United States Patent (19) 11 Patent Number: 4,466,978 Naylor (45
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United States Patent (19) 11 Patent Number: 4,466,978 Naylor (45. Date of Patent: Aug. 21, 1984 54 BODYWEIGHT REDUCING METHOD OTHER PUBLICATIONS 75 Inventor: Graham J. Naylor, Lulgate, Handbook of Nonprescription Drugs, 5th ed., Am. Lucklawhill Balmullo, St. Andrews, Pharm. Assoc., pp. 177-183, (1977). KY16 OBQ, Fife, Scotland Chem, Abst. 92, 40252(q), (1980), Odumosu et al. Primary Examiner-Douglas W. Robinson 73 Assignees: Graham John Naylor; Pamela Hilda Attorney, Agent, or Firm-Murray, Whisenhunt and Naylor, both of St. Andrews, Ferguson Scotland (57) ABSTRACT The present invention provides in one aspect a slimming 21 Appl. No.: 354,016 method and in a further aspect a method for the treat ment or prophylaxis of obesity, comprising the adminis 22 Filed: Mar. 2, 1982 tration of a bodyweight reducing effective dosage of a compound selected from glutathione, physiologically acceptable salts and esters thereof, and ascorbic acid, 30 Foreign Application Priority Data and physiologically acceptable salts and esters thereof, Dec. 10, 1981 GB United Kingdom................. 8137294 and a compound of Formula I 51) Int. Cl. ................... A61K 31/365; A61K 31/54; -- A61K 31/16 S 52 U.S. C. .................................... 424/280; 424/247; Me2N S 424/320 al 58) Field of Search ................................ 424/247, 280 N 56 References Cited wherein X is a physiologically acceptable anion, and bioprecursors thereof, to a subject. FOREIGN PATENT DOCUMENTS 46.9358 9/1971 Japan. 424/280 6 Claims, No Drawings 4,466,978 2 salts or precursors can be readily produced by standard BODYWEIGHT REDUCING METHOD procedures such as metathetical reactions. The inventor has found that the compounds of th This invention relates to a method of reducing body invention have significant in vitro and in vivo activity in weight. the reversal and/or catalysis of reversal, of Na-K There has for many years been a considerable de ATPase inhibition caused in the body by, in particular, mand for safe and effective methods of slimming and vanadate ions. It is believed that this is achieved by the treating obesity in order to improve the aesthetic ap reduction of vanadate (V5+) ions to vanadyl (V4+) ions pearance of the person's body and make that person and/or catalysis of such reduction. The inventor has appear more physically attractive to others at one end 10 also found that elevated vanadate ion levels in the body of the spectrum and to reduce clinical obesity at the are associated with significant body weight gain rates. other end. On the one hand though many relatively safe Whilst not restricting the scope of the present invention methods such as exercise and carefully controlled diets in any way it is believed by the inventor that the effec have limited effectiveness due to the fact that many tiveness of the method of the present invention is by people find these methods difficult to adhere to over an 15 means of the reversal and/or enhancement of reversal, extended period of time. Other methods on the other of the Na-K ATPase inhibition in the body by vanadate hand can have deleterious effects on the human metabo OS. lism. The active compounds of the invention are usually It is an object of the present invention to avoid or administered in the form of a pharmaceutical formula minimize one or more of the above disadvantages and in 20 tion comprising a compound of the invention or bio particular to provide a new slimming method and a precursor thereof together with a pharmaceutically method for the treatment or prophylaxis of obesity. acceptable carrier therefor. The present invention provides in one aspect a slim The carrier must be "acceptable' in the sense of being ming method and in a further aspect a method for the compatible with the other ingredients of the formula treatment or prophylaxis of obesity, comprising the 25 tion and not deleterious to the patient. Such carriers administration of a body-weight reducing effective dos may be solid, liquid or gaseous materials suitable for the age of a compound selected from glutathione, physio purpose of administering the medicament by the desired logically acceptable salts and esters thereof, and ascor route. bic acid, and physiologically acceptable salts and esters These pharmaceutical compositions may be adminis thereof, and a compound of Formula I 30 tered orally or parenterally (including subcutaneous, -- (I) intramuscular and intravenous injection) or as a suppos S itory or pessary. In general the compositions are admin Me2N sa NMe2 istered orally or parenterally. The words formulation X 35 and composition are used synonymously herein. e For parenteral administration the active compound N may be presented in sterile solutions or suspensions in wherein X is a physiologically acceptable anion, and aqueous or oleaginous vehicles, which may also contain bioprecursors thereof, to a subject. preservatives and material for rendering the solution or Preferably there is used a compound of Formula I in suspension isotonic with the blood of the patient. The which the anion is a halide anion especially chloride. In formulations are conveniently presented in unit-dose or the latter case the compound of formula I is known as multi-dose sealed containers. methylene blue or 3,7-bisdimethylaminophenothiazine For oral administration the pharmaceutical composi hydrochloride having the chemical formula tions may be formulated as a draught in water or in a C16H13CIN3S. Other suitable anions which may be 45 syrup, in capsules, cachets, boluses or tablets, as an mentioned include sulphate, nitrate, citrate, carbonate aqueous or oleaginous solution or suspension or in sus and fumarate. pension in a syrup, such suspensions optionally includ For the avoidance of doubt the substance referred to ing suspending agents, or as an oil-in-water or water-in hereinabove as glutathione is the compound having the oil emulsion. Flavouring, sweetening, preserving, thick are: 50 ening or emulsifying agents may also be included in the y-L-glutamyl-L-cysteinylglycine (oxidised or re formulation. - duced form) and the chemical formula Tablets may contain the active compound as a pow HOCCH(NH2)CH2CH2CONHCH(CH2SH der or granules optionally mixed with binders, lubri )CONHCH2CO2H (in the case of the reduced cants, inert diluents or surface-active or dispersing form). 55 agents and may be formed by compression or by mould As well as being substantially free from the above ing in inert liquid diluent. Such tablets may be scored mentioned disadvantages of prior art methods to a and/or coated. greater or lesser extent, the present invention has addi Capsules and cachets may contain the active com tional advantages in that the above compounds are pound alone or in admixture with one or more other relatively inexpensive and readily available. 60 ingredients. Capsules may also contain the active com As indicated above the present invention extends to pound in aqueous or oleaginous solution suspension or the administration of a bioprecursor of a compound emulsion optionally in association with other ingredi specified above, namely a compound which is readily ents. For administration as a suppository or pessary the converted in the human body upon administration into active compound may be presented in admixture with a a said compound of the invention. 65 suitable carrier such as cocoa butter and other material The compounds of the method of the invention are commonly used in the art, and are conveniently shaped well known from the literature as also are their methods by moulding. For administration in discrete unit dosage of preparation and/or extraction. Particular desired forms such as tablets, capsules, suppositories and pessa 4,466,978 3 ries as described above, the active compound is prefera -continued bly present at from 1 mg to 400 mg, most preferably Subjects receiving ascorbic acid lost a mean of 2.89 Kg from 25 mg to 400 mg, per tablet, capsule, suppository Subjects receiving placebo lost a mean of 0.67 Kg or pessary in the case of methylene blue and from 25 mg second 6 weeks: to 1 g, most preferably 200 mg to 1 g for ascorbic acid Subjects receiving ascorbic acid lost a mean of 0.72 Kg and glutathione. Subjects receiving placebo gained a mean of 0.13 Kg. All the above formulations may be produced by stan dard processes comprising bringing the active com Example 2 pound into association with one or more pharmaceuti cally acceptable carriers. O One subject who had been overweight for many years was treated for 8 weeks with methylene blue at a The required effective dosage of the compound of the dosage rate of 300 mg/day. At the start of the proce invention will of course depend on various factors such dure the subject was 42% above ideal weight but after as the activity of the individual compound, the depth, eight weeks had lost 5.8 Kg without any regulation of and severity of the illness, and the responsiveness of the 15 diet. This latter result is particularly significant because individual patient to the treatment regimen used. In of the great difficulty experienced by many persons in general though the compound of the invention will be consistently adhering to strictly controlled diets over administered at a dosage in the range of from 0.1 mg to extended periods of time. On the contrary the method 2g per kg body weight of the slimmer per day, prefera of the invention enables significant results to be ob bly from 0.2 to 8 mg/kg in the case of methylene blue, 20 tained in a relatively short period of time with the from 5 mg to 2 g per kg bodyweight of the slimmer per method of the invention alone. day in the case of ascorbic acid and from 0.2 to 500 mg What is claimed is: per kg bodyweight per day, preferably from 10 to 100 1.