WO1994025038A1 - Use of rifamycin derivatives for the manufacture of a medicament for the treatment of toxoplasmosis - Google Patents

Use of rifamycin derivatives for the manufacture of a medicament for the treatment of toxoplasmosis Download PDF

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WO1994025038A1
WO1994025038A1 PCT/US1994/004765 US9404765W WO9425038A1 WO 1994025038 A1 WO1994025038 A1 WO 1994025038A1 US 9404765 W US9404765 W US 9404765W WO 9425038 A1 WO9425038 A1 WO 9425038A1
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infection
rifabutin
spiropiperidyl
ring
combination
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PCT/US1994/004765
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English (en)
French (fr)
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Jack S. Remington
Fausto G. Araujo
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Palo Alto Medical Foundation
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Priority claimed from US08/203,539 external-priority patent/US5529994A/en
Application filed by Palo Alto Medical Foundation filed Critical Palo Alto Medical Foundation
Priority to AU69050/94A priority Critical patent/AU669300B2/en
Priority to EP94917283A priority patent/EP0648121B1/en
Priority to DE69400631T priority patent/DE69400631T2/de
Priority to JP6524580A priority patent/JPH07509003A/ja
Publication of WO1994025038A1 publication Critical patent/WO1994025038A1/en
Priority to NO950030A priority patent/NO950030D0/no
Priority to GR960403219T priority patent/GR3021828T3/el

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • This invention relates to the field of disease treatment and prophylaxis. More particularly it relates to the treatment and prophylaxis of Toxoplasma gondii infections. Description of the Background
  • Toxoplasmosis is caused by the parasitic protozoan, Toxoplasma gondii.
  • the disease In humans, the disease is traditionally associated with the developing fetus in whom it can cause severe neurological problems manifesting as hydrocephaly, mental retardation and/or blindness [1, 2].
  • the disease In healthy adults, the disease is typically mild, producing few if any symptoms.
  • immunocompromised adults however, the parasite can cause severe or even fatal disease [3, 4, 5].
  • the disease also occurs in other mammals and is a leading cause of spontaneous abortion in sheep.
  • the parasite itself is extremely widespread and is typically acquired through the ingestion of undercooked meat in which tissue cysts containing the parasite may reside. This form is highly infectious if the meat is not well cooked.
  • the parasite can be contracted through ingestion of foods contaminated with oocysts that are shed in the feces of infected cats.
  • the oocyst is the product of the complete sexual cycle.
  • the oocyst form is highly resistant to destruction by natural elements and can persist in the soil for more than one year after excretion by the cat.
  • serological studies indicate that about 10-50% of the population has had contact with the parasite, the prevalence depending on the geographic locales and ethnic group [21].
  • IgG and IgM to deduce whether the titers are due to a current infection or legacy of a past infection.
  • the factors contributing to the severity of disease in the developing fetus have been poorly understood.
  • the only well-established factor is that the time of initial infection of the mother relative to conception is critical: infection significantly before conception such that an effective immune response has been mounted by the mother, results in little if any fetal disease.
  • Infection immediately before or after conception i.e., in the first trimester of pregnancy results in severe disease for about 10-15% of fetuses [21].
  • toxoplasmosis has dramatically increased in a relatively new group of patients who are in some way immunodeficient as a result of post-transplantation therapy [5, 9, 10, 22], neoplastic disease [11, 12, 13, 22] or, most recently, acquired immunodeficiency syndrome (AIDS) [3, 4, 5].
  • AIDS acquired immunodeficiency syndrome
  • the parasite can cause a disseminated, potentially fatal form of the disease [5, 22, 27].
  • Typical AIDS patients with toxoplasmosis exhibit signs referable to the central nervous system as the first symptom of the disease (reviewed in [22]), as one of the tissues most affected by the parasite is the brain, where massive numbers of parasites and of tissue cysts can be found. Infection is not limited to the brain, however, and parasites and tissue cysts can be found throughout the body [11].
  • the typical routine for diagnosis includes serology, computed tomography, magnetic resonance imaging and/or brain biopsy [1, 15, 16]. Of these, the only definitive route to diagnosis is the brain biopsy as this enables the direct visualization of the parasite, using immuno-peroxidase staining [17].
  • toxoplasmosis results from a recrudescence of a previous latent (i.e., chronic) Toxoplasma infection.
  • patients at risk for the acute acquired infection such as the fetus of a previously uninfected pregnant woman or a previously uninfected organ transplant recipient who receives an organ from a sero positive (i.e., Toxoplasma-infected) donor.
  • Acute therapy refers to treatment during an acute phase of an infection. In certain severely immunocompromised patient groups, this is followed by secondary prophylaxis (also known as maintenance therapy), which may be given over the entire life of a patient.
  • Secondary prophylaxis also known as maintenance therapy
  • Primary prophylaxis refers to treatment given to prevent the infection from occurring.
  • Primary prophylaxis is often used in heart transplant recipients who are seronegative and who receive a heart from a seropositive donor.
  • Primary prophylaxis is also used in pregnant women to prevent transmission from the mother to the fetus; that is, treatment is intended to prevent the mother who acquired the acute infection during pregnancy from passing the parasite to her fetus, as well as to treat the fetus in utero.
  • Primary prophylaxis is also frequently used in AIDS patients to prevent activation of their latent (chronic) toxoplasma infections.
  • the course of treatment for toxoplasmosis in pregnant individuals is determined by the stage in pregnancy and whether the infection is acute or chronic.
  • the purpose of early treatment is to attempt to prevent transmission of the parasite to the fetus.
  • the fetus may be treated by treating the mother during gestation. If infection is acute, the antibiotic spiramycin may be administered but is of unproven efficacy.
  • More effective drugs such as pyrimethamine and sulfadiazine, especially when used in combination, are often used after the first trimester of pregnancy (pyrimethamine may be teratogenic) when the diagnosis of infection of the fetus has been established by prenatal diagnostic techniques. Otherwise this particular drug combination is generally not used during pregnancy because of the potential toxicity for the mother and for the developing fetus [21].
  • toxoplasmosis Treatment of toxoplasmosis in non-pregnant individuals is initiated and maintained with a drug regimen involving a combination of folate antagonists, such as pyrimethamine and sulfadiazine [1, 14]. If the disease is identified soon enough, treatment is reasonably effective in combatting the acute disease. However, due to poor tolerance of the drugs, especially of the sulfa compounds in AIDS patients, maintenance on the drug therapy is frequently not possible, and recrudescence of the infection is often observed (that is, the drug therapy reduces but does not eliminate the parasite infection).
  • folate antagonists such as pyrimethamine and sulfadiazine [1, 14].
  • Rifamycin compounds are macrocyclic antibiotics that have been shown to be useful in a number of selective therapeutic applications.
  • rifampin has the following structure:
  • rifampin was tested for effectiveness in treating toxoplasmosis and was shown to have no protective effect in mice challenged with a lethal inoculum of toxoplasma [18].
  • similar concentrations also inhibited growth of L- cells. Because the toxicity of rifampin for L-cells and its inhibition of Toxoplasma multiplication intracellularly in vitro occurred at the same concentration of the drug, it was reported [18] that rifampin was likely to inhibit Toxoplasma multiplication by its toxic effect on the L-cells.
  • rifamycin compounds are generally considered to be effective against a limited number of pathological organisms, generally Gram-positive bacteria (including mycobacteria, staphylococci, and streptococci) and some Gram-negative bacteria (e.g., Brucella. Chlamydia. Haemophilus. Legionella. and Neisseria spp); other Gram- negative bacteria (e.g., enterobacteria) are less sensitive, and spirochaetes and mycoplasma are known to be insensitive to treatment [19].
  • Gram-positive bacteria including mycobacteria, staphylococci, and streptococci
  • some Gram-negative bacteria e.g., Brucella. Chlamydia. Haemophilus. Legionella. and Neisseria spp
  • other Gram- negative bacteria e.g., enterobacteria
  • spirochaetes and mycoplasma are known to be insensitive to treatment [19].
  • Individual compounds within the rifamycin series
  • rifabutin which is a spiropiperidyl rifamycin derivative, has also primarily been used in treating mycobacterial infections, notably tuberculosis [20]. More recently it has been used for primary prophylaxis of Mycobacterium avium-intracellulare infections in patients with AIDS [25]. However, these uses have been directed to bacteria, not protozoans which are members of the animal kingdom).
  • Figure 1A is a graph showing survival of mice infected with T. gondii and treated with various concentrations of rifabutin (RTF).
  • Figure IB is a graph showing survival of mice following infection with cysts of the
  • Figure 2 is a graph showing survival of mice infected with T. gondii and treated with low concentrations of rifabutin (RIF) alone or in combination with sulfadiazine (SUL).
  • RIF rifabutin
  • SUL sulfadiazine
  • Figure 3 is a graph showing survival of mice infected with T. gondii and treated with moderate concentrations of rifabutin alone or in combination with sulfadiazine.
  • Figure 4 is a graph showing survival of mice infected with T. gondii and treated with high concentrations of rifabutin alone or in combination with sulfadiazine.
  • Figure 5 is a graph showing survival of mice infected with T. gondii and treated with rifabutin (RTF) alone or in combination with pyrimethamine (PYR).
  • Figure 6 is a graph showing survival of mice infected with T. gondii and treated with rifabutin (RTF) alone or in combination with clindamycin (CLINDA).
  • FIGs 7A and 7B depict survival of mice infected with T. gondii and treated with rifabutin (RTF) alone or in combination with atovaquone (ATO).
  • Figure 8 is a graph showing survival of mice infected with T. gondii and treated with rifabutin (RIF) alone or in combination with azithromycin (AZITHRO).
  • Figure 9 is a graph showing survival of mice infected with T. gondii and treated with rifabutin (RIF) alone or in combination with clarithromycinin (CLART).
  • RIF rifabutin
  • CLART clarithromycinin
  • Compounds of the invention are semi-synthetic derivatives of rifamycin S comprising a fused imidazole ring that includes carbons at positions 3 and 4 of the rifamycin ring, the carbon at position 2 of the imidazole ring also being a ring carbon at position 4 of a piperidine ring system, thereby forming a spiropiperidyl ring system.
  • the nitrogen atom of the piperidine ring is optionally substituted with a lower hydrocarbon substituent, typically containing from 1 to 8 (preferably 3-5) carbons, usually branched, and most preferably being an iso-butyl group.
  • hydrocarbon groups can be present at this location, such as methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, and iso-hexyl.
  • Unsaturated analogues of these saturated alkyl groups are also permitted.
  • R represents one of the indicated alkyl groups.
  • spiropiperidyl derivatives of rifamycin S are semi-synthetic molecules produced by modification of natural rifamycins produced by Nocardia mediterranei (also known as Streptomyces mediterranei). Mixtures of rifamycins A-E are generally produced in culture, but the proportion of the desired intermediate rifamycin B can be increased by the addition of sodium diethyl barbiturate in the growth medium. Rifamycin B is only an intermediate, since an aqueous oxygenated solutions spontaneously gives rise to other rifamycins, such as O and S.
  • Rifamycin S is the starting point for the production of a number of semi-synthetic rifamycins. These include the specific compound known by the name rifamycin (also referred to as rifamycin SV), which is obtained by mild reduction of rifamycin S. Other derivatives produced by modification of rifamycin S include rifamide and rifampicin (also called rifampin), the latter having a structure as shown in the background section above. Total synthesis of rifamycin S has also been reported. See, for example, H. Nagaoka, et aL, J. Am. Chem. Soc. 102:7962 (1980); H. Iio, et al., ibid.
  • rifabutin is (9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E,24Z)-6,16,18,20- tetrahydroxy- -isobutyl-14-methoxy-7,9, 15,17, 19,21,25-heptamethyl-spiro[9,4-(epoxypenta- decafl, 11, 13]trienimino)-2H-furo[2',3',7,8]naphth[l,2-d]imidazole-2,4'-piperidine]-5, 10,26- (3H,9H)-trione-16-acetate.
  • Compounds of the invention method are soluble in chloroform and methanol, sparingly soluble in ethanol, and slightly soluble in water.
  • the compounds can be prepared in standard pharmaceutical compositions of the same type used for other rifamycin compounds.
  • a composition for use in vivo generally will contain a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier either solid or liquid material, which may be inorganic or organic and of synthetic or natural origin, with which the active component of the composition is mixed or formulated to facilitate administration to a subject. Any other materials customarily employed in formulating pharmaceutical are suitable.
  • Solid carriers include natural and synthetic cloisonne silicates, for example natural silicates such as diatomaceous earths; magnesium silicates, for example talcs; magnesium aluminum silicates, for example attapulgites and vermiculites; aluminum silicates, for example kaolinites, montmorillonites, and micas; calcium carbonate; calcium sulfate; synthetic hydrated silicone oxides and synthetic calcium or aluminum silicates; elements such as carbon or sulfur; natural and synthetic resins such as polyvinyl alcohol; and waxes such as paraffin and beeswax.
  • suitable liquid carriers include water and aqueous solutions containing oxygenated organic compounds such as ethanol.
  • Buffers and other materials normally present in pharmaceutical preparations can also be present.
  • Pharmaceutical carriers differ from typical solutions and suspensions in that they are specifically prepared for use in vivo to exclude substances that may be harmful to the host to whom the composition is administered (e.g., removal of bacterial toxins).
  • rifabutin can be present at 150 mg per capsule in a gelatin capsule intended for oral administration.
  • the remainder of the capsule will contain, for example, as inactive ingredients, microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink.
  • compositions containing spiropiperidyl rifamycins have been indicated for other pharmaceutical uses, such as anti-mycobacterial indications, including tuberculosis.
  • the clinical pharmacology of these compounds is thus known.
  • rifabutin is readily absorbed from the gastrointestinal tract with mean ( ⁇ SD) peak plasma levels (C. ⁇ - of 375 ( ⁇ 267) mg/mL (range: 141 to 1033 mg/mL) attained in 3.3 ( ⁇ 0.9) hours (T ⁇ . range: two to four hours).
  • Plasma concentrations post-C ⁇ decline in an apparent bi-phasic manner.
  • the specific method of the present invention is directed to the treatment and/or prophylaxis of toxoplasmosis.
  • the dosage on the first day is directed to the treatment and/or prophylaxis of toxoplasmosis.
  • a loading dose is often but not necessarily higher than on succeeding days.
  • a typical loading dose would be 0.25-400 mg/kg/day (preferably 1-200, more preferably 2-200), with typical treatment dosages at half these values. These doses are in the range of normal doses for other rifamycin compounds. For prophylactic use, doses in the lower half of the normal range are used, generally without a loading dose.
  • spiropiperidyl rifamycins can be administered to humans as a single dose of about 300 mg per os ("po"; orally) once a day, generally at breakfast, or, if not tolerated in a single dose, can be divided into two doses of about 150 mg each with morning and evening meals.
  • the half-life in serum of rifabutin is 16 hours.
  • the drug is eliminated in part by the kidneys, with urine concentrations being about 100-fold higher than those in the plasma.
  • the drug also appears in the bile at a concentration similar to that in the urine.
  • the drug is taken up by all tissues and is especially concentrated in lungs, where levels reach 5-10 times higher than those in plasma.
  • Subjects to be treated include those acutely infected with Toxoplasma gondii and, for prophylactic use, those subjects who may in the future be exposed to the disease-causing organism or immunosuppressed patients with chronic toxoplasma infection to prevent recrudescence or relapse of the infection. In view of the widespread occurrence of the organism, this can include all immunocompromised individuals. Pregnant individuals, particularly previously uninfected pregnant women, comprise a preferred target population.
  • Sulfonamides comprise a well known group of antimicrobial agents that are mostly derivatives of sulfanilamide (p- aminobenzenesulfonamide). They halt or retard the growth of a wide range of Gram-positive and Gram-negative bacteria, as well as various protozoa (such as coccidia and Plasmodium spp). Sulfanilamides are often used in combination with other chemotherapeutic agents for treating urinary tract infections and various intestinal disorders.
  • Organisms which synthesize their own folic acid and which cannot use an exogenous supply of the vitamin are sensitive to sulfonamides provided that the cells are permeable to the drug. This is a result of the ability of sulfonamides to act as structural analogs of p- aminobenzoic acids (PABA). Sulfonamides competitively inhibit the incorporation of PABA during folic acid synthesis. Thus, the combinations in which they are most often used involve other folic acid antagonists. Organisms which require exogenous folic acid for growth are insensitive to sulfonamide treatment.
  • PABA p- aminobenzoic acids
  • sulfonamide drugs that differ in their clinical properties and toxicities. Most are derivatives bearing substituents at the nitrogen of the sulfonamide group (i.e., NH 2 C 6 H 4 SO 2 NHR, where R represents the substituent). Substitution at the p-amino group normally results in loss of antibacterial activity. However, such derivatives are often hydrolyzed in vivo to an active form and can therefore be administered in inactive form. For example, p-N-succinylsulfathiazole and phthalylsulfathiazole are inactive but are hydrolyzed in the lower intestine to release the active component sulfathiazole.
  • a number of active sulfonamides include, e.g., sulfacetamide (N-[4- aminophenyl)sulfonyl]-acetamide); sulfadiazine; sulfadimethoxine (4-amino-N-(2,6-dimethoxy-
  • the present inventors have discovered that in addition to the spiropiperidyl rifamycin compounds' synergistic interaction with sulfonamides, the spiropiperidyl rifamycin compounds also act synergistically as demonstrated herein with a number of antimicrobial compounds in the treatment of toxoplasmosis, including the antibacterials clindamycin, clarithromycin, and azithromycin; the anti-malarial drug pyrimethamine; and atovaquone.
  • synergestic interactions provide a further advantage within the general scope of the invention (treatment with spiropiperidyl rifamycins, whether or not in combination with other drugs) by providing certain synergestic effects when spiropiperidyl rifamycins are used in combination with selected other classes of drugs.
  • one embodiment of the invention is the use of spiropiperidyl rifamycin compounds in combination with lincosamides to achieve a synergestic effect.
  • Lincosamides comprise a well known group of antimicrobial agents that contain lincosamine (i.e., 6-amino- 6,8-dideoxyoctose). They halt or retard the growth of a range of Gram-positive and Gram- negative bacteria. There are many lincosamide drugs that differ in their clinical properties and toxicities.
  • Any lincosamide can be used in combination with rifabutin or other spiropiperidyl rifamycin compounds in the treatment or prevention of toxoplasmosis; preferred are those that further act synergistically as taught herein.
  • Active lincsoamides include lincomycin, its semisynthetic derivative clindamycin (7-chloro-7-deoxylincomycin), and celesticetin.
  • Other useful lincosamide derivatives include those that can be hydrolyzed in vivo to an active form and can therefore be administered in inactive form.
  • clindamycin palmitate HC1 is inactive in vitro, but rapid in vivo hydrolysis converts it to antibacterially active clindamycin.
  • Clindamycin phosphate, a water soluble ester of clindamycin and phosphoric acid is another preferred lincomycin derivative.
  • a number of individual compounds and classes of compounds act synergestically with spiropiperidyl rifamycin compounds.
  • spiropiperidyl rifamycin compounds act synergistically with pyrimethamine. Pyrimethamine is a folic acid antagonist effective against protozoans.
  • Spiropiperidyl rifamycin compounds also act synergistically with hydroxynaphthoquinones.
  • a preferred hydroxynaphthoquinone is atovaquone.
  • Other preferred hydroxynaphthoquinone antibiotics are those that have activity against T. gondii when used alone.
  • Spiropiperidyl rifamycin compounds act synergistically with azalides.
  • Preferred azalides are azithromycin and its derivatives. Other preferred azalide antibiotics are those that have activity against T. gondii when used alone. Spiropiperidyl rifamycin compounds further act synergistically with macrolide antibiotics. Preferred macrolides are clarithromycin and its derivatives. Other preferred macrolide antibiotics are those that have activity against T. gondii when used alone. Such preferred macrolides include roxithromycin and spiramycin.
  • Macrolides of the invention also include angolamycin, carbomycin, chalcomycin, cirramucin, erythromycin, lankomycin, leucomycin, megalomycin, methymycin, narbomycin, niddamycin, oleandomycin, relomycin, troleandomycin, tylosin, polyene antibiotics, and their active derivatives.
  • antimicrobial agents discussed herein may be natural (produced from natural or genetically engineered sources), semi-synthetic or wholly synthetic. As these are all known compounds, descriptions of synthesis can be found in the published scientific literature.
  • these drugs are used in combination with rifabutin or other spiropiperidyl rifamycin compounds as pharmaceuticals or to produce medicaments useful in the treatment or prevention of toxoplasmosis infection or toxoplasmosic encephalitis ("TE").
  • a pharmaceutical would comprise a therapuetically effective amount of rifabutin or other spiropiperidyl rifamycin compound in combination with a therapeutically effective amount of one or more of the drugs discussed herein as synergistically effective against toxoplasma.
  • these drugs can be used individually to produce medicaments that are then used in combination with rifabutin or other spiropiperidyl rifamycin compounds to treat or prevent toxoplasmosis infection or TE.
  • Combination medicaments or treatments comprise rifabutin or other spiropiperidyl rifamycin compounds with at least one other anti- toxoplasma compound as taught herein.
  • Pharmaceutical carriers, dosages, routes of administration, and treatment regimens are as previously discussed herein, although they can be effectively modified by a clinician, using as a guideline the dosages presented herein and dosages previously known for use in treatment of toxoplasmosis. Of course, because of the synergistic activity discovered herein, lower dosages than those previously reported are now available to the clinician or veterinarian.
  • the spiropiperidyl rifamycin compounds should also act synergistically with a number of antibiotic compounds in the treatment of toxoplasmosis including antivirals such as gamma interferon, compounds effective against T. gondii such as macrolides roxithromycin and spiramycin and tetracylines, e.g. minocycline, and their congeners, and other compounds effective against other protozoan-caused diseases.
  • antivirals such as gamma interferon
  • compounds effective against T. gondii such as macrolides roxithromycin and spiramycin and tetracylines, e.g. minocycline, and their congeners, and other compounds effective against other protozoan-caused diseases.
  • TE can be reduced in severity by administering to a host in need of treatment, either after infection or before exposure to a T.
  • a preferred compound for treatment is rifabutin.
  • TE can be reduced in severity by administering a therapeutically effective amount of a combination of a spiropiperidyl rifamycin compound with a drug discussed herein that enhances the effectiveness a spiropiperidyl rifamycin compound for treatment or prevention of toxoplasmosis.
  • Pharmaceutical carriers, dosages, routes of administration, and treatment regimens are as previously discussed herein for combination drug treatment of toxoplasmosis.
  • spiropiperidyl rifamycin derivatives are effective in the protection of a mammalian host, including an immunocompromised host, against infection with Toxoplasma gondii.
  • the compounds also demonstrate a synergistic effect in combination with other drugs, particularly with sulfonamides, and provide full protection in this model study against toxoplasmosis.
  • rifabutin alone is effective in the treatment of toxoplasma related diseases, and further that rifabutin acts synergistically in combination with other drugs. This adds significantly to the spectrum of drugs available for treating toxoplasmosis, thereby overcoming problems arising from parasite resistance and side effects of existing medications.
  • rifabutin was found to decrease the inflammatory response associated with toxoplasmic encephalitis (Example 8). Accordingly, the results presented herein provide for therapeutic and prophylactic methods that measurably add to the reliability of disease reduction in toxoplasma infections.
  • mice with disseminated acute toxoplasmosis due to infection with RH tachyzoites was enhanced significantly when rifabutin was used in combination with pyrimethamine, sulfadiazine, clindamycin, or atovaquone, as demonstrated in the Examples.
  • These drugs are preferred since they are either presently in use or are undergoing clinical trials for treatment of toxoplasmosis.
  • Azithromycin or clarithromycin in combination with rifabutin were also demonstrated in the Examples as enhancing the anti-7. gondii effect.
  • the present invention allows for effectively treating toxoplasmosis and toxoplasmic encephalitis in severely immunocompromised patients.
  • EXAMPLE 1 Activity of rifabutin against T. gondii in murine model of acute toxoplasmosis. An experiment was carried out to determine the in vivo protective activity of rifabutin against toxoplasmosis. The model used was a mouse model using Swiss Webster female mice weighing approximately 20 grams at the time of the experiment. The rifabutin used in the experiment was obtained commercially from Adria as a pharmacologically pure compound and was solubilized in phosphate buffered saline, pH 7.2, and then sonicated for four pulses of one minute each. The experiment was carried out on four groups of mice (3 experimental and one control) with 10 mice per group. The mice were infected with T.
  • gondii tachyzoites of the RH strain obtained from the peritoneal fluid of carrier mice according to published standard procedures for this model [26].
  • the peritoneal fluid was collected into Earle's balanced salt solution containing 10% fetal calf serum and 10 units of heparin/ml.
  • the preparation was then filtered through glass wool, centrifuged at 500 x g for 5 minutes at 4°C, and the sediment was resuspended and forced through a 27-gauge needle.
  • the organisms were quantified by counting on a Neubauer-Levy hemacytometer, and appropriate dilutions in Eagle's minimum essential medium (MEM) were made.
  • MEM Eagle's minimum essential medium
  • gondii is approximately one tachyzoite. Mice infected with our RH strain never survive with any living parasites. Thus, survivors in our studies had the organism eradicated by the therapy. Mice were infected with an intraperitoneal dose of 2.5 x 10 3 tachyzoites of the RH strain (a dose that normally results in death of 100% of normal mice by day 8 or 9). Beginning 24 hours after ip infection, one group of mice was treated with 50 mg/kg/day of rifabutin, a second with 100 mg/kg/day, and a third with 200 mg/kg/day administered orally by gavage for a period of ten days. Thereafter, mice were followed for an additional 20 days and the date of death noted. Mice dying during the experiment were examined for the presence of T. gondii in their peritoneal fluid for verification of the cause of death.
  • mice treated with doses of rifabutin of 100 mg/kg/day and higher As shown in Figure 1A, significant protection was noted in mice treated with doses of rifabutin of 100 mg/kg/day and higher. Administration of 200 mg/kg/day resulted in survival of 9 out of the 10 mice in that group for the entire 30-day test period. In the 100 mg/kg/day group, six mice were still alive 15 days after infection, while two survived the 30-day observation period. In contrast, all 10 of the control mice died within the expected 9-day period, and only 4 mice survived beyond 10 days in the 50 mg/kg/day group, with all of the latter dying within 14 days. Thus, the dose of 50 mg/kg/day resulted in significant prolongation of time to death as compared with untreated controls even though all of the mice eventually died.
  • mice infected ip with tachyzoites of the RH strain survived when treated with doses of 300 or 400 mg/kg/day rifabutin. Identical results were obtained when rifabutin was prepared by dissolution in phosphate buffered saline, pH 6.8, followed by sonication for 30 seconds.
  • rifabutin activity of different doses of rifabutin (RIF) in disseminated acute murine toxoplasmosis following ip infection with cysts of the C56 strain of T. gondii was also examined.
  • SW Swiss-Webster
  • Treatment was initiated 3 days after infection. Treatment was for 10 days.
  • Rifabutin was prepared by dissolution in phosphate buffered saline, pH 6.8, followed by sonication for 30 seconds. As shown in Figure IB, significant protection was obtained for mice treated with doses of rifabutin of 100 mg/kg/day and higher.
  • RH tachyzoites and C56 cysts were used in these experiments because of previous reports that demonstrated variation in susceptibility of different strains of T.gondii to different drugs [29].
  • the pathogenesis of the infection produced by inoculation of tachyzoites or cysts differ. Ip inoculation of RH tachyzoites results in a fulminant infection with large numbers of tachyzoites being produced in the peritoneal cavity.
  • One hundred percent mortality usually occurs within 5 to 8 days after infection with an inoculum as small as 10 2 organisms.
  • oral inoculation of cysts of the C56 strain results in an infection which progresses slower. Depending on the inoculum size, mortality does not occur until approximately 15 days of infection.
  • EXAMPLE 2 In vivo activity of rifabutin in combination with a sulfonamide against T. gondii in a murine model of acute toxoplasmosis. An experiment was carried out in the manner described for Example 1, but with the additional administration of a sulfonamide. Conditions were as described in the first example except for the following changes. Seven groups of mice (10 mice per group) were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of T. gondii and then given oral treatment by gavage with rifabutin beginning 24 hours after infection and continuing for 10 days. Sulfadiazine, sodium salt, was obtained from Sigma Chemical Co. or City Chem. Corp., New York, NY, and was administered ad libitum during the entire period of treatment in the drinking water at a concentration of 80 mg/liter to some groups as follows:
  • Group 3 Rifabutin alone, 200 mg/kg/day.
  • Group 4 Sulfadiazine alone at 80 mg/L.
  • Groups 1, 2 and 3 are similar to the three experimental groups discussed and set forth separately in Example 1 and Figure 1A. For the control group, see Example 1. Results of the experiment are set out in Figures 2-4. Figure 2 shows the results of treatment with low concentrations of rifabutin alone, sulfadiazine alone, or the combination of the two. The effect of sulfadiazine alone was slight, in that only one mouse survived beyond the 9-day period of survival for the control animals. This single mouse died by day 11.
  • mice were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of T. gondii. Treatment with rifabutin alone (50 or 100 mg/kg/day) or in combination with pyrimethamine (10 mg/kg/day) was initiated 24 hours after infection and continued for 10 days. Both drugs were administered orally by gavage as a single daily dose, wither alone or in combination. Test groups were as follows: Group 1 - Control
  • Group 2 Rifabutin alone, 50 mg/kg/day.
  • Group 3 Rifabutin alone, 100 mg/kg/day.
  • Group 5 - Rifabutin 50 mg/kg/day, plus pyrimethamine, 10 mg/kg/day.
  • Group 6 - Rifabutin 100 mg/kg/day, plus pyrimethamine, 10 mg/kg/day.
  • Clindamycin (hydrochloride salt, lot 627HJ, Upjohn Co., Kalamazoo, MI) was dissolved in sterile PBS and administered orally by gavage in a single daily dose of 25 or 50 mg/kg. Conditions were as described in the first example except for the following changes.
  • Four groups of mice (5 in the control group, 10 or 15 in the treatment groups as indicated in Figure 6) were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of 71 gondii RH strain.
  • Clindamycin is the drug most frequently used as an alternative to sulfonamides when side-effects develop during treatment with the pyrimethamine-sulfonamide combination [34, 35].
  • the combination of ineffective doses of rifabutin and clindamycin resulted in a synergistic and significant protection of mice with disseminated acute toxoplasmosis.
  • EXAMPLE 5 In vivo activity of rifabutin in combination with atovaquone against T. gondii in an acute model of murine toxoplasmosis. Experiments were carried out in the manner described for Examples 1 and 3, but with the additional administration of atovaquone instead of pyrimethamine.
  • a stock solution of atovaquone (lot 8810001-158, Burroughs- Welcome, Co.) was prepared in PBS and sonicated for 3 pulses of 30 seconds each.
  • Working solutions to provide a dose for each mouse of 5 or 10 mg/kg were prepared in 0.25% carboxymethyl-cellulose and sonicated again for one 30-second pulse just prior to administration by gavage.
  • Conditions were as described in the first example except for the following changes.
  • Four groups of mice (5 in the control group, 10 in the treatment groups as indicated in Figure 7A and 7B) were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of T. gondii RH strain.
  • rifabutin alone at 100 mg/kg/day or 50 mg/kg/day or in combination with atovaquone (ATO) at 5 mg/kg/day was initiated 24 hours after infection and continued for 10 days. Both drugs were administered orally by gavage as a single daily dose, either alone or in combination. Control mice were treated with the drug diluent only.
  • gondii in a murine model of acute toxoplasmosis Experiments were carried out in the manner described for Examples 1 and 3, but with the additional administration of azithromycin instead of pyrimethamine. Conditions were as described in the first example except for the following changes.
  • Four groups of adult Swiss-Webster female mice (5 in the control group, 5 or 10 in the treatment groups as indicated in Figure 8) were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of T. gondii RH strain.
  • Control mice were treated with drug diluent only.
  • mice treated with the combination survived at 30 days whereas none of the mice treated with either drug alone survived at 30 days.
  • EXAMPLE 7 In vivo activity of rifabutin in combination with clarithromycin against T. sot ⁇ dii in a murine model of acute toxoplasmosis. Experiments were carried out in the manner described for Examples 1 and 3, but with the additional administration of clarithromycin instead of pyrimethamine. Conditions were as described in the first example except for the following changes. Four groups of adult Swiss-Webster female mice (5 in the control group, 5 or 10 in the treatment groups as indicated in Figure 9) were infected by intraperitoneal injection of 2.5 x 10 3 tachyzoites of T.
  • gondii RH strain Treatment with 50 mg/kg of rifabutin (RIF) or 50 mg/kg of clarithromycin (CLARI) alone or in combination was administered using a feeding tube, was initiated 24 hours after infection and continued for 10 days. Control mice were treated with drug diluent only.
  • RIF rifabutin
  • CLARI clarithromycin
  • mice treated with the combination survived at 30 days whereas 20% of the mice treated with clarithromycin alone survived at 30 days.
  • EXAMPLE 8 In vivo activity of rifabutin against T. eondii in a murine model of toxoplasmic encephalitis ("TE").
  • Infected CBA mice were used 5 weeks following infection [37, 39]. Histopathological examination of brains of 3 mice euthanized at this time revealed extensive TE with profuse inflammatory infiltrates in the meninges, parenchyma and around small capillaries as well as large numbers of cysts of T. gondii.
  • Rifabutin was dissolved in phosphate buffered saline, pH 6.8, and sonicated for 30 seconds. Treatment with 200 mg/kg of rifabutin administered as a single daily oral dose by gavage was then initiated and continued for 30 days. Five treated and 5 control mice were euthanized by CO 2 narcosis 15 and 30 days after initiation of treatment and their brains collected for determination of number T. gondii cysts and for histopathologic examination as previously described [30, 32, 41].
  • Histopathology of brains of control mice 30 days after infection were compared with histopathology of brains of rifabutin treated mice 30 days after infection. Histopathology of brains of control mice treated with the diluent only revealed extensive inflammatory exudates in the meninges, parenchyma and around small capillaries as well as numerous cysts of T. gondii. Treatment of infected CBA mice with 200 mg/kg/day of rifabutin administered alone for 15 days did not significantly reduce the inflammatory response or numbers of T. gondii cysts in brains of the 5 treated mice as compared with controls.
  • rifabutin used alone is effective for treatment of the infection in the central nervous system. Since the numbers of T. gondii cysts in the brains of treated mice were not significantly reduced at the end of the therapy, these results may be due to a previously unreported, anti-inflammatory activity of rifabutin. Alternatively, rifabutin may act only against free parasites and/or against rapidly replicating parasites within cells. The drug may not be able to act against the slowly replicating bradyzoites protected within the cyst wall. However, the present invention is not limited by a particular mechanism of rifabutin action.
  • EXAMPLE 9 In vivo activity of rifabutin in combination with clindamycin against T. gondii in an immunocomprimised mammalian host. Treatment of a T. gondii infected, immunocomprimised mammalian host using rifabutin in combination with clindamycin was studied. Immunocompromised T- and B-cell deficient SCID ("severe combined immunodeficient") mice [44] were infected p.o. with cysts of the ME49 strain of T. gondii. ME49 cysts are less virulent than C56 cysts, and accordingly are more suitable for studies involving immunocompromised hosts. Clindamycin was dissolved in sterile PBS.

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AU69050/94A AU669300B2 (en) 1993-05-05 1994-04-29 Use of rifamycin derivatives for the manufacture of a medicament for the treatment of toxoplasmosis
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DE69400631T DE69400631T2 (de) 1993-05-05 1994-04-29 Verwendung von rifamycinderivaten zur herstellung eines arzneimittels zur behandlung der toxoplasmose
JP6524580A JPH07509003A (ja) 1993-05-05 1994-04-29 トキソプラスマ症（ｔｏｘｏｐｌａｓｍｏｓｉｓ）の治療のための薬剤の製造のためのリファマイシン（ｒｉｆａｍｙｃｉｎ）誘導体の使用
NO950030A NO950030D0 (no) 1993-05-05 1995-01-04 Anvendelse av Rifamycin-derivater for fremstilling av et medikament for behandling av toxoplasmose
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