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US2920012A - Therapeutic compositions for inhibiting carbonic anhydrase activity - Google Patents

Therapeutic compositions for inhibiting carbonic anhydrase activity Download PDF

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US2920012A
US2920012A US532113A US53211355A US2920012A US 2920012 A US2920012 A US 2920012A US 532113 A US532113 A US 532113A US 53211355 A US53211355 A US 53211355A US 2920012 A US2920012 A US 2920012A
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carbonic anhydrase
triazine
carbanilate
therapeutic compositions
amino
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US532113A
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Robert G Sanders
Roland R Read
Richard J Palazzolo
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Warner Lambert Co LLC
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Warner Lambert Pharmaceutical Co
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

  • This invention relates to therapeutic compositions and 2 more particularly to therapeutic compositions which are eifective to inhibit carbonic anhydrase activity.
  • compositions comprising a compound having the fortmula:
  • the invention also includes the method of inhibiting carbonic anhydrase activity through the use of the above-noted compounds.
  • carbonic anhydrase activity indirectly determines the number of hydrogen ions which are available to re- .place sodium ions inbuffercompounds from the blood, suchas, for example, disodium phosphate-rand sodium bicarbonate.
  • the sodium .ions thus replaced are conserved and return to the blood, and carbonic acid formed in the above reaction catalyzed by carbonic anhydrase also returns to the blood.
  • the diuretic action of these triazine compounds is believed to be due to the inhibition of tubular reabsorption brought about by a partial anoxia from the inhibition of respiratory enzymes involved in the tubular reabsorption of water and sodium chloride.
  • the increase in diuretic action noted when one of these'tria'zine compounds is included in the therapeutic" compositions'of the invention is more than can be accounted for by the additive eifect of the carbanilate compound andthe triazine compound on the basis of their action individually, as' is shown by the tests described hereinafter.
  • nontoxic salts of 2, 4- diamino s-triazine, 2-amino-4-[3-carboxy ethyl amino s-triazine, 2,4-(f3-carboxy ethyl amino) striazine, 2- amino-4-ani1ino-1,3,5-triazine and 2-amino-4-(p-chloroanilino)-l,3,5-triazine which are useful as components of the compositions of the invention may be mentioned the hydrochloride, sulfate, phosphate and tartrate salts.
  • the salts of the alkali metals, ammonia and amines may also be utilized.
  • the amount of triazine component, when includedin the compositions of the invention may be varied considerably and may be, for example, approximately 27% by weight.
  • the p-sulfamyl carbanilate compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable and nontoxic.
  • intraperitoneal doses of; p-Sulfamyl fl-hydroxy ethyl carbanilate .up to 1600 mg/kg were tolerated by. male white rats, and only three animalsout of .a group of ..nine. receiving 1800 Ing /kg. intraperitoneally died.1.
  • oral doses up to 1500 rngjlgg. of this carbanilate. compound did not prpduce any ill effectjn male whiterats.
  • Three groups of white rats, with six animals in each group received 6 00 QOQ and 1200 mg./kg. respectively of p-sulfamyl fl-hydr'oxy ethyl carbanilate-per day for twelve days and gross pathology after being sacrificed showed "a" normal and autopsied on the thirteenth day.
  • the carbanilate compounds of the novel therapeutic compositions of the invention have the formula:
  • compositions of the present invention comprise a compound of the above mentioned class and a pharmaceutical carrier which may be either a liquid or solid material. It is preferred that the pharmaceutical carrier be a solid material such as, for example, starch, gelatin, lactose, talc, calcium stearate or the like. Any of the pharmaceutical carriers conventionally used in therapeutic compositions may be utilized where such materials are compatible with the aforementioned carbanilate compounds. These compositions include tablets, capsules and the like, and may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions, elixirs and the like.
  • the percentage of the carbanilate compound incorporated in the therapeutic compositions of the invention may be varied considerably.
  • Exemplary compositions may contain approximately 80% by weight of one of the above mentioned carbanilate compounds, although greater or smaller amounts than 80% may also be used in the practice of the invention.
  • the daily dosage administered to a patient may also vary considerably, depending upon the patients condition and the amount prescribed by the physician in charge. In the case of edema, the daily dosage of these novel compositions may be such that the patient ingests on the order of 250 mg. to 500 mg. of one of the carbanilate compounds per day.
  • Example 1 Therapeutic diuretic tablets were prepared having the following composition:
  • G p-Sulfamyl fi-hydroxy ethyl carbanilate 0.500 Formoguanamine 0.250 Betaine hydrochloride 0.065 Corn starch U.S.P. 0.100 Calcium stearate 0.010 Talcum powder 0.005
  • Example 2 Therapeutic diuretic tablets were prepared having the following composition:
  • the tablets were prepared by first mixing the p-sulfamyl fl-hydroxy ethyl carbanilate, 2-amino-4-anilino-l,3,5-trtazine hydrochloride and betaine hydrochloride in the dry state. This mixture was then wet granulated with isopropyl alcohol (0.125 ml. per tablet) and water (0.125 ml. per tablet). The wet granulated mixture was thereafter dried on trays at a temperature of F. for 15 hours, and the dry mixture was ground in an oscillator using a No. 11 heavy wire screen. The corn starch, calcium stearate and talcum powder were added and, after thorough mixing, the mixture was compressed into tab ets.
  • Example 3 The inhibition of carbonic anhydrase activity by psulfamyl allyl carbanilate was determined as follows:
  • the carbonic anhydrase employed was prepared from rabbit red blood cells by the method of Keilin and Mann (Biochem. J. 34, 1166, 1940). The red blood cells were Washed three times with saline by centrifugation. To the washed cells (10 ml.) in a centrifuge tube were added distilled water (6 ml.), ethyl alcohol (4 ml.) and chloroform (5 ml.). The mixture was shaken well and centrifuged for 25 minutes at 2500 r.p.m. A three phase system was formed consisting of a top layer of enzyme solution, a central layer of denatured protein and a bottom layer of chloroform.
  • the top layer was removed and the activity of the carbonic anhydrase determined by a modification of the meth 0d of Meldrum and Roughton (J. Physiol. 80, 116-124, 1934), which measures the catalytic effect of the carbonic anhydrase enzyme on the rate of evolution of carbon dioxide from sodium bicarbonate solutions when mixed with phosphate buffer of pH 6.8.
  • a sodium bicarbonate solution (1.1 ml.) (0.2 M) (prepared by dissolving the sodium bicarbonate in a 0.02 M sodium hydroxide solution) was placed in the main compartment of a 15 ml.
  • compositions of the invention corresponding to the above described compositions andgcontaining comparable amounts of p-sulfamyl ethyl carbanilate, p-sulfamyl, allyl carbanilate and one of the aforementioned triazine compounds may be prepared and are effective in the practice of the invention.
  • compositions of the invention may be employed in the treatment of any condition where the inhibition of carbonic anhydrase activity will produce a beneficial result.
  • a therapeutic composition comprising a compound having the formula:
  • R represents a radical selected from the group consisting of ethyl, p-hydroxy ethyl and allyl, a compound selected from the group consisting of 2,4-diamino s-triazine, 2-amiuo-4-p-carboxy ethyl amino s-triazine, 2,4- (B-carboxy ethyl amino) s-triazine, 2-amino-4-anilino- 1,3,5-triazine, 2-amino-4-(p-chloroa-nilino)-1,3,5-triazine and the nontoxic salts thereof, and a pharmaceutical carrier.
  • a therapeutic composition comprising p-sulfamyl a hydroxy ethyl carbanilate, 2-amino-4- -anilino-1,3,5-triazine and a pharmaceutical carrier.
  • a therapeutic composition comprising p-sulfamyl ethyl carbanilate, 2-amino-4-anilino-1,3,5-triazine and a pharmaceutical carrier.
  • a therapeutic composition comprising p-sulfamyl allyl carbanilate, 2-amino-4-anilino-1,3,5-triazine and a pharmaceutical carrier.
  • a therapeutic composition comprising p-sulfamyl References Cited in the file of this patent U.S. Dispensatory, 25th ed., pp. 191-492.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent "face 2,920,012 Patented Jan. 5, 1960 Robert G. Sanders, Clayton, Roland R. Read, Ladue, and Richard J. Palaz'zolo, Alfton, Mo., assignors to Warner-Lambert Pharmaceutical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Application September 1, 1955 Serial No. 532,113
7 Claims. (Cl. 167-515) This invention relates to therapeutic compositions and 2 more particularly to therapeutic compositions which are eifective to inhibit carbonic anhydrase activity.
This application is a continuation-in-part of our applik cation Serial No. 456,639, filed September 16, ,1954, now -abandoned.
Briefly, the present invention is directed to therapeutic compositions comprising a compound having the fortmula:
NHCOOR -wherein Ris-ethyl, p-hydroxy ethyl or allyl, auda' pharmaceutical carrier. The invention also includes the method of inhibiting carbonic anhydrase activity through the use of the above-noted compounds.
Among the several objectsof the invention may'be noted the provision of therapeutic compositions and methods which are efiective to inhibit the activity of the enzyme carbonic anhydrase; the provision of such therapeutic compositions which are effective diuretic compositions; and the provision of therapeutic compositions of the class described which are stable and nontoxic. Other objects and features will be in part apparent and in part pointed out hereinafter. a
- The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.
The enzyme carbonic anhydrase plays an important role in the acidification of the urine through its catalysis of the reversible reaction:
The carbonic acid so formed yields hydrogen and bicarbonate ions through the reversible reaction:
'Thus, carbonic anhydrase activity indirectly determines the number of hydrogen ions which are available to re- .place sodium ions inbuffercompounds from the blood, suchas, for example, disodium phosphate-rand sodium bicarbonate. The sodium .ions thus replaced are conserved and return to the blood, and carbonic acid formed in the above reaction catalyzed by carbonic anhydrase also returns to the blood.
In accordance with the present invention, it has been found that carbonic anhydraseactivity can be effectively inhibited and the excretiontof water, sodium and potassium in the urine increased by the use of therapeutic compositions including a p-sulfamyl carbanilate compound having the following formula:
SiOgNHg NHCOOR wherein R is ethyl, S-hydroxy ethyl or allyl. The inhibition of carbonic anhydrase activity by the composi tionsof the present invention resultsin a reduction of hydrogen ions available for the acidification of the urine. As a consequence, the pH of the urine increases, fewer sodium ions of the buffer compounds are replaced by hydrogen ions, and larger amounts of sodium, chloride and bicarbonate are excreted in the urine. Further, because the formation of carbonic acid from carbon dioxide and water is inhibited, water excretion is increased. Thus, the diuretic action provided by the compositions of the inventionis useful to relieve edema, for example, caused bycongestive heart failure or other causes.
It has further been found in accordance with the present invention that when 2,4-diamino s-triazine (also known as formoguanamine), 2-arnino-4-B-carboxy ethyl amino, s triazine, 2,4-(fl-carboxy ethyl amino) s-triazine, 2 amino 4 anilino 1,3,5 triazine, 2 amino 4- (p-chloroanilino)-l,3,5-triazine or the nontoxic salts of one of these compounds is included in these novel therapeutic compositions, the amount of water, sodium and chloride, particularly the latter, secreted in the urine is markedly increased. The diuretic action of these triazine compounds is believed to be due to the inhibition of tubular reabsorption brought about by a partial anoxia from the inhibition of respiratory enzymes involved in the tubular reabsorption of water and sodium chloride. The increase in diuretic action noted when one of these'tria'zine compounds is included in the therapeutic" compositions'of the invention is more than can be accounted for by the additive eifect of the carbanilate compound andthe triazine compound on the basis of their action individually, as' is shown by the tests described hereinafter. Among the exemplary nontoxic salts of 2, 4- diamino s-triazine, 2-amino-4-[3-carboxy ethyl amino s-triazine, 2,4-(f3-carboxy ethyl amino) striazine, 2- amino-4-ani1ino-1,3,5-triazine and 2-amino-4-(p-chloroanilino)-l,3,5-triazine which are useful as components of the compositions of the invention may be mentioned the hydrochloride, sulfate, phosphate and tartrate salts. The salts of the alkali metals, ammonia and amines may also be utilized. The amount of triazine component, when includedin the compositions of the invention, may be varied considerably and may be, for example, approximately 27% by weight.
The p-sulfamyl carbanilate compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable and nontoxic. For example, intraperitoneal doses of; p-Sulfamyl fl-hydroxy ethyl carbanilate .up to 1600 mg/kg, were tolerated by. male white rats, and only three animalsout of .a group of ..nine. receiving 1800 Ing /kg. intraperitoneally died.1.Moreover,. oral doses up to 1500 rngjlgg. of this carbanilate. compound did not prpduce any ill effectjn male whiterats. Three groups of white rats, with six animals in each group, received 6 00 QOQ and 1200 mg./kg. respectively of p-sulfamyl fl-hydr'oxy ethyl carbanilate-per day for twelve days and gross pathology after being sacrificed showed "a" normal and autopsied on the thirteenth day.
The carbanilate compounds of the novel therapeutic compositions of the invention have the formula:
NHCOOB.
wherein R represents ethyl, B-hydroxy ethyl or allyl. The therapeutic compositions of the present invention comprise a compound of the above mentioned class and a pharmaceutical carrier which may be either a liquid or solid material. It is preferred that the pharmaceutical carrier be a solid material such as, for example, starch, gelatin, lactose, talc, calcium stearate or the like. Any of the pharmaceutical carriers conventionally used in therapeutic compositions may be utilized where such materials are compatible with the aforementioned carbanilate compounds. These compositions include tablets, capsules and the like, and may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions, elixirs and the like.
The percentage of the carbanilate compound incorporated in the therapeutic compositions of the invention may be varied considerably. Exemplary compositions may contain approximately 80% by weight of one of the above mentioned carbanilate compounds, although greater or smaller amounts than 80% may also be used in the practice of the invention. The daily dosage administered to a patient may also vary considerably, depending upon the patients condition and the amount prescribed by the physician in charge. In the case of edema, the daily dosage of these novel compositions may be such that the patient ingests on the order of 250 mg. to 500 mg. of one of the carbanilate compounds per day.
The following examples illustrate the invention.
Example 1 Therapeutic diuretic tablets were prepared having the following composition:
Component: G. p-Sulfamyl fi-hydroxy ethyl carbanilate 0.500 Formoguanamine 0.250 Betaine hydrochloride 0.065 Corn starch U.S.P. 0.100 Calcium stearate 0.010 Talcum powder 0.005
Example 2 Therapeutic diuretic tablets were prepared having the following composition:
Component: G. p-Sulfamyl S-hydroxy ethyl carbanilate 0.250
2 amino 4 anilino-1,3,5-triazine hydrochloride 0.125 Betaine hydrochloride 0.065 Corn starch U.S.P. 0.100 Calcium stearate 0.010 Talcum powder 0.005
The tablets were prepared by first mixing the p-sulfamyl fl-hydroxy ethyl carbanilate, 2-amino-4-anilino-l,3,5-trtazine hydrochloride and betaine hydrochloride in the dry state. This mixture was then wet granulated with isopropyl alcohol (0.125 ml. per tablet) and water (0.125 ml. per tablet). The wet granulated mixture was thereafter dried on trays at a temperature of F. for 15 hours, and the dry mixture was ground in an oscillator using a No. 11 heavy wire screen. The corn starch, calcium stearate and talcum powder were added and, after thorough mixing, the mixture was compressed into tab ets.
Example 3 The inhibition of carbonic anhydrase activity by psulfamyl allyl carbanilate was determined as follows:
The carbonic anhydrase employed was prepared from rabbit red blood cells by the method of Keilin and Mann (Biochem. J. 34, 1166, 1940). The red blood cells were Washed three times with saline by centrifugation. To the washed cells (10 ml.) in a centrifuge tube were added distilled water (6 ml.), ethyl alcohol (4 ml.) and chloroform (5 ml.). The mixture was shaken well and centrifuged for 25 minutes at 2500 r.p.m. A three phase system was formed consisting of a top layer of enzyme solution, a central layer of denatured protein and a bottom layer of chloroform.
The top layer was removed and the activity of the carbonic anhydrase determined by a modification of the meth 0d of Meldrum and Roughton (J. Physiol. 80, 116-124, 1934), which measures the catalytic effect of the carbonic anhydrase enzyme on the rate of evolution of carbon dioxide from sodium bicarbonate solutions when mixed with phosphate buffer of pH 6.8. A sodium bicarbonate solution (1.1 ml.) (0.2 M) (prepared by dissolving the sodium bicarbonate in a 0.02 M sodium hydroxide solution) was placed in the main compartment of a 15 ml. Warburg flask while phosphate buffer (1 ml.) made by mixing equal volumes of disodium phosphate solution (0.2 M) and potassium acid phosphate solution (0.2 M) was placed in one side arm of the flask. The flask was attached to a manometer and the solution equilibrated 1 at 25 C in a shaking machine. The rate of carbon dioxide evolution in the presence of carbonic anhydrase enzyme solution (1 ml.) was measured and compared with a blank. It was found that at a concentration of l mg./ml. of p-sulfamyl allyl carbanilate 84% inhibition of carbonic anhydrase activity was effected when tested according to this method.
Other compositions of the invention corresponding to the above described compositions andgcontaining comparable amounts of p-sulfamyl ethyl carbanilate, p-sulfamyl, allyl carbanilate and one of the aforementioned triazine compounds may be prepared and are effective in the practice of the invention.
It will be understood, of course, that the therapeutic compositions of the invention may be employed in the treatment of any condition where the inhibition of carbonic anhydrase activity will produce a beneficial result.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
We claim:
1. A therapeutic composition comprising a compound having the formula:
NHCOOR wherein R represents a radical selected from the group consisting of ethyl, p-hydroxy ethyl and allyl, a compound selected from the group consisting of 2,4-diamino s-triazine, 2-amiuo-4-p-carboxy ethyl amino s-triazine, 2,4- (B-carboxy ethyl amino) s-triazine, 2-amino-4-anilino- 1,3,5-triazine, 2-amino-4-(p-chloroa-nilino)-1,3,5-triazine and the nontoxic salts thereof, and a pharmaceutical carrier.
2. A therapeutic composition comprising p-sulfamyl a hydroxy ethyl carbanilate, 2-amino-4- -anilino-1,3,5-triazine and a pharmaceutical carrier.
3. A therapeutic composition comprising p-sulfamyl ethyl carbanilate, 2-amino-4-anilino-1,3,5-triazine and a pharmaceutical carrier.
4. A therapeutic composition comprising p-sulfamyl allyl carbanilate, 2-amino-4-anilino-1,3,5-triazine and a pharmaceutical carrier.
5. A therapeutic composition comprising p-sulfamyl References Cited in the file of this patent U.S. Dispensatory, 25th ed., pp. 191-492.
J. Am. Chem. Soc., vol. 72, November 1950, pp. 4893-4896.
Chem. Abst., vol. 41, 1947, pp. 4809-4811.
Vogl: Diuretic Ther., Williams and Wilkins Co., 1953, p. 47, Baltimore, Md.
I.A.M.A., vol. 151, No. 16, Apr. 18, 1953, p. 1430.

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1. A THERAPEUTIC COMPOSITION COMPRISING A COMPOUND HAVING THE FORMULA:
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US4917108A (en) * 1988-06-29 1990-04-17 Mault James R Oxygen consumption meter
US5836300A (en) * 1996-03-11 1998-11-17 Mault; James R. Metabolic gas exchange and noninvasive cardiac output monitor
US6135107A (en) * 1996-03-11 2000-10-24 Mault; James R. Metabolic gas exchange and noninvasive cardiac output monitor
US6277645B1 (en) 1998-08-03 2001-08-21 James R. Mault Method and apparatus for respiratory gas analysis employing measurement of expired gas mass
US6309360B1 (en) 1997-03-17 2001-10-30 James R. Mault Respiratory calorimeter
US20010044588A1 (en) * 1996-02-22 2001-11-22 Mault James R. Monitoring system
US20020047867A1 (en) * 2000-09-07 2002-04-25 Mault James R Image based diet logging
US20020055857A1 (en) * 2000-10-31 2002-05-09 Mault James R. Method of assisting individuals in lifestyle control programs conducive to good health
US6402698B1 (en) 1998-02-05 2002-06-11 James R. Mault Metabolic calorimeter employing respiratory gas analysis
US6406435B1 (en) 1998-11-17 2002-06-18 James R. Mault Method and apparatus for the non-invasive determination of cardiac output
US20020133378A1 (en) * 2000-10-13 2002-09-19 Mault James R. System and method of integrated calorie management
US20020138213A1 (en) * 2001-03-02 2002-09-26 Mault James R. System and method of metabolic rate measurement
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US20030163321A1 (en) * 2000-06-16 2003-08-28 Mault James R Speech recognition capability for a personal digital assistant
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US6629934B2 (en) 2000-02-02 2003-10-07 Healthetech, Inc. Indirect calorimeter for medical applications
US20030208133A1 (en) * 2000-06-07 2003-11-06 Mault James R Breath ketone analyzer
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US20030220579A1 (en) * 2002-04-01 2003-11-27 Mault James R. System and method of determining an individualized drug administration protocol
US20030226695A1 (en) * 2000-05-25 2003-12-11 Mault James R. Weight control method using physical activity based parameters
US6790178B1 (en) * 1999-09-24 2004-09-14 Healthetech, Inc. Physiological monitor and associated computation, display and communication unit

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Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4917108A (en) * 1988-06-29 1990-04-17 Mault James R Oxygen consumption meter
US20010044588A1 (en) * 1996-02-22 2001-11-22 Mault James R. Monitoring system
US5836300A (en) * 1996-03-11 1998-11-17 Mault; James R. Metabolic gas exchange and noninvasive cardiac output monitor
US6135107A (en) * 1996-03-11 2000-10-24 Mault; James R. Metabolic gas exchange and noninvasive cardiac output monitor
US6309360B1 (en) 1997-03-17 2001-10-30 James R. Mault Respiratory calorimeter
US6645158B2 (en) 1998-02-05 2003-11-11 Healthetech, Inc. Metabolic calorimeter employing respiratory gas analysis
US6402698B1 (en) 1998-02-05 2002-06-11 James R. Mault Metabolic calorimeter employing respiratory gas analysis
US6506608B2 (en) 1998-08-03 2003-01-14 Healthetech, Inc. Method and apparatus for respiratory gas analysis employing measurement of expired gas mass
US6277645B1 (en) 1998-08-03 2001-08-21 James R. Mault Method and apparatus for respiratory gas analysis employing measurement of expired gas mass
US6406435B1 (en) 1998-11-17 2002-06-18 James R. Mault Method and apparatus for the non-invasive determination of cardiac output
US20030167016A1 (en) * 1999-05-10 2003-09-04 Mault James R. Airway-based cardiac output monitor and methods for using same
US6517496B1 (en) 1999-05-10 2003-02-11 Healthetech, Inc. Airway-based cardiac output monitor and methods for using same
US6468222B1 (en) 1999-08-02 2002-10-22 Healthetech, Inc. Metabolic calorimeter employing respiratory gas analysis
US6955650B2 (en) 1999-08-02 2005-10-18 Healthetech, Inc. Metabolic calorimeter employing respiratory gas analysis
US6899683B2 (en) 1999-08-02 2005-05-31 Healthetech, Inc. Metabolic calorimeter employing respiratory gas analysis
US20030065274A1 (en) * 1999-08-02 2003-04-03 Mault James R. Method of respiratory gas analysis using a metabolic calorimeter
US20030065275A1 (en) * 1999-08-02 2003-04-03 Mault James R. Metabolic calorimeter employing respiratory gas analysis
US6790178B1 (en) * 1999-09-24 2004-09-14 Healthetech, Inc. Physiological monitor and associated computation, display and communication unit
US6478736B1 (en) 1999-10-08 2002-11-12 Healthetech, Inc. Integrated calorie management system
US6612306B1 (en) 1999-10-13 2003-09-02 Healthetech, Inc. Respiratory nitric oxide meter
US6629934B2 (en) 2000-02-02 2003-10-07 Healthetech, Inc. Indirect calorimeter for medical applications
US6482158B2 (en) 2000-05-19 2002-11-19 Healthetech, Inc. System and method of ultrasonic mammography
US20030226695A1 (en) * 2000-05-25 2003-12-11 Mault James R. Weight control method using physical activity based parameters
US20030208110A1 (en) * 2000-05-25 2003-11-06 Mault James R Physiological monitoring using wrist-mounted device
US20030208133A1 (en) * 2000-06-07 2003-11-06 Mault James R Breath ketone analyzer
US20030163321A1 (en) * 2000-06-16 2003-08-28 Mault James R Speech recognition capability for a personal digital assistant
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