System and Method for Real-Time Diagnosis, Treatment, and Therapeutic Drug Monitoring

• US 20070258894A1
• Filed: 02/28/2005
• Published: 11/08/2007
• Est. Priority Date: 11/08/2000
• Status: Abandoned Application

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Inventors: Dennis, Donn, Melker, Richard, Gold, Mark, Sackellares, James
• Application Number:
  US10/588,749
• Publication Number:
  US 20070258894A1
• Time in Patent Office: Days
• US Class Current: 424/9.100
• CPC Class Codes: A61B 5/0836 Measuring rate of CO2 production
• CPC Class Codes: A61B 5/145 Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissuemeasuring of blood pressure or blood flow A61B5/02; non-radiation detecting or locating of foreign bodies in blood A61B5/06
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• CPC Class Codes: A61B 5/4833 Assessment of subject's compliance to treatment
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath

Abstract

Systems and methods for diagnosing and/or treating diseases as well as monitoring disease treatment. For diagnosis, the present invention uses nanoparticle-based assemblies, which comprise a nanoparticle; a surrogate marker; and a means for detecting a specific chemical entity. In certain embodiments, nanoparticle-based assemblies include a payload for simultaneous diagnosis and treatment of disease. In further embodiments, a therapeutic drug and therapeutic drug marker are administered to a patient to monitor disease treatment. Bodily fluid samples are analyzed using sensor technology to detect the presence of surrogate and/or therapeutic drug markers to provide an efficient and accurate means for diagnosing a disease and/or monitoring disease treatment.

Claims

1-56. -56. (canceled)

57. A method of monitoring a patient during administration of at least one therapeutic drug, said method comprising:

administering to the patient at least one therapeutic drug;

exposing at least one sensor to expired gases from the patient;

detecting one or more target markers from the therapeutic drug with said sensor.

58. The method of claim 57 wherein said target marker is the therapeutic drug.

59. The method of claim 57 wherein said target marker is a metabolite of the therapeutic drug indicative of the therapeutic drug.

60. The method of claim 57 wherein said target marker is selected from a group consisting of dimethyl sulfoxide (DMSO), acetaldehyde, acetophenone, trans-Anethole (1-methoxy-4-propenyl benzene) (anise), benzaldehyde (benzoic aldehyde), benzyl alcohol, benzyl cinnamate, cadinene, camphene, camphor, cinnamaldehyde (3-phenylpropenal), garlic, citronellal, eresol, cyclohexane, eucalyptol, and eugenol, eugenyl methyl ether;

butyl isobutyrate (n-butyl 2, methyl propanoate) (pineapple);

citral (2-trans-3,7-dimethyl-2,6-actadiene-1-al);

menthol (1-methyl-4-isopropylcyclohexane-3-ol); and

α

-Pinene (2,6,6-trimethylbicyclo-(3,1,1)-2-heptene).

61. The method of claim 57 wherein at least one therapeutic drug is administered to the patient orally.

62. The method of claim 57 wherein at least one therapeutic drug is delivered intravenously.

63. The method of claim 57 wherein the detecting step comprises detecting both presence and concentration of the target marker to determine at least one therapeutic drug concentration in blood.

64. The method of claim 63 further comprising assigning a numerical value to the concentration as analyzed upon reaching a level of therapeutic effect of said therapeutic drug in said patient and, thereafter, assigning higher or lower values to the concentration based on its relative changes.

65. The method of claim 64, further comprising monitoring the concentration by monitoring changes in said value and adjusting administration of the therapeutic drug to maintain a desired therapeutic effect.

66. The method of claim 63 further comprising determining an appropriate dosage of at least one therapeutic drug based on the concentration of at least one target marker detected in said expired gases.

67. The method of claim 57 wherein the steps are repeated periodically to monitor pharmacodynamics and pharmacokinetics of at least one therapeutic drug over time.

68. The method of claim 57 wherein at least one therapeutic drug is for depression.

69. The method of claim 57 wherein at least one therapeutic drug is for analgesia.

70. The method of claim 57 wherein at least one therapeutic drug is selected for the treatment of a condition selected from group consisting of rheumatoid arthritis, systemic lupus erythematosus, angina, coronary artery disease peripheral vascular disease, ulcerative colitis, Crohn'"'"'s disease, organ rejection, epilepsy, anxiety, degenerative arthritis, vasculitis, and inflammation.

71. The method of claim 57 wherein the detecting is continuous.

72. The method of claim 57 wherein the detecting is periodic.

73. The method of claim 57 wherein at least one therapeutic drug is selected from the group consisting of:

α

-Hydroxy-Alprazolam;

Acecainide (NAPA);

Acetaminophen (Tylenol);

Acetylmorphine;

Acetylsalicylic Acid (as Salicylates);

α

-hydroxy-alprazolam;

Alprazolam (Xanax);

Amantadine (Symmetrel);

Ambien (Zolpidem);

Amikacin (Amikin);

Amiodarone (Cordarone);

Amitriptyline (Elavil) &

Nortriptyline;

Amobarbital (Amytal);

Anafranil (Clomipramine) &

Desmethylclomipramine;

Ativan (Lorazepam);

Aventyl (Nortriptyline);

Benadryl (Dephenhydramine);

Benziodiazepines;

Benzoylecgonine;

Benztropine (Cogentin);

Bupivacaine (Marcaine);

Bupropion (Wellbutrin) and Hydroxybupropion;

Butabarbital (Butisol);

Butalbital (Fiorinal) Carbamazepine (Tegretol);

Cardizem (Diltiazem);

Carisoprodol (Soma) &

Meprobamate; and

Celexa (Citalopram &

Desmethylcitalopram).

74. The method of claim 57 wherein at least one therapeutic drug is selected from the group consisting of:

Celontin (Methsuximide) (as desmethylmethsuximide);

Centrax (Prazepam) (as Desmethyldiazepam);

Chloramphenicol (Chloromycetin);

Chlorodiazepoxide;

Chloropromazine (Thorazine);

Chloropropamide (Diabinese);

Clonazepam (Klonopin);

Clorazepate (Tranxene);

Clozapine;

Cocaethylene;

Codeine;

Cogentin (Benztropine);

Compazine (Prochlorperazine);

Cordarone (Amiodarone);

Coumadin (Wardarin);

Cyclobenzaprine (Flexcril);

Cyclosporine (Sandimmune);

Cylert (Pemoline);

Dalmane (Flurazepam) &

Desalkylflurazepam;

Darvocet;

Darvon (Propoxyphene) &

Norpropoxyphene;

Demerol (Meperidine) &

Normeperidine;

Depakene (Valproic Acid);

Depakote (Divalproex) (Measured as Valproic Acid);

Desipramine (Norpramin);

Desmethyldiazepam;

Desyrel (Trazodone);

Diazepam &

Desmethyldiazepam;

Diazepam (Valium) Desmethyldiazepam;

Dieldrin;

Digoxin (Lanoxin);

Dilantin (Phenytoin);

Disopyramide (Norpace);

Dolophine (Methadone);

Doriden (Glutethimide);

Doxepin (Sinequan) and Desmethyldoxepin;

Effexor (Venlafaxine);

Ephedrine;

Equanil (Meprobamate) Ethanol;

Ethosuximide (Zarontin);

Ethotoin (Peganone);

Felbamate (Felbatol);

Fentanyl (Innovar);

Fioricet;

Fipronil;

Flunitrazepam (Rohypnol);

Fluoxetine (Prozac) &

Norfluoxetine;

Fluphenazine (Prolixin);

Fluvoxamine (Luvox);

Gabapentin (Neurontin);

Gamma-Hydroxybutyric Acid (GHB);

Garamycin (Gentamicin);

Gentamicin (Garamycin);

Halazepan (Paxipam);

Halocion (friazolam);

Haldol (Haloperidol);

Hydrocodone (Hycodan);

Hydroxyzine (Vistaril);

Ibuprofen (Advil, Motrin, Nuprin, Rufen);

Imipramine (Tofranil) and Desipramine;

Inderal (Propranolol);

Keppra (Levetiracetam);

Ketamine;

Lamotrigine (Lamictal);

Lanoxin (Digoxin);

Lidocaine (Xylocaine);

Lindane (Gamma-BHC);

Lithium;

Lopressor (Metoprolol);

Lorazepam (Ativan); and

Ludiomil.

75. The method of claim 57 wherein at least one therapeutic drug is selected from the group consisting of:

Maprotiline;

Mebaral (Mephobarbital) &

Phenobarbital;

Mellaril (Thioridazine) &

Mesoridazine;

Mephenytoin (Mesantoin);

Meprobamate (Miltown, Equanil);

Mesantoin (Mephenytoin);

Mesoridazine (Serentil);

Methadone;

Methotrexate (Mexate);

Methsuximide (Celontin) (as desmethsuximide);

Mexiletine (Mexitil);

Midazolam (Versed);

Mirtazapine (Remeron);

Mogadone (Nitrazepam);

Molindone (Moban);

Morphine (Mysoline (Primidone) &

Phenobarbital;

NAPA &

Procainamide (Pronestyl);

NAPA (N-Acetyl-Procainamide);

Navane (Thiothixene);

Nebein (Tobramycin);

Nefazodone (Serzone);

Nembutal (Pentobarbital);

Nordiazepam;

Olanzapine (Zyprexa);

Opiates;

Orinase (Tolbutamide);

Oxazepam (Serax);

Oxcarbazepine (Trileptal) as 10-Hydroxyoxcarbazepine;

Oxycodone (Percodan);

Oxymorphone (Numorphan);

Pamelor (Nortiptyline);

Paroxetine (Paxil);

Paxil (Paroxetine);

Paxipam (Halozepam);

Peganone (Ethotoin);

PEMA (Phenylethylmalonamide);

Pentothal (Thiopental);

Perphenazine (Trilafon);

Phenergan (Promethazine);

Phenothiazine;

Phentermine;

Phenylglyoxylic Acid;

Procainamide (Pronestyl) &

NAPA;

Promazine (Sparine);

Propafenone (Rythmol);

Protriptyline (Vivactyl);

Psuedoephedrine;

Quetiapine (Seroquel);

Restorid (Temazepam);

Risperdal (Risperidone) and Hydroxyrisperidone;

Secobarbital (Seconal);

Sertraline (Zoloft) &

Desmethylsertraline;

Stelazine (Trifluoperazine);

Surmontil (Trimipramine);

Tocainide (Tonocard); and

Topamax (Topiramate).

76. The method of claim 57 wherein said sensor is selected from the group consisting of:

metal-insulator-metal ensemple (MIME) sensors, cross-reactive optical microsensor arrays, fluorescent polymer films, surface enhanced raman spectroscopy (SERS), diode lasers, selected ion flow tubes, metal oxide sensors (MOS), bulk acoustic wave (BAW) sensors, colorimetric tubes, infrared spectroscopy, gas chromatography, semiconductive gas sensor technology;

mass spectrometers, gluorescent spectrophotometers, conductive polymer gas sensor technology;

aptamer sensor technology;

amplifying fluorescent polymer (AFP) sensor technology;

or surface acoustic wave gas sensor technology.

77. The method of claim 76 wherein the sensor technology produces a unique electronic fingerprint to characterize the detection and concentration of said at least one target marker.

78. The method of claim 57 further comprising the step of recording data from said sensor.

79. The method of claim 57 further comprising the step of transmitting data from said sensor.

80. The method of claim 57 further comprising comparing at least one target marker detected with a predetermined signature profile.

81. The method of claim 57 further comprising capturing a sample of expired gases prior to exposing said sensor to expired gases.

82. The method of claim 57 further comprising dehumidifying expired gases prior to exposing said sensor to expired gases.

83. The method of claim 57 further comprising exposing said sensor to expired gases during exhalation of the patient'"'"'s breath.

84. The method of claim 57 further comprising assigning a numerical value to the concentration as analyzed upon reaching a level anesthetic effect in said patient and, thereafter, assigning higher or lower values to the concentration based on its relative changes.

85. The method of claim 57 wherein said sensor is portable.

86. The method of claim 57 wherein at least one therapeutic drug is a psychiatric drug.

87. The method of claim 86 wherein at least one therapeutic drug is selected from the group consisting of antidepressants, anti-psychotics, anti-anxiety drugs, and depressants.

88. A therapeutic drug delivery and monitoring system for delivering an appropriate dosage of the therapeutic drug to a patient:

at least one therapeutic drug supply having a controller for controlling the amount of therapeutic drug provided by the supply to the patient;

an expired gas sensor for analyzing the patient'"'"'s breath for the presence and concentration of at least one target marker indicative of therapeutic drug concentration in the patient'"'"'s bloodstream, and for sending a signal regarding the concentration of the therapeutic drug in the patient'"'"'s bloodstream; and

a system controller connected to the therapeutic drug supply;

which receives and analyzes the signal from the sensor and controls the amount of therapeutic drug administered to the patient based on the signal.

89. The system of claim 88 wherein the expired gas sensor comprise a sensor for analyzing the gas for concentration of at least one target marker indicative of the therapeutic drug concentration in the patient'"'"'s bloodstream and a processor for calculating the pharmacodynamic and pharmacokinetic effect of the therapeutic drug based on the concentration of the therapeutic drug.

90. The system of claim 89 wherein the sensor is selected from the group consisting of:

metal-insulator-metal ensample (MIME) sensors, cross-reactive optical microsensor arrays, fluorescent polymer films, surface enhanced raman spectroscopy (SERS), diode lasers, selected ion flow tubes, metal oxide sensors (MOS), bulk acoustic wave (BAW) sensors, colorimetric tubes, infrared spectroscopy, gas chromatography, semiconductive gas sensor technology;

mass spectrometers, gluorescent spectrophotometers, conductive polymer gas sensor technology;

aptamer sensor technology;

amplifying fluorescent polymer (AFP) sensor technology;

or surface acoustic wave gas sensor technology.