TREATMENT OF NOCTURNAL POLYURIA USING AN ACE INHIBITOR IN COMBINATION WITH A DIURETIC

Abstract: The invention relates to the use of an angiotensin converting enzyme (ACE) inhibitor and a diuretic for the manufacture of a medicament for the treament of nocturnal polyuria. It also relates to a method of treating nocturnal polyuria using a pharmaceutical formulation comprising an ACE inhibitor and a diuretic.

Description: TREATMENT OF NOCTURNAL POLYURIA USING AN ACE INHIBITOR IN COMBINATION WITH A DIURETIC The present invention relates to the use of an angiotensin converting enzyme (ACE) inhibitor in combination with a diuretic for the manufacture of a medicament for the treatment of nocturnal polyuria in humans. The invention also relates to a method of treating nocturnal polyuria using a pharmaceutical formulation comprising an ACE inhibitor, a diuretic and a pharmaceutically acceptable carrier therefor, and to such a pharmaceutical formulation itself. There is a condition in men aged over 60 where they frequently need to rise from their beds to pass urine. This phenomenon is known aε nocturnal polyuria and has been variously reported to occur in 40-70% of elderly men. The frequency at night causes disturbed sleep, which results in fatigue and difficulty in coping through the day. The condition is often confused with prostate problems, but investigation of this aspect usually ra veals a normal healthy prostate. Abrams P. in Recent Advances in the Management of Incontinence, Report of the December 1993 Conference, page 12, decribed how there were three main causes of nocturia: there may be excess urine production at night, the bladder capacity may be reduced or there may be sleep disturbances. He observed that normal nocturnal reduction in urine production did not occur in men suffering from nocturnal polyuria, and indeed urine production seemed to increase. He proposed that the mechanism for this appeared to be either the reduction of antidiuretic hormone (ADH) secretion, and/or an increase in atrial naturetic peptide (ANP) production, due to a rise in the right atrial pressure while the patient is horizontal. Abrams suggested that treatment could involve timed daytime use of loop diuretics . A clinical investigation was carried out using desmopressin acetate (DDAVP) to treat a group of elderly male patients who suffered from nocturnal polyuria. There was no statistically significant decrease in overnight urine production with dosages of 20 meg or 40 meg of DDAVP, when compared with a placebo-treated group of patients. Ozawa T . et al, in Intern Med . 1993, 32(3) , 225-227 described how a patient with Shy-Drager Syndrome (SDS) , exhibited nocturnal polyuria associated with abnormal circadian rhythm of ADH secretion. Mathias CJ. et al, in Bri. Med. J. 1986, 293, 353-354, described how desmopressin given intramuscularly in the evening reduced nocturnal polyuria in patients with autonomic failure. WO 93/1768 describes pharmaceutical formulations for the treatment of essential hypertension and disorders associated therewith, such as congestive heart failure, which have as active ingredients an ACE inhibitor and a diuretic. Such formulations have greater efficacy in reducing elevated blood pressure to normal levels than if used in monotherapy. It has now unexpectedly been found that, by administering in the middle of the day a low dose of ACE inhibitor, together with a low dose of a diuretic to a patient suffering from nocturnal polyuria, there is a reduction in the number of times urine needs to be passed at night down to no episodes, or a single episode. According to one aspect of the invention there is provided the use of an angiotensin converting enzyme (ACE) inhibitor and a diuretic for the manufacture of a medicament for the treatment of nocturnal polyuria . According to a second aspect of the invention there is provided a method of treating nocturnal polyuria which comprises administering to a patient in need of such treatment an ACE inhibitor and a diuretic. Preferably the ACE inhibitor and diuretic are administered together with a pharmaceutically acceptable carrier in a single pharmaceutical formulation. Thus, according to yet another aspect of the invention there is provided a pharmaceutical formulation comprising a low dose of an ACE inhibitor and a low dose of a diuretic together with a pharmaceutically acceptable carrier therefor. By low dose is meant a dose of ACE inhibitor, or diuretic, which is lower than that normally taken for conventional therapeutic indications. ACE inhibitors which may be useful in the treatment of nocturnal polyuria in combination with a diuretic are captopril, enalapril, lisinopril, alacipril, benazapril, αla-zap-ril, delapril, fosinopril, perindopril, quinapril, ramipril, moveltipril, spirapril, ceronapril, imidapril, temocapril, trandolopril , utilbapril, zofenopril, libenzapril, zalicipril, Equaten ™, Prentyl ™ and Synecar ™. The preferred ACE inhibitors are enalapril, lisinopril, captopril, perindopril, benzapril, quinapril and cilazapril. The most preferred ACE inhibitor is captopril . The diuretics which may be useful in the treatment of nocturnal polyuria, in combination with an ACE inhibitor, are frusemide, hydrochlorothiazide (HCTZ) , altizide, trichloromethazide, triflumethazide, bemetizide, cyclothiazide , methylchlothiazide, azosemide, chlorothiazide , butizide, bendroflumethazide, cyclopenthiazide , benzoclortriazide, polythiazide , hydroflumethazide, benzthiazide, ethiazide, and penflutazide . The preferred diuretics are HCTZ, trichloromethazide, frusemide and altizide. The most preferred diuretic is frusemide. The ACT inhibitor and diuretic used in the present invention are combined together in a single formulation together with a pharmaceutically acceptable carrier. The preferred combination of captopril and frusemide may be used at a dosage of about 6 mg or less, preferably about 4 mg , and about 20 mg respectively, per unit dose. Such a dosage is preferably taken by the patient once a day in the middle of the day, for example between 12 noon and 2 pm. The medicament of this invention is preferably for oral administration and therefore may be presented as tablets , capsules, gel caps or as a sustained release formulation. Alternatively, the formulation may be designed as a syrup or elixir for oral administration , or as a suppository for rectal administration . Excipients which may be incorporated with the ACE inhibitor and diuretic include carriers, binders, stabilizers , preservatives and flavours. Examples of suitable excipients which may be incorporated into the formulations include a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch , pregelatinized starch, alginic acid and the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavouring agent such as orange, peppermint, oil of wintergreen or cherry. When the formulation is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the formulation. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavouring such as cherry or orange flavour. The following example is illustrative of the invention: Example 1 Twelve men suffering from nocturnal polyuria, but otherwise not exhibiting any other clinical symptoms, each took a low dose of captopril (6 mg) and a low dose of frusemide (20 mg) at approximately 2 pm each day for 14 days. Results Prior to the commencement of treatment each of the twelve patients reported that they needed to pass urine at night on average four times. After 14 days of treatment each of the twelve patients reported that they did not need to pass urine at night at all, or only had to get up on a single occasion in the early hours of the morning. Example 2 Capsule Formulation Capsules, each containing 4 mg captopril and 20 mg frusemide, are prepared by grinding 12.5 mg captopril tablets, batch no. SG020 manufactured by Squibb, and 20 mg frusemide tablets, batch no. FA82 manufactured by Cox , and dry blending the ground up tablets with lactose in a blender. The mixture is then passed through a screen and mixed again in the mixer, after which the mixture is filled into two-piece gelatin capsules each containing :- 20 mg frusemide, 4 mg captopril, 550 mg lactose, 74 mg tablet excipients.

Claims: CLAIMS 1. The use of an angiotensin converting enzyme (ACE) inhibitor and a diuretic for the manufacture of a medicament for the treatment of nocturnal polyuria. 2. The use of Claim 1 wherein the ACE inhibitor is captopril. 3. The use of Claim 1 wherein the diuretic is frusemide. 4. The use of any one of Claims 1 to 3 wherein the medicament contains about 6 mg of ACE inhibitor and about 20 mg of diuretic per unit dose. 5. The use of any one of Claims 1 to 3 wherein the medicament contains about 4 mg of ACE inhibitor and about 20 mg of diuretic per unit dose. 6. A method of treating nocturnal polyuria which comprises the administration to a patient in need of such treatment of a pharmaceutical formulation comprising an ACE inhibitor, a diuretic and a pharmaceutically acceptable carrier therefor. 7. The method of Claim 6 wherein the ACE inhibitor is captopril. 8. The method of Claim 6 wherein the diuretic is frusemide. 9. The method of any one of Claims 6 to 8 wherein the pharmaceutical formulation contains about 6 mg of ACE inhibitor and about 20 mg of diuretic per unit dose. 10. The method of any one of Claims 6 to 8 wherein the pharmaceutical formulation contains about 4 mg of ACE inhibitor and about 20 mg of diuretic per unit dose.

Inventors: FELL PETER JOHN, FELL, PETER, JOHN
Applicants: FELL PETER JOHN, OXFORD HEALTH MANAGEMENT LTD, FELL, PETER, JOHN, OXFORD HEALTH MANAGEMENT LIMITED
Application year: 1996
Main classification: A61K38
IPC codes: A61K31, A61K38