WO2000013509A1 - Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique - Google Patents

Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique Download PDF

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Publication number
WO2000013509A1
WO2000013509A1 PCT/US1999/020451 US9920451W WO0013509A1 WO 2000013509 A1 WO2000013509 A1 WO 2000013509A1 US 9920451 W US9920451 W US 9920451W WO 0013509 A1 WO0013509 A1 WO 0013509A1
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Prior art keywords
risk
urologic
event
man
serum psa
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PCT/US1999/020451
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English (en)
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Elizabeth Stoner
Joanne Waldstreicher
Daniel Z. Wang
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Merck & Co., Inc.
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Priority to AU61373/99A priority Critical patent/AU6137399A/en
Publication of WO2000013509A1 publication Critical patent/WO2000013509A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/342—Prostate diseases, e.g. BPH, prostatitis

Definitions

  • Benign prostatic hyperplasia is common in older men, with symptoms that impact quality of life, including interference with activities and perception of well being. BPH can be progressive, with risk of BPH-related surgery, urinary retention, infections, bladder calculi and renal failure. Although many men with mild to moderate symptoms do well without intervention, bothersome symptoms and complications can progress in others, leading to medical therapy or surgery.
  • Acute urinary retention is a painful condition characterized by the inability to initiate voiding and empty the bladder. Acute urinary retention may be classified as either spontaneous or precipitated. Spontaneous acute urinary retention is often considered by patients to be the most serious outcome of BPH.
  • Spontaneous acute urinary retention is an episode of acute urinary retention that is due to BPH and is not tied to a precipitating event.
  • Precipitated acute urinary retention is an episode of acute urinary retention that is precipitated factors other than BPH; for example: anesthesia or surgery within 72 hours; a precipitating medical event such as stroke or congestive heart failure; a medical condition such as prostatitis or urinary tract infection; or ingestion of medication or drugs known to precipitate retention, e.g., pseudoephedrine hydrochloride, cold medicine, pain medication such as narcotics or sedatives, or benadryl.
  • a precipitating medical event such as stroke or congestive heart failure
  • a medical condition such as prostatitis or urinary tract infection
  • ingestion of medication or drugs known to precipitate retention e.g., pseudoephedrine hydrochloride, cold medicine, pain medication such as narcotics or sedatives, or benadryl.
  • Surgery for BPH includes balloon dilatation, microwave hyperthermia, laser prostatectomy, open prostatectomy, suprapubic prostatectomy, transurethral incision of the prostate (TULP), transurethral laser incision of the prostate (TULIP), transurethral microwave thermotherapy (TUMT), transurethral resection of the prostate (TURP), and video laser ablation of the prostate (VLAP).
  • TULP transurethral incision of the prostate
  • TULIP transurethral laser incision of the prostate
  • TUMT transurethral microwave thermotherapy
  • TURP transurethral resection of the prostate
  • VLAP video laser ablation of the prostate
  • Jacobsen J. Urology, vol. 158, pp. 481-487 (1997) demonstrated that patients with increased prostate volume had a higher risk of acute urinary retention. Jacobsen did not address the risk of BPH-related surgery.
  • the present invention is directed to a method for determining the risk for the development of urologic events, such as BPH-related surgery and acute urinary retention, by measuring serum prostate-specific antigen (PSA) levels.
  • PSA serum prostate-specific antigen
  • the present invention is also directed to a method of reducing the risk for the development of urologic events, such as BPH-related surgery and acute urinary retention, by administering an inhibitor of 5-alpha-reductase to a man determined to be at risk for the development of urologic events via the serum PSA risk reduction method.
  • Serum PSA is currently the most widely used marker for prostate cancer detection, and a yearly measurement is recommended in men over 50 years old to aid in the early detection of prostate cancer.
  • the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone (T) to the more potent androgen, 5cc-dihydrotestosterone ("dihydrotestosterone" or DHT), as shown below:
  • isozymes of 5 ⁇ -reductase there are two isozymes of 5 ⁇ -reductase in humans.
  • One isozyme (type 1) predominates in the sebaceous glands of skin tissue.
  • the other (type 2) predominates in the prostate.
  • Finasteride (17 ⁇ -(N-tert-butylcarbamoyl)-3-oxo-4-aza-5 ⁇ -androst-l- en-3-one), as shown below, is a potent inhibitor of the human type 2 enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Under the tradename PROPECIA®, finasteride is also prescribed for the treatment of male pattern hair loss.
  • BPH benign prostatic hyperplasia
  • PROPECIA® finasteride is also prescribed for the treatment of male pattern hair loss.
  • This invention is concerned with a method of determining the risk of a urologic event, particularly an event selected from BPH-related surgery and acute urinary retention, in a man by measuring the man's serum PSA level.
  • the present invention also provides for a method of reducing the risk of the urologic event in a man determined to be at risk by the present urologic event risk-determining method by administration to the man of a compound which inhibits 5 ⁇ -reductase.
  • FIGURE 1 is a graph of the cumulative incidences for spontaneous acute urinary retention (AUR) over four years by increments of baseline serum PSA thresholds in the clinical study detailed in Example 1. This graph shows that in the placebo group, the cumulative incidence of spontaneous AUR increases with increasing serum PSA values; and in the finasteride-treated patients, this effect is nearly absent.
  • FIGURE 2 is a graph of the cumulative incidences for all AUR
  • FIGURE 3 is a graph of the cumulative incidences BPH-related surgery over four years by increments of baseline serum PSA thresholds in the clinical study detailed in Example 1. This graph shows that in the placebo group, the cumulative incidence of BPH-related surgery increases linearly across PSA values from 10-24%, while it increases only in finasteride-treated patients in men with a baseline PSA above 5.0 ng/mL.
  • the present invention is a method of determining the risk of a urologic event in a man by measuring the serum PSA level of the man. In another embodiment of the present invention is provided a method for determining the risk of a urologic event selected from BPH-related surgery and acute urinary retention in a man by measuring the man's serum PSA level.
  • In one class of this embodiment is the method for determining the risk of BPH-related surgery in a man by measuring the man's serum PSA level.
  • in another class of this embodiment is the method for determining the risk of acute urinary retention in a man by measuring the man's serum PSA level.
  • Another embodiment of the present invention is a method of determining the risk of a urologic event in a man by measuring the serum PSA level of the man and determining if the value is over 3.3 ng/mL.
  • Another embodiment of the present invention is a method of determining the risk of a urologic event in a man by measuring the serum PSA level of the man and determining if the value is over 1.3 ng/mL.
  • An additional embodiment of the present invention is a method of reducing the risk of a urologic event in a man determined to have a risk of a urologic event by the present method of determining the risk of the urologic event by the administration to the man of a compound which inhibits 5 ⁇ -reductase.
  • in yet another embodiment of the present invention is a method of reducing the risk of a urologic event in a man determined to be at high risk by the present method of determining the risk of a urologic event by the administration to the man of a compound which inhibits 5 ⁇ -reductase.
  • Still another embodiment of the present invention is a method of reducing the risk of a urologic event in a man at risk for a urologic event by having a serum PSA level of over 1.3 ng/mL by the administration to the man of a compound which inhibits 5 ⁇ -reductase.
  • Yet another embodiment of the present invention is a method of reducing the risk of a urologic event in a man at risk for a urologic event by having a serum PSA level of over 3.3 ng/mL by the administration to the man of a compound which inhibits 5 ⁇ -reductase.
  • Still another embodiment of the present invention is a kit for determining the risk of a urologic event in a man comprising a test for serum PSA and for relating the serum PSA measurement to the risk of a urologic event.
  • the kit comprises a test for serum PSA and a graph of PSA versus risk of a urologic event. In another class of this embodiment, the kit comprises a test for serum
  • PSA and a chart relating serum PSA and risk of a urologic event.
  • the kit comprises a test for total serum PSA and a graph of total PSA versus risk of a urologic event.
  • the kit comprises a test for total serum PSA or percent free PSA and a chart relating total serum PSA or percent free PSA and risk of a urologic event.
  • the kit comprises a test for free serum PSA and a graph of free PSA versus risk of a urologic event.
  • the kit comprises a test for free serum PSA and a chart relating free PSA versus risk of a urologic event.
  • the kit comprises a test for percent free PSA and a graph of percent PSA versus risk of a urologic event.
  • the kit comprises a test for percent free PSA and a chart relating percent PSA versus risk of a urologic event.
  • Inhibitors of 5 -reductase type 2 are known in the art. For a given compound, its 5 ⁇ -reductase type 2 inhibitory activity may be determined by assaying its activity as described in Example 3 in the present application. Compounds having an IC50 under about 100 nM are 5 ⁇ -reductase type 2 inhibitors useful in the present invention. Compounds also having both 5 ⁇ -reductase type 2 and 5 ⁇ -reductase type 1 activity, often called “dual inhibitors" are also compounds useful in the methods of the present invention. Further, inhibitors of 5 ⁇ -reductase type 1 may be useful in the methods of the present invention.
  • R is selected from:
  • R is selected from
  • R is t- butyl
  • R is 2,5-bis(trifluoromethyl)phenyl.
  • inhibitors of 5 ⁇ -reductase type 2 useful in the methods of the present invention include epristeride and turosteride, shown below: epristeride turosteride
  • halo or “halogen” is meant to include fluoro, chloro, bromo and iodo.
  • Ci-io alkyl is meant to include both straight-and branched- chain alkyl groups of one to ten carbon atoms in length, not limited to: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl and the isomers thereof such as isopropyl, isobutyl, secbutyl, t-butyl, isopentane, isohexane, etc.
  • solvates can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates".
  • Solvates of compounds of structural formula I are within the scope of the present invention.
  • Many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of the compounds of structural formula I or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.
  • the method of determining the risk may be employed in an adult male human.
  • the method of reducing the risk may be employed in an adult male human determined by the risk determination method to be at risk for a urologic event.
  • the method of determining the risk may be employed in a physician's office. An individual male subject having a risk of bleeding may present to the physician. This individual would be at a high risk for complications during surgery.
  • the physician could measure the serum PSA of the subject, and determine the risk of the subject for a urologic event. Using this information, the physician is better able to evaluate the subject's risk of having a urologic event requiring surgery in the future and may prescribe a 5 ⁇ -reductase inhibitor to reduce the risk of surgery if such a risk is high.
  • FIGURES 1, 2, and 3 provide a graphic assessment to aid in this decision.
  • the cumulative incidence of spontaneous AUR for placebo- treated patients increases dramatically above serum PSA levels of approximately 1.3 ng/mL.
  • the cumulative risk for all patients is approximately 4% or 1 in 25 men over four years, it reaches 9% or nearly 1 in 10 patients for those with a PSA over 4.0 ng/mL at baseline ( Figure 1).
  • the risk remains unchanged over the entire serum PSA spectrum for finasteride-treated patients. Similar observations hold true for the cumulative risk for both spontaneous and precipitated AUR, as well as for BPH-related surgery ( Figures 2 and 3).
  • the 5 ⁇ -reductase inhibitor finasteride attenuates the predictive power of prostate volume and serum PSA regarding surgery and AUR. In fact, to make predictions about the risk of surgery and/or AUR once treatment is initiated is less important than to be able to give patients and health care providers information prior to a treatment decision regarding possible future BPH-related outcomes.
  • serum PSA is a good candidate parameter to aid in the individualized discussion that takes place between patients and physicians before initiation of therapy for BPH.
  • Finasteride decreases the risk of developing a BPH- related outcome by approximately half in all subgroups examined.
  • the absolute risk of having an outcome is substantially different across the different levels of PSA and prostate volume. Risk is viewed differently by patients, physicians and administrators. The data provided in this report should be helpful to all parties involved in the decision whether or not to treat BPH based on predictable risks and predictable reductions in risk with finasteride.
  • Serum PSA may be measured by measuring the total amount of PSA per volume of serum by a variety of known methods.
  • the methods of the present invention may be employed by measuring free PSA per volume of serum or percent free PSA by methods known in the art.
  • the PSA measurement techniques available from Hybritech.
  • an “effective amount” means the amount of 5 ⁇ -reductase inhibitor that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • an “effective amount” for risk reduction means the amount of the 5 ⁇ -reductase inhibitor that reduces serum PSA (either total PSA, free PSA or percent free PSA) by approximately 50%.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the inhibitors of 5 -reductase employed in the present invention are useful as pharmacological agents for mammals, especially for humans, for the prevention of and reduction of the risk of precipitated acute urinary retention.
  • the daily dosage of the 5 ⁇ -reductase inhibitor may be varied over a wide range from 0.01 to 500 mg per adult human per day.
  • the 5 ⁇ -reductase inhibitor is administered at a dose of 1.0 to 100 mg per day.
  • the 5 ⁇ -reductase inhibitor is administered at a dose of 0.5 to 10 mg per day.
  • compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 to 7 mg/kg of body weight per day.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the inhibitor of 5 ⁇ -reductase inhibitor may preferably be administered to the individual to avoid the risk for precipitated acute urinary retention and to reduce the risk of having such an episode in the future.
  • the administration of the 5 ⁇ -reductase inhibitor may be commenced before a scheduled precipitating event (such as surgery or anesthesia) to prevent the occurrence of acute urinary retention related to the event.
  • Formulations of the 5 ⁇ -reductase inhibitors employed in the present method for medical use comprise the 5 -reductase inhibitor together with an acceptable carrier thereof.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient subject of the formulation.
  • the 5 ⁇ -reductase inhibitor may be administered as the sole active agent or together with another active agent such as an antiandrogen, a GnRH analog, a GnRH antagonist or with another active agent such as an antiandrogen, a GnRH analog, a GnRH antagonist or with another active agent such as an antiandrogen, a GnRH analog, a GnRH antagonist or with another active agent such as an antiandrogen, a GnRH analog, a GnRH antagonist or with another active agent.
  • the present invention therefore, further provides a pharmaceutical formulation comprising a 5 ⁇ -reductase type 2 inhibitor together with a pharmaceutically acceptable carrier thereof.
  • the formulations include those suitable for oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous administration).
  • the formulations may be presented in a unit dosage form and may be prepared by any of the methods known in the art of pharmacy. All methods include the step of bringing the active compound in association with a carrier which constitutes one or more ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound in association with a liquid carrier, a waxy solid carrier or a finely divided solid carrier, and then, if needed, shaping the product into the desired dosage form.
  • the 5 ⁇ - reductase inhibitor may be the sole active agent or may be present together with another active agent such as an antiandrogen, a GnRH analog, a GnRH antagonist or with another 5 ⁇ -reductase inhibitor.
  • treatment may encompass administration of a combination of a compound of formula I with a 5 ⁇ -reductase 2 inhibitor and/or another active agent such as an alpha 1 or an alpha la adrenergic receptor antagonist (alphal a receptor antagonists were formerly called alphalc receptor antagonists).
  • a 5 ⁇ -reductase 2 inhibitor and/or another active agent such as an alpha 1 or an alpha la adrenergic receptor antagonist (alphal a receptor antagonists were formerly called alphalc receptor antagonists).
  • the 5 ⁇ -reductase inhibitor may be administered together with an endothelin antagonist.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the active compound, preferably in powdered form, with a suitable carrier.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Oral liquid forms such as syrups or suspensions in suitably flavored suspending or dispersing agents such as synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like may be made by adding the active compound to the solution or suspension.
  • suspending or dispersing agents such as synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like
  • Additional dispersing agents include glycerin and the like.
  • Formulations for rectal administration may be presented as a suppository with a conventional carrier, i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with the 5 ⁇ -reductase inhibitors, and is stable in storage and does not bind or interfere with the release of the compound.
  • Suitable bases include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax and polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, and hydrogenated vegetable oils.
  • a preservative such as methylparaben or propylparaben may be employed.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations.
  • carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcho lines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • Formulations suitable for parenteral administration include formulations that comprise a sterile aqueous preparation of the active compound that is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject. Such formulations may contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceutically and pharmacologically acceptable acid addition salt of the active compound that has appropriate solubility for the solvents employed. Useful salts include the hydrochloride isothionate and methanesulfonate salts. Useful formulations also comprise concentrated solutions or solids comprising the active compound which on dilution with an appropriate solvent give a solution suitable for parenteral administration.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Alpha- 1 adrenergic receptor antagonists suitable for administration together with the 5 ⁇ -reductase inhibitors according to the method fo the present invention include those such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed. More particularly, the combined therapy can comprise administering a 5 -reductase, such as e.g., finasteride, and an alpha-la adrenergic receptor antagonist (formerly called an alpha- lc adrenergic receptor antagonist).
  • a 5 -reductase such as e.g., finasteride
  • an alpha-la adrenergic receptor antagonist previously called an alpha- lc adrenergic receptor antagonist
  • Example 1 demonstrates that the cumulative risk increases in a linear fashion for all three serum PSA tertiles.
  • the difference in risk between treatment groups in the higher tertiles (>1.3 ng/mL) becomes evident as early as the first follow-up visit at 4 months.
  • FIGURES 1 , 2, and 3 provide a graphic assessment to aid in the decision of setting a threshold for preventive health care measures.
  • the cumulative incidence of spontaneous AUR for placebo-treated patients increases dramatically above of a cut-point of serum PSA of approximately 1.3 ng/mL.
  • Acute urinary retention (AUR) and surgery for BPH were predefined secondary end-points.
  • the endpoint committee blinded to treatment group, reviewed all study-related documents related to episodes of acute urinary retention, and all prostate surgeries for BPH, excluding surgery for prostate cancer.
  • the endpoint committee classified episodes of AUR as spontaneous versus precipitated (when contributing factors such as urinary tract infection, surgery anesthesia, ingestion of alpha sympathomimetic drugs or anticholinergics were identified).
  • the measurement characteristics of baseline in prediction of BPH- related outcomes were evaluated using receiver operating characteristic (ROC) curves.
  • ROC receiver operating characteristic
  • AUC area under the ROC curve
  • the AUC's were computed using the method of Hani ey and McNeil. Differences between AUC's in the finasteride and placebo group were tested using normal statistics with standard deviations computed by the same method.
  • Patients in the third tertile of serum PSA( 3.3 - 12 ng/mL) had a 4-year relative risk for finasteride versus placebo treated patients of 0.40 (95% CI 0.29 to 0.56), with a 60% risk reduction on finasteride (p ⁇ .001).
  • About 1 out of 5 patients in the highest tertile is likely to experience either urinary retention or surgery for BPH, and the risk reduction with finasteride treatment is 60% (based on serum PSA).
  • FIGURES 1, 2, and 3 show the cumulative incidences for spontaneous AUR (FIGURE 1), all AUR (spontaneous and precipitated combined) (FIGURE 2), and BPH-related surgery (FIGURE 3) over four years by increments of baseline serum PSA thresholds.
  • FIGURE 1 shows the cumulative incidence for spontaneous AUR (FIGURE 1), all AUR (spontaneous and precipitated combined) (FIGURE 2), and BPH-related surgery (FIGURE 3) over four years by increments of baseline serum PSA thresholds.
  • the cumulative incidence for spontaneous AUR FIGURE 1
  • all AUR spontaneous and precipitated combined
  • BPH-related surgery FIGURE 3
  • FIGURE 1 shows that the increased risk for AUR and/or surgery with increasing baseline serum PSA is nearly obliterated with finasteride therapy.
  • ROC curve analyses evaluating the performance of baseline serum PSA in predicting outcomes in comparison to the more traditional baseline parameters of BPH, including symptom severity, bothersomeness, peak urinary flow rate, residual urine volume and age are shown in Table 1, below.
  • Table 1 AUC (area under the curve) ⁇ standard error values for ROC curves for several baseline parameters for spontaneous AUR (acute urinary retention) and prostate related surgery
  • Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl-sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • a crude nuclear pellet was prepared by centrifugation of the homogenate at 1,500 x g for 15 min. The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%.
  • the enzyme suspension was frozen in aliquots at -80°C. The prostatic and scalp reductases were stable for at least 4 months when stored under these conditions.
  • the reaction mixture for the type 1 5 ⁇ -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7--1H] -testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the reaction mixture for the type 2 5 ⁇ - reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7- ⁇ H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 ⁇ L of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 rpm in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC (10 cm Whatman Partisil 5 silica column equilibrated in 1 mL/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1-9.7 min).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ Autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A 120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5 ⁇ -reductase type 1 and type 2 inhibition.
  • a compound referred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5 -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • the compounds are tested in the above-described assay for 5 ⁇ - reductase type 1 and type 2 inhibition, and were found to have IC50 values under about 100 nM for inhibition of the type 1 isozyme.
  • Compounds found to have IC50 values of under about 50 nM for inhibition of the type 1 isozyme are called type 1 inhibitors.
  • the compounds called “dual inhibitors” were inhibitors of both 5 ⁇ - reductase type 1 and 5 ⁇ -reductase type 2 as defined above.

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Abstract

L'invention concerne un procédé de détermination chez l'homme d'un risque de survenue d'un problème urologique, notamment un problème lié à une chirurgie associée à l'adénome prostatique, ou à une rétention urinaire, ce procédé consistant à mesurer le taux sérique des antigènes spécifiques de la prostate. Elle concerne également une méthode de diminution du risque de survenue de ce type de problème, chez un homme présentant un risque tel que déterminé au moyen du procédé décrit, cette méthode consistant à administrer à cet homme un composé inhibant la 5α-réductase. L'invention concerne également une trousse de détermination du risque de survenue d'un problème urologique.
PCT/US1999/020451 1998-09-09 1999-09-03 Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique WO2000013509A1 (fr)

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Cited By (1)

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WO2005080589A1 (fr) * 2004-02-19 2005-09-01 Bayer Healthcare Ag Agents diagnostiques et therapeutiques pour maladies associees a la kallicreine 3 (klk3)

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WO1997004002A1 (fr) * 1995-07-21 1997-02-06 Pharmacia & Upjohn S.P.A. EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE
WO1997010217A1 (fr) * 1995-09-15 1997-03-20 Merck & Co., Inc. 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques
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WO1997004002A1 (fr) * 1995-07-21 1997-02-06 Pharmacia & Upjohn S.P.A. EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE
WO1997010217A1 (fr) * 1995-09-15 1997-03-20 Merck & Co., Inc. 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques
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COHEN ET AL: "Comparison of the effects of new specific azasteroid inhibitors of steroid 5alpha-reductase on canine hyperplastic prostate: suppression of prostatic DHT correlated with prostate regression", THE PROSTATE, vol. 26, 1995, pages 55 - 71, XP002923081 *
DJAVAN ET AL: "Der einfluss der 5-alpha-reduktase-inhibitoren auf die benigne prostatahyperplasie (The effect of 5-alpha-reductase inhibitors on benign prostatic hyperplasia)", WIENER MEDIZINIZSCHE WOCHENSCRIFT, vol. 146, no. 2, 1996, pages 165 - 168, XP002923077 *
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ROEHRBORN ET AL: "Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia", UROLOGY, vol. 53, March 1999 (1999-03-01), pages 473 - 480, XP002923076 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080589A1 (fr) * 2004-02-19 2005-09-01 Bayer Healthcare Ag Agents diagnostiques et therapeutiques pour maladies associees a la kallicreine 3 (klk3)

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