adamantane, 1- amino-3,5-dimethyl-7-ethyl adamantane, l-amino-3,5-diethyl-7-methyl adamantane, 1-N-pyrrolidino and 1-N-piperidine derivatives, l-amino-3- methy 1-5 -propyl adamantane, l-amino-3-methyl-5-butyl adamantane, 1-amino- 3-methyl-5-pentyl adamantane, l-amino-3-methyl-5-hexyl adamantane, 1- amino-3-methyl-5-cyclohexyl adamantane, l-amino-3-methyl-5-phenyl adamantane, l-amino-3-ethyl-5-propyl adamantane, l-amino-3-ethyl-5-butyl adamantane, l-amino-3-ethyl-5-pentyl adamantane, l-amino-3-ethyl-5-hexyl adamantane, l-amino-3-ethyl-5-cyclohexyl adamantane, l-amino-3-ethyl-5- phenyl adamantane, l-amino-3-propyl-5-butyl adamantane, l-amino-3-propyl- 5-pentyl adamantane, l-amino-3-propyl-5-hexyl adamantane, l-amino-3- propyl-5-cyclohexyl adamantane, l-amino-3-propyl-5-phenyl adamantane, 1- amino-3-butyl-5-pentyl adamantane, l-amino-3-butyl-5-hexyl adamantane, 1- amino-3-butyl-5-cyclohexyl adamantane, their optical isomers, diastereomers, enantiomers, hydrates, N-methyl, N,N-dimethyl, N-ethyl, N-propyl derivatives, their pharmaceutically acceptable salts, and mixtures thereof.

The compounds of formulas XVb and XVd may be prepared by alkylation of halogenated adamantanes, preferably bromo- or chloroadamantanes. The di- or tri-substituted adamantanes may be obtained by additional halogenation and alkylation procedures. The amino group is introduced either by oxidation with chromiumtrioxide and bromination with HBr or bromination with bromine and reaction with formamide followed by hydrolysis. The amino function can be alkylated according to generally- accepted methods. Methylation can, for example, be effected by reaction with chloromethyl formate and subsequent reduction. The ethyl group can be introduced by reduction of the respective acetamide. For more details on synthesis see, e.g., U.S. Patent Nos. 5,061,703 and 6,034,134.

Other amantadine analogs are described by formula XVII:

wherein R₁ is NHC(O)R₅, C(O)NHR₅, (CR₅R₆)_HNR₅R₆ or (CR₅Re)_nCO₂R₅; n is an integer ranging from 0 to 4; R₂, R₃ and R₄ are each independently selected from the group consisting of H, fluoro, Cj-C₆ alkyl, and hydroxy; and each R₅ and R₆ is independently H or C]-C₆ alkyl.

Amantadine analogs of formula XVII include methyl-3-fluoro-5- hydroxyadamantane- 1 -carboxylate; fluoroadamantane-1-carboxylic acid; 3,5- difluoro-adamantan-1-ylamine; 3, 5-difluoroadamantane-l-carboxylic acid; 3- fluoroadamantan- 1 -ylamine; methyl-3,5-difluoro-7-hydroxyadamantane- 1 - carboxylate; 3,5,7-trifluoroadamantane-l-carboxylic acid; 3,5,7- trifluoroadamantan-1 -ylamine; and the pharmaceutically acceptable salts of the foregoing compounds.

Still other amantadine analogs are described by formula XVIII:

wherein each of Ri and R₂ is independently hydrogen or a straight or branched Cj-C₆ alkyl or, in conjunction with N, a heterocyclic radical with 5 or 6 ring C atoms; each ofR₃ and R₄ is independently hydrogen, a straight or branched C₁- C₆ alkyl, a C₅ or C₆ cycloalkyl, or phenyl; and R₅ is hydrogen or a straight or branched C₁-C₆ alkyl, or a pharmaceutically-acceptable acid addition salt thereof.

Amantadine analogs of formula XVIII include 1 -amino adamantane, 1- amino-3 -phenyl adamantane, 1-amino-methyl-adamantane, l-amino-3 -ethyl adamantane, l-amino-3 -isopropyl adamantane, l-amino-3 -n-butyl adamantane, l-amino-3, 5 -diethyl adamantane, l-amino-3, 5-diisopropyl adamantane, 1- amino-3,5-di-n-butyl adamantane, l-amino-3-methyl-5-ethyl adamantane, 1-N- methylamino-3, 5 -dimethyl adamantane, l-N-ethylamino-3,5-dimethyl adamantane, l-N-isopropyl-amino-3,5-dimethyl adamantane, l-N,N-dimethyl- amino-3,5-dimethyl adamantane, 1 -N-methyl-N-isopropyl-amino-S-methyl-S- ethyl adamantane, l-amino-3-butyl-5-phenyl adamantane, l-amino-3 -pentyl adamantane, l-amino-3, 5-dipentyl adamantane, l-amino-3-pentyl-5-hexyl adamantane, l-amino-3-pentyl-5-cyclohexyl adamantane, l-amino-3-pentyl-5- phenyl adamantane, l-amino-3 -hexyl adamantane, l-amino-3, 5 -dihexyl adamantane, l-amino-3-hexyl-5-cyclohexyl adamantane, l-amino-3-hexyl-5- phenyl adamantane, l-amino-3-cyclohexyl adamantane, l-amino-3, 5- dicyclohexyl adamantane, l-amino-3-cyclohexyl-5-phenyl adamantane, 1- amino-3,5-diphenyl adamantane, l-amino-3, 5, 7-trimethyl adamantane, 1- amino-3,5-dimethyl-7-ethyl adamantane, 1 -amino-3,5-diethyl-7-methyl adamantane, 1-N-pyrrolidino and 1 -N-piperidine derivatives, l-amino-3- methyl-5-propyl adamantane, l-amino-3-methyl-5-butyl adamantane, 1-amino- 3-methyl-5-pentyl adamantane, l-amino-3 -methyl- 5 -hexyl adamantane, 1- amino-3-methyl-5-cyclohexyl adamantane, l-amino-3 -methyl-5-phenyl adamantane, l-amino-3 -ethy 1-5 -propyl adamantane, l-amino-3-ethyl-5-butyl adamantane, l-amino-3-ethyl-5-pentyl adamantane, l-amino-3-ethyl-5-hexyl adamantane, l-amino-3-ethyl-5-cyclohexyl adamantane, l-amino-3 -ethy 1-5- phenyl adamantane, l-amino-3-propyl-5-butyl adamantane, l-amino-3 -propyl- 5-pentyl adamantane, l-amino-3-propyl-5-hexyl adamantane, l-amino-3- propyl-5-cyclohexyl adamantane, l-amino-3 -propyl- 5 -phenyl adamantane, 1- amino-3-butyl-5-pentyl adamantane, l-amino-3 -buty 1-5 -hexyl adamantane, 1- amino-3-butyl-5-cyclohexyl adamantane, their N-methyl, N,N-dimethyl, N- ethyl, N-propyl derivatives and their acid addition compounds.

Still other amantadine analogs are described by formula XIXa or formula XIXb.

wherein R] is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR₆ or C(O)R₆; R₂ is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR₆, or C(O)R₆; R₃ is H, alkyl, heteroalkyl, aryl or heteroaryl; R₄ is H, alkyl, heteroalkyl, aryl or heteroaryl; R₅ is OR₇, alkyl-OR₇, or heteroalkyl-OR₇; R₆ is alkyl, heteroalkyl, aryl, or heteroaryl. R₇ is NO₂, C(O)R₆, C(O)alkyl-ONO₂, or C(O)heteroalkyl-ONO₂. The following substituents are preferred: Ri and R₂ are H; R₃ and R₄ are H or alkyl; and R₇ is NO₂ or C(O)alkyl-ONO₂. Methods of making these

compounds are described, for example, in U.S. Patent 6,620,845.

Amantadine analogs of formula XIXa or XIXb include l-acetamido-3,5- dimethyl-7-hydroxyadamantane, 1 -amino-3 ,5-dimethyl-7-hydroxyadamantane hydrochloride, 1 -tert-butylcarbamate-S^-dimethyl-T-hydroxy-adamantane, 1 - tert-butylcarbamate-3,5-dimethyl-7-nitrate-adamantane, 1 -amino-3, 5-dimethyl- 7-nitrateadamantane hydrochloride, l-acetamido-3,5-dimethyl-7- nitrateadamantane, 1 , 1 -dibenzylamino-3,5-dimethyl-7-hydroxy-adamantane, 1 - amino-3, 5-dimethyl-7-acetoxyadamantane hydrochloride, 1- (benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxyadamantane, 1 - (benzyloxycarbonyl)amino-3,5-dimethyl-7-(3- bromopropylcarbonyloxy)adamantane, l-(benzyloxycarbonyl)amino-3,5- dimethyl-7-(3-nitratepropylcarbonyloxy)adamantane, l-Acetamido-3,5- dimethyl-7-carboxylic acidadamantane, 1 -acetamido-3,5-dimethyl-7- hydroxymethyladamantane, l-amino-3,5-dimethyl-7-hydroxymethyladamantane hydrochloride, l-(benzyloxycarbonyl)amino-3,5-dimethyl-7-hydroxymethyl adamantane, l-(benzyloxycarbonyl)amino-3,5-dimethyl-7-nitratemethyl- adamantane, 1 -amino-3, 5-dimethyl-7-nitratemethyladamantane hydrobromide, and 1 -acetamido-3,5-dimethyl-7-nitratemethyl-adamantane.

Amantadine analogs also include N-( 1 -adamanty 1) diethylamine, N-(3- methyl-1-adamantyl) isopropylamine, N-(3,5-dimethyl-l -adamanty 1)

ethylmethylamine, N-(I -adamanty 1) moφholine, N-(3,5,7-trimethly-l- adamantyl) piperidine, N,N'-bis(l-adamantyl)-l,3-propanediamine, N,N'-bis(3- methyl- 1 -adamantyl)- 1 , 10-decanediamine, N,N'-bis(3,5,7-trimethyl- 1 - adamanty I)- 1 ,6-hexanediamine, N-(I -adamantyl) cyclohexylamine, N-(I- adamantyl) cyclooctylamine, N-(l-adamantyl)-α-furfurylamine, N-(3-methyl-l- adamantyl)-β-thienylamine, N-(3,5,7-trimethyl- 1 -adamantyl)-α-furfurylamine, N-( 1 -adamantyl)-β-thienylamine, N-β-(2-pyridyl)ethyl- 1 -adamantylamine, N- (3,5-dimethyl-l-adamantyl)-5-phenylpentylamine , bis-adamantylamine, bis(3- methyl- 1-adamantyl) amine, bis(3,5-dimethyl-l-adamantyl) amine, N-(I- adamantyl) dodecylamine, N-(l-adamantyl)-N'-phenylpiperazine, N-(I- adamantyl) piperazine, N-( 1-adamantyl) aniline, N-( 1-adamantyl) benzylamine, N-( 1-adamantyl) phenethylamine, N-( 1-adamantyl) homoveratylamine, bis(3,5,7-trimethyl- 1 -adamantyl) amine, N-(3,5,7-trimethyl- 1 -adamantyl)- 1 - adamantylamine, 1-aminoadamantane, and N-(3,5,7-trimethyl-l-adamantyl)-N'- pheny lpiperazine .

Amantadine analogs also include adatanserin, tromantadine, amantanium bromide, rimantadine, somantadine, adapalene, N-l-adamantyl-N'-cyclohexyl- 4-morpholinecarboxamidine, dopamantine, adaprolol maleate, (-)-N-(2-(8- methyl- 1 ,4-benzodioxan-2-y lmethylamino)ethyl)adamantane- 1 -carboxamide, N-(l-adamantyl)-N', N'-(l,5-(3-(4(5)-l H-imidazolyl-pentanediyl)))

formamidine, adamantoyl-Lys-Pro-Tyr-Ile-Leu, 1 -(2-pyridyl)-4-( 1 -methy l-2-( 1 - adamantylamino) ethyl)piperazine, adafenoxate, (1 R,3S)-3 -(I -adamantyl)- 1- aminomethyl-3,4-dihydro-5,6-dihydroxy- 1 H-2-benzopyran, adamantylamide L-Ala-L-isoGlu, 2-adamantylamino-benzoic acid, N(alpha)-(1- adamantanesulphonyl)-N-(4-carboxybenzoyl)-L-lysyl-alanyl-L-valinal, 4- acylamino- 1 -aza-adamantane, L-leucy l-D-methionyl-glucyl-N-(2-adamantyl)- L-phenylalanylamide, Tyr-(D)-Met-Gly-Phe-adamantane, l-N-(p- bromobenzoyl)methyladamantylamine, 4-butyl- 1 ,2-dihydro-5-(( 1 - adamantanecarbonyl)oxy) - 1 ,2-diphenyl-3H-pyrazol-3-one, N(alpha)-( 1 - adamantanesulphonyl)-N(epsilon)-succinyl-L-lysyl-L-prolyl-L-valinal, and the amantadine salt of N-acetyl-DL-phenylalanine.

Amantadine analogs also include (2-hydroxy-adamantan-2-yl)-acetic acid ethyl ester, (2-methyl-adamantan-2-yloxy)-acetic acid, (2-piperidin-l-yl- adamantan-2-yl)-methylamine, (4-adamantan- 1 -yl)-thiazol-2-ylamine, (4- adamantan- 1 -y l-phenoxy)-acetic acid (4-tricyclo[3.3.1.13 ,7]decan- 1 -y 1- phenoxy-acetic acid), (adamantan-l-ylmethoxy)-acetic acid, (adamantan-1- yloxy)-acetic acid, (adamantan-l-ylsulfanyl)-acetic acid,

(tricyclo[3.3.1.13,7]decan-l-carbonyl-3-aminophenyl-amide), [3-(3,4-dimethyl- phenyl)-adamantan- 1 -yl]-methylamine, 1 -( 1 -adamanty l)ethyl(2-nitro-5- piperazinophenyl)amine, 1 -( 1 -adamantyl)ethyl(5-chloro-2-nitrophenyl)amine, 1 -( 1 -adamanty l)ethylamine hydrochloride, 1 -(4-hexahydro- 1 -pyrazinyl-3 - nitrophenylcarboxamido)-3,5-dimethyladamantane, 1 -(4-hexahydro- 1 - pyrazinyl-3 -nitrophenylcarboxamido)-adamantane, 1 ,3 -adamantanediacetic acid, 1,3-adamantanedicarboxamide, 1,3-adamantanedicarboxylic acid, 1,3- adamantanedimethanol, 1 ,3-dibromoadamantane, 1 ,3-dihydroxyadamantane (1,3-adamantanediol), 1,3-dimethyladamantane, 1,4-dibromoadamantane, 1-[1- (4-hexahy dro- 1 -pyrazinyl-3 -nitropheny lcarboxamido)-ethy 1] adamantane, 1 - acetamidoadamantane, l-adamantan-l-yl-2-methyl-propan-l-one, 1- adamantan- 1 -yl-2-phenyl-ethanone, 1 -adamantan- 1 -yl-3-methyl-butan- 1 -one, 1 - adamantan- 1 -y 1-3 -pheny 1-propan- 1 -one, 1 -adamantan- 1 -yl-butan- 1 -one, 1 - adamantan- 1 -yl-butan-2-one, 1 -adamantan- 1 -yl-propan- 1 -one, 1 -adamantan- 1 - yl-propan-2-one, 1-adamantanamine, 1-adamantanamine hydrochloride, 1- adamantanamine sulfate, 1 -adamantaneacetic acid, 1-adamantaneacetyl chloride, 1-adamantanecarbonitrile, 1-adamantanecarbonyl chloride, 1- adamantanecarboxamide, 1-adamantanecarboxylic acid, 1-adamantaneethanol, 1 -adamantanemethanol, 1-adamantanemethylamine, 1-adamantanol (1- hydroxyadamantane), 1 -adamanty 1 bromomethyl ketone, 1-adamantyl methyl ketone, l-amino-3-hydroxy-adamantane hydrochloride, 1-aminoadamantane sulfate (bis[l-aminotricyclo (3.3.1.1.3.7)decane]sulfate), l-bromo-3,5- dimethyladamantane, 1-bromoadamantane, l-chloro-3,5-dimethyladamantane, 1 -chloroadamantane, 1 -hydroxy-3,5-dimethyladamantane, 1 -hydroxy-3-amino- 5,7-dimethyladamantane hydrochloride, l-hydroxy-3-nitro-5,7- dimethyladamantane, 1-isocyanato-adamantane (1-isocyanato- tricyclo[3.3.1.13,7]decane), 1 -nitro-3,5-dimethyladamantane, 2-( 1 -adamantyl)- 4,5-dichloropyridazin-3(2H)-one (4,5-dichloro-2- tricyclo[3.3.1.13,7]decan- 1 - yl-2h-pyridazin-3-one), 2-( 1 -adamantyl)-5-(chloromethyl)- 1 ,3-thiazole (5- chloromethyl-2-tricyclo[3.3.1.13,7]decan- 1 -yl-thiazole), 2-(4-hexahydro- 1 - pyrazinyl-3-nitrophenylcarboxamido)-adamantane, 2-(adamantan- 1 -ylamino)- ethanol (2-(tricyclo[3.3.1.13,7]decan-l-yl amino)-ethanol), 2-(adamantan-l- ylthio)-ethanamine (2-(tricyclo[3.3.1.13,7]decan- 1 -ylsulfanyl)-ethylamine), 2- (adamantan-2-ylamino)-ethanol, 2-[(adamantan- 1 -ylmethyl)-amino]-ethanol hydrochloride, 2-adamantan-l-yl-ethylamine, 2-adamantanamine

hydrochloride, 2-adamantanol, 2-adamantanone (2-hydroxyadamantane), 2- adamantanone oxime, 2-aminoadamantane hydrochloride (2-adamantanamine HCl), 2-bromoadamantane, 2-ethyl-2-adamantanol, 2-methyl-2-adamantanol, 2- methyl-2-adamantyl acrylate, 2-piperidin-l-yl-adamantane-2-carbonitrile, 3- (3,4-dimethyl-phenyl)-adamantane-l-carboxylic acid, 3-(adamantan-l-yl)-3- oxo-propionitrile, 3-(adamantan-l-yl)-4-hydroxy-5-methoxy-benzoic acid, 3- (adamantan- 1 -ylsulfanyl)-[ 1 ,2,4]-thiadiazol-5-ylamine (3- (tricyclo[3.3.1.13 ,7]decan- 1 -ylsulfanyl)- 1 ,2,4-thiadiazol-5-ylamine), 3- (adamantan- 1 -ylsulfanyl)-propylamine, 3,5-dimethyl- 1 -adamantanol, 3- adamantan-l-yl-3-oxo-propionic acid ethyl ester (tricyclo[3.3.1.13,7]decane-l- propanoic acid, β-oxo-ethyl ester), 3-adamantan-l-yl-4-methoxy-benzoic acid (4-methoxy-3- tricyclo[3.3.1.13,7]decan -1-yl-benzoic acid), 3- hydroxyadamantane-1-carboxylic acid, 3-noradamantanecarboxylic acid, 4,4'- ( 1 ,3-adamantanediyl)diphenol, 4-adamantan- 1 -yl- 1 ,2,3 -thiadiazole (4- tricyclo[3.3.1.13 ,7]dec- 1 -yl- 1 ,2,3-thiadiazole), 4-adamantan- 1 -yl-2- aminophenol (2-amino-4- tricyclo[3.3.1.13,7]decan-l-yl-phenol), 4-adamantan- l-yl-5-ethyl-thiazol-2-ylamine, 4-adamantan- l-yl-5-isopropyl-thiazol-2- ylamine, 4-adamantan- 1 -yl-5-methyl-thiazol-2-ylamine, 4-adamantan- 1 -yl-5- phenyl-thiazol-2-ylamine, 4-aza-tricyclo[4.3.1.13,8]undecan-5-one, 4-aza- tricyclo[4.3.1.13,8]undecane, 5'- methylspiro[adamantan-2,2'-[l,3]-dioxane]5'- carboxylic acid, 5'-methylspiro[adamantan-2,2'-[l,3]-dioxane]-5'-amine, 5- adamantan-l-yl-[l,3,4]-oxadiazole-2-thiol (2-thiol-5- tricyclo[3.3.1.13,7]dec-l- yl-l,3,4-oxadizol), 5-adamantan-l-yl-2h-pyrazole-3-carboxylic acid methyl ester, 5-adamantan-l-yl-2-methoxy-benzoic acid (2-methoxy-5- tricyclo[3.3.1.13,7]decan -1-yl-benzoic acid), 5-adamantan-l-yl-2-methyl- furan-3-carboxylic acid (5- tricyclo[3.3.1.13,7]decan-l-yl-furan-3-carboxylic acid), 5-adamantan-l-yl-2-methyl-fυran-3-carboxylic acid methyl ester (5- tricyclo[3.3.1.13,7]decan-l-yl-fiiran-3-carboxylic acid methyl ester), 5- adamantan- 1 -yl-2-methyl-phenylamine (2-methyl-5- tricyclo[3.3.1.13,7]decan- 1 -yl-phenylamine), 5-adamantan-l-yl-3-ethyl-isoxazole-4-carboxylic acid, 5- adamantan- 1 -yl-3-methyl-isoxazole-4-carboxylic acid, 5-adamantan- 1 -yl-furan- 2-carboxylic acid (5- tricyclo[3.3.1.13,7]decan-l-yl-furan-2-carboxylic acid), 5- adamantan-l-yl-furan-2-carboxylic acid methyl ester (5- tricyclo[3.3.1.13,7]decan-l-yl-furan-2-carboxylic acid methyl ester), 5-chloro- 2-nitrophenyl(adamantan-2-yl)amine, 5-hydroxy-2-adamantanone, adamantan- 1-yl-methylamine, adamantan-2-ylidene-acetonitrile, adamantane, adamantane- 1 -carbonyl isothiocyanate (tricyclo[3.3.1.13,7]decane- 1 -carbonyl

isothiocyanate), adamantane- 1-carbothioic acid amide

(tricyclo[3.3.1.13,7]decane-l-carbothioic acid amide), adamantane- 1 -carboxylic acid (3-amino-phenyl)-amide, adamantane- 1 -carboxylic acid (4-amino-2- methoxy-phenyl)-amide (tricyclo[3.3.1.13 ,7]decan- 1 -carbonyl-2-methoxy-3- aminophenyl-amide), adamantane- 1 -carboxylic acid (4-amino-phenyl)-amide (tricyclo[3.3.1.13 ,7]decan- 1 -carbonyl-4-aminophenyl-amide), adamantane- 1 - sulfinyl chloride, congressane, dimethyl 1,3-adamantanedicarboxylate, dimethyl- 1, 3 -adamantanedicarboxylate, ethyl 1 -adamantanecarboxylate, methyl 1-adamantanecarboxylate, N-(l-adamantyl)ethylenediamine, N-(I- adamantyl)urea, N-(2-adamantyl)-N-(4-bromophenyl)amine, N-(adamantan-2- yl)-N-(2-chloro-ethyl)-amine hydrochloride, N-2-(5-hexahydro-l-pyrazinyl-2- nitrophenyl)adamantan-2-yl-amine, N-adamantan- 1 -oy 1-piperazine, N- adamantan- 1 -yl-2-amino-benzamide (2-amino-N- tricyclo[3.3.1.13 ,7]decan- 1 - yl-benzamide), N-formyl- l-amino-3,5-dimethyladamantane, N-methyl- (adamantan- 1 -yl)methylamine, and p-(l-adamantyl)phenol.

T-705

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an inhibitor of viral polymerase and has been found to have potent inhibitory activity against influenza A, B, and C. Studies have suggested that host cell kinases convert T- 705 into the active form T-705 ribofuranosyl triphosphate (T-705 RTP), which inhibits viral polymerase without affecting host cellular RNA or DNA synthesis. T-705 can be administered orally. The structure of T-705 is given below:

Antibacterial agents

Antibacterial agents, also known as antibiotics, are substances that can kill or inhibit the growth of bacteria. Exemplary antibacterial agents include amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin or cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin, vancomycin, azithromycin, clarithromycin,, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,

moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,

sparfloxacin, mafenide, prontosil (archaic), sulfacetamide, sulfamethizole, sulfanamide (archaic), sulfasalazine, sulfϊsoxazole, trimethoprim,

trimethoprim-sulfamethoxazole (co-trimoxazole) (TMP-SMX), demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin,, nitrofurantoin, platensimycin, pyrazinamide,

quinupristin/dalfopristin, rifampicin (rifampin in the U.S.), thiamphenicol, and tinidazole.

Doxycycline

Doxycycline is a member of the tetracycline antibiotics group and can be used to treat a number of bacterial infections. Doxycycline was developed by Pfizer and is available commercially under the trade name Vibramycin. The chemical synthesis of doxycycline has been described in Science 308:395, 2005. The structure of doxycycline is given below:

Combinations

The invention includes the individual combination of each vitamin E compound with each antiviral or antibacterial agent provided herein as if each combination were explicitly stated. In a particular example, the vitamin E is α- tocopherol and the antiviral agent is oseltamivir. In another example, the combination comprises γ-tocotrienol, oseltamivir, and amantadine. In another example, the combination comprises α-tocopherol and doxycycline. In another example, the combination comprises a mixture of the compounds shown in (III). Formulation of pharmaceutical compositions

The compositions, methods, and kits of the invention can include formulation(s) of compound(s) that, upon administration to a subject, result in a concentration of the compound(s) that treats a viral or bacterial infection. The compound(s) may be contained in any appropriate amount in any suitable carrier substance, and are generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously or intramuscularly), rectal, determatological, cutaneous, nasal, vaginal, inhalant, skin (patch), ocular, intrathecal, or intracranial administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Pharmaceutical compositions according to the invention or used in the methods of the invention may be formulated to release the active compound immediately upon administration or at any predetermined time or time period after administration. The latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (ii) formulations that after a

predetermined lag time create substantially constant concentrations of the agent(s) of the invention within the body over an extended period of time; (iii) formulations that sustain the agent(s) action during a predetermined time period by maintaining a relatively constant, effective level of the agent(s) in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the agent(s) (sawtooth kinetic pattern); (iv) formulations that localize action of agent(s), e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; (v) formulations that achieve convenience of dosing, e.g., administering the composition once per week or once every two weeks; and (vi) formulations that target the action of the agent(s) by using carriers or chemical derivatives to deliver the combination to a particular target cell type. Administration of compound(s) in the form of a controlled release formulation is especially preferred for compounds having a narrow absorption window in the gastrointestinal tract or a relatively short biological half-life.

Any of a number of strategies can be pursued in order to obtain controlled release in which the rate of release outweighs the rate of metabolism of the compound in question. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Thus, the compound(s) are formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the

compound(s) in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, molecular complexes, microspheres, nanoparticles, patches, and liposomes.

Delivery of compound(s)

It is not intended that administration of compounds be limited to a single formulation and delivery method for all compounds of a combination. The combination can be administered using separate formulations and/or delivery methods for each compound of the combination using, for example, any of the above-described formulations and methods. In one example, a first agent is delivered orally, and a second agent is delivered intravenously. Dosages

The dosage of a compound or a combination of compounds depends on several factors, including: the administration method, the type of viral infection to be treated, the severity of the infection, whether dosage is designed to treat or prevent a viral infection, and the age, weight, and health of the patient to be treated.

The recommended dosage of a compound may be determined by dietary reference intakes (DRI) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies. DRIs are reference values used to plan and assess nutrient intakes of health people. One type of DRI, the recommended dietary allowance (RDA), is the average daily intake of the amount of a substance sufficient to meet the nutrient requirements of nearly all (98-99%) healthy people. Another type of DRI, the tolerable upper intake level (UL), is the maximum daily intake of a substance that is unlikely to cause adverse health effects.

Table 4 lists the (RDAs) for alpha-tocopherol in milligrams (mg) and in international units (IU) of the natural form. An IU is a unit of measurement for the amount of a substance, wherein one IU of the substance is defined as a specified mass of a given form of the substance. For example, 1 IU of alpha- tocopherol is equal to 2/3 mg of natural alpha-tocopherol or to 0.45 mg of synthetic alpha-tocopherol. Therefore, 15 mg of natural alpha-tocopherol is equal to 22.4 IU. The corresponding IU for 15 mg of synthetic alpha- tocopherol is 33.3 IU.

Table 4

Table 5 lists ULs for vitamin E based on their potential to cause hemorrhagic effects. The ULs apply to all forms of supplemental alpha- tocopherol, including the stereoisomers present in synthetic vitamin E. Doses of up to 1,000 mg/day (1,500 IU/day of the natural form or 1,100 IU/day of the synthetic form) in adults appear to be safe, although the data are limited and based on small groups of people taking at least 2,000 IU for a few weeks or months. Long-term intakes above the UL increase the risk of adverse health effects. Vitamin E ULs for infants have not been established.

Table 5

In some embodiments of the invention, it may be desirable to administer the compounds at doses higher or lower than a standard dosing. For example, alpha-tocopherol may be administered at doses that are 100%, 200%, 500%, or 1000% of RDA. The RDA values for tocotrienols, tocomonoenols, tocodienols and their derivatives have not yet been established.

For combinations that include an antiviral agent or an antibacterial agent in addition to a compound(s) identified herein, the recommended dosage for the antiviral agent is can be less than or equal to the recommended dose as given in the Physician 's Desk Reference, 60^l Edition (2006). In other cases, the dosage of the compound(s), antiviral agent(s), or antibacterial agent(s) may be higher than the recommended dose.

As described above, the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably

performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied. The correct dosage of a compound can be determined by examining the efficacy of the compound in viral replication assays, as well as its toxicity in humans.

An agent is usually given by the same route of administration that is known to be effective for delivering it as a monotherapy. For example, when used in combination therapy an agent is dosed in amounts and frequencies equivalent to or less than those that result in its effective monotherapeutic use.

A combination described herein may be administered to the patient in a single dose or in multiple doses. Components of the combination may be administered separately or together, and by the same or different routes. In addition, various components of the combination may be administered at the same or different times. When multiple doses are administered, the doses may be separated from one another by, for example, one, two, three, four, or five days; one or two weeks; or one month. For example, the combination may be administered once a week for, e.g., 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more weeks. Both the frequency of dosing and length of treatment may be different for each compound of the combination. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. For example, the dosage of the combination, or components thereof, can be increased if the lower dose does not sufficiently treat the viral or bacterial infection. Conversely, the dosage of the combination can be decreased if the infection is cleared from the patient.

In other embodiments, agents, either as monotherapies in combination with other agents can be administered at higher dosages than the recommended dosage.

Example 1

Activity of tocopherols, tocotrienols and combinations thereof against adenovirus

Selected compounds were tested in a cell-based antiviral adenovirus assay. First, the compounds were dissolved in DMSO to obtain 1000-fold stock solutions (100 μM). A dilution plate was prepared by performing a two-fold serial dilution from the stock solution into assay medium for each compound in quadruplicate. A total of nine dilutions were tested in quadruplicate. A typical layout of a microtiter plate used for testing is shown in Figure IA.

For the antiviral assay, 15,000 A549 lung cells were plated in virus growth medium (F 12 + 2 % FBS) in clear plates to obtain 80-90 % confluency on the day of infection (dθ). On dθ, the compounds were diluted 250 times in virus growth medium (VGM) in the dilution plate and subsequently 25 μl was transferred to the assay plate. 25 μl of VGM was added and the cells were pre- incubated with the compounds for 2 hours. After the pre-incubation, a virus working solution of 300 pfu/ml of adenovirus 4 (ATCC) was prepared in VGM. 50 μl of virus working dilution was added to each well and the plate was incubated for 8 days. Plates were subsequently microscopically observed for complete lysis of the cells in the virus control (virus control = cells treated with DMSO only) before staining with crystal violet. Absorbance was measured at 530nm.

In parallel with the antiviral assay, cells were plated on white plates to perform a cytotoxicity assay. Briefly, the cells were pre-treated with

compounds as in the antiviral assay described above, except that after 2 hours the wells are topped off with 50 μl of VGM instead of virus working dilution. After 8 days of incubation, the cells were washed with PBS and lOOμl of CeIl- Titer Glow (Promega) reagent was added. Luminescence was quantified by an Envision plate reader.

The activities (IC50, CC50, and TI) of selected compounds against adenovirus 4 are given in Table 6, which shows that alpha tocopherol and alpha tocotrienol inhibit adenovirus replication at low nanomolar IC50 and high micromolar CC50. Zalcitabine was run in parallel as a positive control for antiviral activity.

Table 6

The order of antiviral activity was confirmed as: α- tocotrienol > α- tocopherol > tocotrienol/tocopherol mix > δ-tocotrienol, wherein α-tocotrienol is the most active compound over the broadest range of concentrations, α- tocopherol showed similar activity to the tocotrienol/tocopherol mix, whereas δ-tocotrienol was about 20-40 times less active. All tested compounds reached practical levels of total virus inhibition at concentrations that are not toxic to the cells. The order of toxicity was confirmed as: α-tocopherol >=

tocotrienol/tocopherol mix > δ-tocotrienol >= α-tocotrienol, wherein α- tocopherol was the least toxic compound. Finally, the therapeutic indices (TI) followed the activities of the compounds: α-tocotrienol > α-tocopherol > tocotrienol/tocopherol mix > δ-tocotrienol, wherein α-tocotrienol had the highest TI.

Example 2

Enhancement of anti-influenza activity of oseltamivir in the presence of α- tocotrienol and δ-tocotrienol

To identify the activity of tocotrienols against influenza infection, we measured time-of-mortality and survival in a mouse model of influenza infection.

C57/BL6 mice were infected intranasally with 10 TCID50 of Influenza A/NWS/33 (HlNl) virus under light anaesthesia. Twenty four hours after infection, the mice were treated with vehicle-0.5% extracted olive oil (group 1 : control vehicle group), oseltamivir 10mg/kg (group 2), oseltamivir 10mg/kg + α-tocotrienol 300mg/kg (group 3), oseltamivir 10mg/kg + γ-tocotrienol 300mg/kg (Group 4), oseltamivir lOmg/kg + δ-tocotrienol 300mg/kg (Group 5), or oseltamivir 10mg/kg + a mixture of tocotrienols 300mg/kg (Group 6). Animals were observed for mortality and body weight changes daily during the length of the experiment. The results are given in Table 7:

Table 7

The above data shows that alpha-tocotrienol, delta-tocotrienol, and a mixture thereof increases the efficacy of oseltamivir in improving the survival rate of mice after a high titer of influenza infection. Oseltamivir alone resulted in a 40% survival rate at 16 days post-influenza infection in mice. The combination of alpha-tocotrienol or delta tocotrienol with oseltamivir increased the survival rate at 16 days post-influenza infection to 60%. When the mixture of tocotrienols was used, the survival rate at 16 days post- influenza infection was 60%.

Example 3

Antiviral activity of a tocotrienol mix and δ-tocotrienol on influenza infection

C57/BL6 mice were infected intranasally with 10⁴⁰ TCID50 of Influenza A/NWS/33 (HlNl) virus under light anaesthesia. Twenty four hours after infection, the mice were treated with vehicle-0.5% extracted olive oil (group 1 : control vehicle group), oseltamivir 10mg/kg (group 2), α-tocotrienol 300mg/kg (group 3), δ-tocotrienol 300mg/kg (Group 4), or a mixture of tocotrienols 300mg/kg (Group 5). Animals were observed for mortality and body weight changes daily during the length of the experiment. As shown in Table 8, there was improvement in time-of-mortality and survival of the animals in the δ-tocotrienol treated group and the mixture treated group relative to the vehicle treated group.

Table 8

Example 4

Activity of tocopherols, tocotrienols and combinations thereof against

Wolbachia

Activity was assayed in C6/36 cells stably infected with Wolbachia. Cells were plated into 96-well microtiter plates and incubated with a compound added at the beginning of the experiment. Cells were incubated for 9 days in the presence of the compound. At the end of the incubation period, cells are washed and lysed. DNA was extracted from the cells and the quantity of intracellular bacteria in each extract was assayed in a qPCR assay for bacterial 16S ribosomal RNA. Cell toxicity of compounds was assayed in a cell titer glow assay. Figure 2 shows the percentage inhibition of Wolbachia treated with vitamin E compounds.

Other Embodiments

All patents, patent applications, and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent, patent application, or publication was specifically and individually indicated to be incorporated by reference.

Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the fields of molecular biology, medicine, immunology, pharmacology, virology, or related fields are intended to be within the scope of the invention.

Other embodiments are in the claims.

What is claimed is:

Claims

1. A composition comprising:

(a) one or more vitamin E compounds having the formula Ia, Ib, Ic, or Id

wherein:

each vitamin E compound contains 40 or fewer carbon atoms;

R₁ - R₁₀ are independently:

H; CH3; (CH₂)_nCH₃ wherein n is any integer from 1 to 20; X; OH; NH₂; NH₃ ⁺X-; COOH; COO^"M⁺ wherein M⁺ is any alkali metal cation;

, wherein the alkyl chain is fully saturated;

, wherein n may be any integer from 1 to

O (CH₂CH₂O^H, wherein n can be any integer from 1 to 100; O (CH(CH₃)CH₂O)₇₇H, wherein n can be any integer from 1 to 100; or

OC(O)R₁₂;

X is F, Cl, Br, or I;

Y is O, NR_n, or S;

Ri i is H or a linear or branched alkyl or aryl group containing 1 to 10 carbon atoms that is saturated or unsaturated; and

R₁₂ is:

COOH or (CH₂)_^COOH, where n is any integer from 1 to 10, or any salt or alkoxy derivative thereof, including CH₂CH₂C(O)O(CH₂CH₂O)_7nH wherein m is any integer from 1 to 100; CH₂CH₂C(O)O(CH(CH₃)CH₂O)_7nH wherein m is any integer from 1 to 100; or any amino ester derivative or a salt thereof, including CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NH₃ ⁺X^",

CH₂NH₂CH₃ ⁺X^", CH₂NH(CHs)₂ ⁺X^", and CH₂N(CH₃)₃ ⁺X^"; and

(b) an antiviral agent or an antibacterial agent.

2. The composition of claim 1, wherein at least one vitamin E compound is α- tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β- tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ- tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ- tocotrienol, desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl- tocodienol, or desmethyl-tocotrienol.

3. The composition of claim 2, wherein at least one vitamin E compound is a d-stereoisomer thereof.

4. The composition of claim 1, wherein at least one vitamin E compound is naturally occurring.

5. The composition of claim 1, wherein at least one vitamin E compound is synthetic.

6. The composition of claim 1, wherein said antiviral agent is oseltamivir, zanamivir, peramivir, or an analog thereof.

7. The composition of claim 1, further comprising an additional antiviral agent.

8. The composition of claim 7, wherein said additional antiviral agent is amantadine, rimantadine, T-705, or an analog thereof.

9. The composition of claim 7, further comprising one or more additional antiviral agents.

10. The composition of claim 1, wherein said antibacterial agent is

doxycycline.

11. The composition of claim 1, wherein said vitamin E compounds and said antiviral agent are present in amounts that together are effective to treat or prevent a viral infection.

12. The composition of claim 11, wherein said viral infection is caused by an adenovirus or an influenza virus.

13. The composition of claim 12, wherein said influenza virus is a type A influenza virus.

14. The composition of claim 12, wherein said influenza virus is a type B influenza virus.

15. The composition of claim 12, wherein said influenza virus is a type C influenza virus.

16. The composition of claim 13, wherein said influenza virus is a subtype HlNl influenza virus.

17. The composition of claim 12, wherein said viral infection is influenza-like illness, pneumonia, a multi-organ infection in an immunocompromised transplant patient, a multi-organ infection in an chronic obstructive pulmonary disease (COPD) patient, or a multi-organ infection in an asthma patient.

18. The composition of claim 12, wherein said viral infection is acute respiratory disease (ARD), pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, follicular conjunctivitis, pneumonia, pertussis-like syndrome, acute hemorrhagic cystitis, acute infantile gastroenteritis, an adenoviral infections in an immunocompromised host, intussusception, meningitis, obesity, adenovirus hepatitis, or encephalitis.

19. The composition of claim 1, wherein said vitamin E compounds and said antibacterial agent are present in amounts that together are effective to treat or prevent a bacterial infection.

20. The composition of claim 20, wherein said bacterial infection is caused by Chlamydia or Wolbachia.

21. The composition of claim 20, wherein said bacterial infection is onchocerciasis or elephantiasis.

22. The composition of claim 1, wherein said composition is formulated for oral or systemic administration.

23. The composition of claim 1, wherein said composition consists of one or more pharmaceutically acceptable excipients and active ingredients, wherein said active ingredients consist of said vitamin E compounds and said antiviral agent or antibacterial agent.

24. The composition of claim 7, wherein said composition consists of one or more pharmaceutically acceptable excipients and active ingredients, wherein said active ingredients consist of said vitamin E compounds, said antiviral agent, and said additional antiviral agent.

25. A method for treating or preventing a viral or bacterial infection in a patient, said method comprising administering to said patient one or more vitamin E compounds having the formula Ia, Ib, Ic or Id in an amount that is sufficient to treat or prevent said infection in said patient, wherein each vitamin E compound contains 40 or fewer carbon atoms.

26. The method of claim 25, wherein at least one vitamin E compound is α- tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β- tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ- tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ- tocotrienol, desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl- tocodienol, or desmethyl-tocotrienol.

27. The method of claim 26, wherein at least one vitamin E compound is a d- stereoisomer thereof.

28. The method of claim 27, wherein at least one vitamin E compound is naturally occurring.

29. The method of claim 28, wherein at least one vitamin E compound is synthetic.

30. The method of claim 25, further comprising administering to said patient an antiviral agent or an antibacterial agent.

31. The method of claim 30, wherein said antiviral agent is oseltamivir, zanamivir, peramivir, or an analog thereof.

32. The method of claim 30, wherein said antibacterial agent is doxycycline or an analog thereof.

33. The method of claim 30, further comprising administering to said patient an additional antiviral agent or antibacterial agent.

34. The method of claim 33, wherein said additional antiviral agent is amantadine, rimantadine, T-705, or an analog thereof.

35. The method of claim 25, wherein said viral infection is caused by an adenovirus or an influenza virus.

36. The method of claim 35, wherein said influenza virus is a type A influenza virus.

37. The method of claim 35, wherein said influenza virus is a type B influenza virus.

38. The method of claim 35, wherein said influenza virus is a type C influenza virus.

39. The method of claim 36, wherein said influenza virus is a subtype HlNl influenza virus.

40. The method of claim 35, wherein said viral infection is influenza-like illness, pneumonia, a multi-organ infection in an immunocompromised transplant patient, a multi-organ infection in an chronic obstructive pulmonary disease (COPD) patient, or a multi-organ infection in an asthma patient.

41. The method of claim 35, wherein said viral infection is acute respiratory disease (ARD), pharyngitis, pharyngoconjunctival fever, epidemic

keratoconjunctivitis, follicular conjunctivitis, pneumonia, pertussis-like syndrome, acute hemorrhagic cystitis, acute infantile gastroenteritis, an adenoviral infections in an immunocompromised host, intussusception, meningitis, obesity, adenovirus hepatitis, or encephalitis.

42. The method of claim 25, wherein said bacterial infection is caused by Chlamydia or Wolbachia.

43. The method of claim 25, wherein said bacterial infection is onchocerciasis or elephantiasis.

44. The method of claim 25, wherein said administration is oral or systemic.

45. The method of claim 30, wherein said vitamin E compound(s) and said antiviral agent or antibacterial agent are administered within 7 days of each other.

46. The method of claim 30, wherein said vitamin E compound(s) and said antiviral agent or antibacterial agent are administered within 1 day of each other.

47. The method of claim 30, wherein vitamin E compound(s) and said antiviral agent or antibacterial agent are administered within 1 hour of each other.

48. The method of claim 30, wherein vitamin E compound(s) and said antiviral agent or antibacterial agent are administered substantially simultaneously.

49. A kit comprising:

(a) one or more compounds having the formula Ia, Ib, Ic or Id, wherein each compound contains 40 or fewer carbon atoms; and

(b) instructions for administering (a) to a patient for treating or

preventing a viral or bacterial infection.

50. A kit comprising:

(b) instructions for administering (a) with at least one antiviral agent to a patient for treating or preventing a viral infection.

51. A kit comprising:

(b) instructions for administering (a) with at least one antibacterial agent to a patient for treating or preventing a bacterial infection.

52. A kit comprising:

(a) one or more compounds having the formula Ia, Ib, Ic or Id, wherein each compound contains 40 or fewer carbon atoms;

(b) an antiviral or antibacterial agent; and

(c) instructions for administering (a) and (b) to a patient for treating or preventing a viral or bacterial infection.

53. A kit comprising:

(b) an antiviral agent;

(c) amantadine, rimantadine, or T-705; and

(d) instructions for administering (a), (b), and (c) to a patient for treating or preventing a viral infection.

54. A kit comprising:

(a) one or more compounds having the formula Ia, Ib, Ic or Id, wherein each compound contains 40 or fewer carbon atoms; (b) an antiviral agent; and

(c) instructions for administering (a) and (b) with amantadine, rimantadine, or T-705 to a patient for treating or preventing a viral infection.