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WO1998003175A1 - Traitement de l'obesite - Google Patents

Traitement de l'obesite Download PDF

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Publication number
WO1998003175A1
WO1998003175A1 PCT/AU1997/000453 AU9700453W WO9803175A1 WO 1998003175 A1 WO1998003175 A1 WO 1998003175A1 AU 9700453 W AU9700453 W AU 9700453W WO 9803175 A1 WO9803175 A1 WO 9803175A1
Authority
WO
WIPO (PCT)
Prior art keywords
nicotine
leptin
obesity
patient
nicotinic
Prior art date
Application number
PCT/AU1997/000453
Other languages
English (en)
Inventor
Paul Zev Zimmet
Roderick Alan Westerman
Gregory Collier
Original Assignee
International Diabetes Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by International Diabetes Institute filed Critical International Diabetes Institute
Priority to AU34296/97A priority Critical patent/AU3429697A/en
Publication of WO1998003175A1 publication Critical patent/WO1998003175A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • 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
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin

Definitions

  • the invention relates to the treatment of obesity in all subjects, whether diabetic or nondiabetic, with or without concomitant other therapies, and in particular it relates to a novel method of treatment using nicotinic mechanisms and compounds active at nicotinic binding sites and affecting other relevant sites such as leptin, neuropeptide Y (NPY), galanin, serotonin or dopamine receptors in nerve cells to increase the sensitivity of brain responsiveness to leptin.
  • NPY neuropeptide Y
  • galanin neuropeptide Y
  • serotonin serotonin
  • dopamine receptors in nerve cells to increase the sensitivity of brain responsiveness to leptin.
  • leptin a 16 kilodalton protein
  • iipostat a sensing hormone
  • leptin receptors have been located in the hypothalamus of the diabetic (db) mouse (4) providing further support for the feedback hypothesis that was generated over 20 years ago by Coleman et al from parabiosis experiments in obese (ob/ob) and diabetic (db/db) mice (5).
  • the present invention provides a method for the treatment of obesity, or for the prevention of obesity in persons pre-disposed to obesity, in which the sensitivity of hypothalamic leptin or other receptors, such as NPY etc, is modified so that leptin synthesis is modulated and as a consequence body weight is controlled.
  • the present invention relates to a method for the treatment of obesity in a patient, which comprises administration to the patient of an effective amount of nicotine or a nicotine analogue.
  • the present invention relates to a method for the prevention of obesity in a patient pre-disposed to obesity, which comprises administration to the patient of an effective amount of nicotine or a nicotine analogue.
  • the patient is a human patient, and the methods of the present invention extend to treatment or prevention of obesity in both diabetic and non- diabetic patients.
  • Nicotine is of course a well known substance. It is to be understood, however, that the present invention also extends to the use of nicotinic analogues such as ABT 418, (+)-2-methylpiperidine, and other agonists or antagonists of nicotine shown to alter the brain and hypothalamic responsiveness to leptin.
  • nicotinic analogues such as ABT 418, (+)-2-methylpiperidine
  • Various nicotine analogues which are agonists or antagonists of nicotine are disclosed by Williams el a/ (1994) Drug News and Perspectives, Vol. 7, No. 4, 205-223, the contents of which are incorporated herein by reference.
  • the present invention extends to the use of these nicotine analogues, particularly those which are selective for the hypothalamic leptin receptors in humans.
  • nicotine analogues as discussed above, such as ABT 418 and (+)-2-methylpiperidine, in the method of this invention may be preferable.
  • Such nicotine analogues may also have fewer side effects, and may be tailored to the specific hypothalamic nicotine acetylcholine receptor (nAchR) epitope which may be involved in the modulation of leptin receptor sensitivity, either directly or indirectly.
  • nAchR hypothalamic nicotine acetylcholine receptor
  • the present invention extends to combination therapy in which more than one active component is used in the therapeutic and prophylactic methods of treatment of obesity.
  • combinations of nicotine and nicotine analogues may be used in such combination therapy, including a combination such as an agonist together with an antagonist which may be particularly useful in modulating leptin sensitivity and weight gain.
  • nicotine and nicotine analogues in accordance with the present invention may be combined with the use of leptin in an synergistic treatment of obesity in order to improve the sensitivity to leptin and to achieve the same therapeutic or prophylactic effect in treating obesity at lower doses and cost.
  • a synergistic treatment may involve either co-administration or separate administration of leptin with the active component(s) of the present invention.
  • the nicotine or nicotine analogue will be administered in the form of a pharmaceutical composition.
  • Suitable pharmaceutically acceptable carriers and/or diluents include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art, and it is described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA.
  • compositions of the present invention can also be incorporated into the compositions. It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the human subjects to be treated; each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier and/or diluent.
  • the specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active ingredient and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active ingredient for the particular treatment.
  • a variety of administration routes are available. The particular mode selected will depend, of course, upon the particular condition being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practised using any mode of administration that is medically acceptable, meaning any mode that produces therapeutic levels of the active component of the invention without causing clinically unacceptable adverse effects.
  • modes of administration include oral, topical, transmucosal, transdermal, rectal, nasal or parenteral (e.g. subcutaneous, intramuscular and intravenous) routes.
  • Continuous transdermal administration by means of a skin patch or the like is a known, medically acceptable method of administration of nicotine and may be used in the therapeutic and prophylactic methods of the present invention.
  • compositions may conveniently be prepared by any of the methods well known in the art of pharmacy.
  • Compositions 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 component, in liposomes or as a suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, or an emulsion.
  • Such preparations may also include a fixed- or metered-dose nasal spray.
  • the active component may be formulated as a chewing gum for intermittent oral administration.
  • sustained or slow release delivery systems can include sustained or slow release delivery systems.
  • Preferred sustained or slow release delivery systems are those which can provide for release of the active component of the invention in sustained or slow release lozenges, tablets, pellets or capsules.
  • Many types of sustained release delivery systems are available. These include, but are not limited to: (a) erosional systems in which the active component is contained within a matrix, and (b) diffusional systems in which the active component permeates at a controlled rate through a polymer.
  • Oral administration for many conditions will be preferred because of the convenience to the patient, although topical and localised sustained or slow delivery may be even more desirable for certain treatment regimens.
  • the active component is administered in an effective amount.
  • Reference herein to an effective amount means that amount necessary at least partly to attain the desired effect, or to delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the particular condition being treated. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters including age, physical condition, size, weight and concurrent treatment. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgement. It will be understood by those of ordinary skill in the art, however, that a lower dose or tolerable dose may be administered for medical reasons, psychological reasons or for virtually any other reasons.
  • the effective amount will be selected so that administration of the active component will be free of adverse or undesired side effects.
  • daily oral doses of active component will be from about 0.01 mg/kg per day to 10 mg/kg per day. Small doses (0.01-1 mg/kg per day) may be administered initially, followed by increasing doses up to about 5-10 mg/kg per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localised delivery route) may be employed to the extent patient tolerance and side effects permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds. In the treatment of obesity in morbidly obese individuals, daily doses of 2-20 mg of active component may be required.
  • Leptin Importance in diabetes.
  • the human ob gene is normal in obese humans (13, 14) and in these subjects there is over- rather than under-expression , with increased amounts of ob messenger RNA produced (15,16) which correlated with body weight and fat mass.
  • leptin receptors and hypothalamic feedback mechanisms in humans have not yet been defined.
  • the leptin/insulin relationship held even in subjects with diabetes, supporting the decision to combine data from diabetic and non-diabetic individuals.
  • the duration of diabetes was nevertheless relatively short.
  • subjects with longer duration of NIDDM and impaired insulin secretion the linear relationship between insulin and leptin may be weakened. Nevertheless, insulin has been shown to have an important effect on leptin production in adipocytes (31).
  • leptin receptor may be synonymous with Neel's thrifty gene and lead to Syndrome X (18).
  • Possible mechanisms by which leptin may affect insulin sensitivity are only speculative, but include: (a) Down regulation of hypothalamic leptin receptors leads to increased leptin levels. This causes further leptin synthesis and release with further downregulation of hypothalamic receptors and this vicious cycle results in hyperinsulinaemia, adiposity and dyslipidaemia, precursors to NIDDM; (b) Leptin itself could cause insulin resistance or increased food-energy intake, leading to increased adipocyte mass and decreased insulin sensitivity. This primary increase in central adipose tissue mass in NIDDM increases leptin production, loss of appetite control, weight gain, and further insulin resistance and hyperleptinaemia.
  • the nicotine analogues will be useful as insulin sensitisers in the therapy of all insulin resistant states such as diabetes.
  • Acetylcholine (Ach) receptors in the mammalian central nervous system (CNS) have been divided into muscarinic (mAChR) and nicotinic (nAChR) subtypes, based on the relative agonist activities of the natural alkaloids muscarine and nicotine (52).
  • ACh replacement strategies with choline precursors, cholinesterase inhibitors like tacrine and velnacrine, Ach-releasing agents like linopirdine, and directly acting Ach receptor agonists have all been used to replace or potentiate the actions of ACh at the synaptic cleft. These have predominantly targeted agonists active at mAChRs but the majority of mAChR ligands tested to date have been disappointing in terms of the goal of centrally active agents devoid of peripheral side effects (52).
  • nAChRs play a significant role in mediating the molecular events related to cognitive performance, affect modulation, and enhancement of brain function. So far, at least 7 putative neuronal nAChR subtypes have been identified in transfected oocyte preparations (53,54). The wide distribution of the a2, a3,a4 and b2 transcripts in human brain indicates that neuronal nAChRs are a major neurotransmitter receptor superfamily, structurally related to the other ligand-gated ion channel families that include GABA A N-methyl-D-aspartate(NMDA) and glycine (55,56).
  • NMDA N-methyl-D-aspartate
  • nAChRs are presently characterised by radioligand binding techniques: those that have a high affinity (0.5-5nM) for [ 3 H]-acetylcholine (57), [ 3 HJ- nicotine (58), [ 3 H]-cytisine (59) and 3 [ H]-methylcarbamylcholine (60); those that recognise a-BgT with high affinity (0.5nM) (58) and a population of nAChRs that display marked selectivity for n-BgT (61).
  • DH ⁇ E dihydro- ⁇ - erythroidine
  • nAChR function can also be modulated in a more persistent manner by phosphorylation of receptor proteins (65).
  • At least four protein kinases - a cAMP-dependent kinase, PKA, protein kinase C, a tyrosine kinase and a Ca++ -calmodulin kinase differentially phosphorylate muscle, neuronal and Torpedo nAChR subunits. This provides potential for the indirect modulation of nAChR equilibrium transitional states by neuropeptides (66).
  • Ligand binding sites on the nAChR Ligand binding sites on the nAChR
  • the combination of neuronal nAChR subunits present will determine the nAChR pharmacological and functional properties.
  • the ACh binding site has been localised at the interfaces between the a- and b- subunits and the a- and g- subunits (67).
  • Alternative channel activator sites are distinct from the sites at which Ach and nicotine bind, and include cholinesterase inhibitors physostigmine and galanthium (64).
  • (+)-2-Methyl-piperidine enhances receptor interactions with the endogenous ligand, Ach, facilitating only ongoing or evoked cholinergic neurotransmission, thereby limiting the potential for side-effect liability (68).
  • This type of compound resembles glycine antagonists acting at NMDA receptors or the various allosteric modulators of the GABA/benzodiazepine receptor complex (55,56).
  • Non-competitive blockers N-competitive blockers
  • NCBs are an important class of compounds affecting nAChRs.
  • Steroids can allosterically desensitize the nAChR by occupying their binding sites on neuronal nAChRs.
  • progesterone testosterone, dexamethasone, hydrocortisone and prednisolone can act as noncompetitive inhibitors of nAChRs (67).
  • corticosteroids [ 1 5 l]-a-BgT binding proteins and behavioural sensitivity to nicotine (71).
  • corticosterone inhibited binding of [ 125 l]-a-BgT to rat brain membranes and reduced the affinity of nicotine for this site, consistent with a negative allosteric interaction.
  • DHPs like nimodipine interact with neuronal nAChR at clinically relevant concentrations (72) and may limit vasoconstrictor effects of excess circulating catecholamines (evoked by increased sympathetic outflow).
  • Findings suggest that chromaffin neuronal nAChRs contain a DHP site whose occupation blocks ligand-gated Na+ entry through the ionophore, limiting the ensuing membrane depolarization, firing of APs, recruitment of Ca++ channels, Ca++ entry.
  • Direct binding of Ca++ and other divalent cations to sites within the nAChR channel can decrease the single-channel conductance in a voltage-dependent way and enhance the desensitization of muscle nAChRs.
  • extracellular Ca++ affects some neuronal nAChRs in the opposite direction, with Ca++ potentiating the response to agonists at both positive and negative membrane potentials at sites located outside of the ion channel (67).
  • Ca++ In the habenula nucleus Ca++ in physiological concentrations increases the frequency but not the duration of channel opening (73).
  • Nicotine modulates brain function by enhancing ion flux and neuronal transmitter release, leading to a facilitation or gating of a number of neuronal systems, and thus eliciting a number of behavioural states (74).
  • the only proven site of nicotinic AChR neurotransmission is the motor neuron-Renshaw cell synapse in spinal cord (75).
  • nicotine responses can also be observed in retina, spinal cord, hippocampus, brainstem respiratory nuclei, cerebral and cerebellar cortex, thalamus, hypothalamus, interpeduncular nucleus, septal nucleus, substantia nigra, striatum and locus coeruleus (76).
  • activation of presynaptic nAChRs leads to facilitation of the release of Ach, dopamine, noradrenaline, serotonin, GABA, and glutamate (76,77).
  • a number of CNS functions are regulated via the basal forebrain cholinergic system, including aspects of attention (78) cognitive performance (79), cerebral blood flow (80), cerebral glucose utilization (69), and neocortical electrical activity (81). Nicotinic agonists augment these activities, and they are reduced by mecamylamine (82), age-related decrements of the basal forebrain cholinergic system, or abolished by excitotoxin-evoked destruction of the system (69).
  • Surgically induced and age-associated deficits in central acetylcholinergic systems can produce an impairment of performance in various models of cognitive function (83, 84,85,86) his raises the possibility of a beneficial effect in Alzheimer's disease and nicotine has been shown to improve cognitive performance in animal (87,88 ) and human studies (82). Again, it would be of interest to have epidemiological studies to determine whether there is an inverse relationship between a history of smoking and the development of Alzheimer's disease, and prospective studies are in progress to determine whether nicotine analogues are of therapeutic value.
  • nicotinic agonists Another effect of membrane depolarization by nicotinic agonists is rapid transient stimulation of transcription of the c-fos proto-oncogenes and actin genes .
  • nicotinic receptors appear to regulate the late onset genes, and nicotine stimulates late transcription of proencephlin A and tyrosine hydroxylase genes in bovine chromaffin cells (97).
  • BDNF brain-derived neurotrophic factor
  • NGF nerve growth factor
  • Nicotinic nAChR binding sites are present in spinal cord and cerebral cortex on capsaicin- sensitive neurons (101) many of which are involved in nociception and consonant with nicotine having analgetic and anxiolytic actions(100).
  • Chronic nicotine does not upregulate nAChR binding in spinal cord but does, in a dose-dependent manner in cerebral cortex (102,103) emphasizing the regional and even site-specificity of its actions.
  • Nicotine and its analogues have been administered by mouth eg as chewing gum, applied as transdermal patches (104) in attempts to assist smoking cessation. Combined therapy using the antagonist mecamylamine together with the agonist nicotine has proven very helpful.
  • Novel nicotinic cholinergic ligands with ion- channel-selective enhancing or blocking properties are now being examined for their therapeutic efficacy in various state (105). Although this field is now extremely active, no specific actions on hypothalamic leptin receptors have been proposed or foreshadowed apart from the proposals by Hodge et al (50).
  • Waist/hip ratio 0.91 (0.05) 0.91 (0.06) 0.413
  • Non- Smokers P Non- Smokers P smokers smokers
  • Animals were followed during a run-in period of approximately 7 days. Animals were then implanted with Alzet mini-osmotic pumps containing either saline (control) or nicotine. The pumps delivered nicotine at a dosage of 12 mg/day. After 6 days, the animals were sacrificed and a number of tissues (including adipose stores and muscle) removed for body fat and muscle distribution and future RNA analyses. During the study, body weight, food intake, glucose and insulin were measured on days 0, 2 and 6 from the date of implantation of the mini-osmotic pumps.
  • Considine RV Considine EL
  • Bauer TL et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J din Invest 1995; 95:2986-88.
  • Klesges RC Klesges LM The relationship between body mass and cigarette smoking using a biochemical measure of smoking exposure. Int J Obesity 1993; 17:585-591.
  • Yost SC Dodson BA. Inhibition of nicotinic acetylcholine receptor by barbiturates and by procaine: do they act at different sites? Cellular Mol Neurobiol 1993; 13: 159-172.
  • Papke RI The kinetic properties of neuronal nicotinic acetylcholine receptors: Genetic basis of functional diversity. Prog Neurobiol, 41 : 509- 531.
  • Nicotinic agonists modulate basal forebrain (BF) control of cortical cerebral blood flow in anaesthetized rats. J Pharmacol Exp 77?er 1993; 267: 440-448.
  • McCormick DA Cellular mechanism of cholinergic control of neocortical and thalamic neuronal excitability. In: Brain cholinergic systems. M Steriade, D Biesold (Eds). Oxford University Press, 1990, 236-264.
  • Giacobini E Cholinergic receptors in human brain: Effects of aging and Alzheimer's disease. J Neurosci Res 1990; 27: 548-560.
  • ABT 418 A novel cholinergic channel ligand with the potential to treat anxiety disorders. J Pharmacol Exp Ther 1994; in press.

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Abstract

Ce procédé de traitement de l'obésité chez un patient, ou de prévention de celle-ci chez un patient prédisposé à l'obésité, consiste à administrer à celui-ci une dose efficace de nicotine ou d'un analogue de la nicotine.
PCT/AU1997/000453 1996-07-18 1997-07-18 Traitement de l'obesite WO1998003175A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34296/97A AU3429697A (en) 1996-07-18 1997-07-18 Treatment of obesity

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Application Number Priority Date Filing Date Title
AUPO1085A AUPO108596A0 (en) 1996-07-18 1996-07-18 Treatment of obesity
AUPO1085 1996-07-18

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WO1998003175A1 true WO1998003175A1 (fr) 1998-01-29

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7591859B2 (en) 2006-08-15 2009-09-22 Whirlpool Corporation Water supply control for a steam generator of a fabric treatment appliance using a weight sensor
US7627920B2 (en) 2006-06-09 2009-12-08 Whirlpool Corporation Method of operating a washing machine using steam
US10844533B2 (en) 2007-05-07 2020-11-24 Whirlpool Corporation Method for controlling a household washing machine

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Publication number Priority date Publication date Assignee Title
DE3438284A1 (de) * 1984-10-16 1985-03-07 Hans-Harald von 2400 Lübeck Tilly Nikotinhaltiges depotpflaster
WO1988003803A1 (fr) * 1986-11-18 1988-06-02 Forschungsgesellschaft Rauchen Und Gesundheit Mbh Capsule a administration orale avec un milieu fluide contenant de la nicotine
EP0366240A1 (fr) * 1988-10-28 1990-05-02 Pharmacia AB Pansement de nicotine à activité prolongée
WO1996000070A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine pour administration par voie orale
WO1996000071A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition liquide contenant de la nicotine et de la cafeine ou de la xanthine, pour administration par voie nasale
WO1996000072A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine, pouvant etre administree par voie transdermique ou a travers les muqueuses
WO1996000069A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition solide ou semi-solide contenant de la nicotine et de la cafeine ou de la xanthine, notamment pour administration par voie nasale
US5573774A (en) * 1993-02-02 1996-11-12 Keenan; Robert M. Nicotine metabolites, nicotine dependence and human body weight

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3438284A1 (de) * 1984-10-16 1985-03-07 Hans-Harald von 2400 Lübeck Tilly Nikotinhaltiges depotpflaster
WO1988003803A1 (fr) * 1986-11-18 1988-06-02 Forschungsgesellschaft Rauchen Und Gesundheit Mbh Capsule a administration orale avec un milieu fluide contenant de la nicotine
EP0366240A1 (fr) * 1988-10-28 1990-05-02 Pharmacia AB Pansement de nicotine à activité prolongée
US5573774A (en) * 1993-02-02 1996-11-12 Keenan; Robert M. Nicotine metabolites, nicotine dependence and human body weight
WO1996000070A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine pour administration par voie orale
WO1996000071A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition liquide contenant de la nicotine et de la cafeine ou de la xanthine, pour administration par voie nasale
WO1996000072A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine, pouvant etre administree par voie transdermique ou a travers les muqueuses
WO1996000069A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition solide ou semi-solide contenant de la nicotine et de la cafeine ou de la xanthine, notamment pour administration par voie nasale

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7627920B2 (en) 2006-06-09 2009-12-08 Whirlpool Corporation Method of operating a washing machine using steam
US7591859B2 (en) 2006-08-15 2009-09-22 Whirlpool Corporation Water supply control for a steam generator of a fabric treatment appliance using a weight sensor
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