# US 10,869,997 B2 · Methods for improving drug efficacy

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- Number: US 10,869,997 B2
- Document ID: US10869997B2
- Status: Granted
- Kind: B2
- Application number: 15/191,603
- Filed: 2016-06-24
- Published: 2017-02-23
- Granted: 2020-12-22
- Earliest claimed: 2012-12-27
- Assignees: Nuvaira, Inc.
- Applicants: Nuvaira, Inc.
- Inventors: Martin L. Mayse
- Web page: https://patentgrep.com/patent/US10869997B2

## CPC

- A61M 37/00: Other apparatus for introducing media into the body (for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30); Percutany, i.e. introducing medicines into the body by diffusion through the skin (salt baths A61H33/04)
- A61B 17/32: Surgical cutting instruments ({A61B18/042 takes precedence; suture cutters A61B17/0467;} implements for ligaturing and cutting {A61B17/122, A61B17/12; instruments for rupturing the amniotic membrane A61B17/4208; specially adapted knives for eye surgery A61F9/0133})
- A61B 18/1492: {having a flexible, catheter-like structure, e.g. for heart ablation (A61B18/1477 takes precedence)}
- A61B 18/18: by applying electromagnetic radiation, e.g. microwaves
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 1/3611: {Respiration control (stimulating respiratory organs A61N1/3601)}
- A61B 2018/00023: {closed, i.e. without wound contact by the fluid}
- A61B 2018/0022: {Balloons}
- A61B 2018/00541: {Lung or bronchi}
- A61B 2018/00577: {Ablation}
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## Abstract

The present disclosure provides methods for improving drug efficacy in a patient having an obstructed airway in a lung. Such methods modulate nerve activity in the autonomic nervous system of a patient to reduce obstruction of an airway in a lung of the patient prior to administering a drug to the patient. These methods are especially useful in improving efficacies of bronchodilators in treating obstructive lung diseases, such as chronic obstructive pulmonary disease.

## Claims

### Claim 1

A method for improving drug efficacy in a patient having an obstructive lung disease, comprising:
administering a therapeutically effective dose of an inhaled anticholinergic drug to the patient, wherein the inhaled anticholinergic drug has a reference efficacy when given as an initial bronchodilator, and a second reference efficacy when given as a second bronchodilator, wherein the patient has undergone, prior to the administration of the inhaled anticholinergic drug, a denervation procedure that includes injuring, either temporarily or permanently, a nerve trunk extending along a wall of an airway or a bronchial branch of the vagus nerve to modulate nerve activity in the autonomic nervous system of the patient by preventing acetylcholine from influencing postjunctional activities to reduce airway obstruction in at least one obstructed airway in a lung of the patient, and wherein a post-treatment efficacy of the inhaled anticholinergic drug following said denervation procedure is greater than the second reference efficacy of the inhaled anticholinergic drug when given as a second bronchodilator.

### Claim 2

A method for treating a patient having an obstructive lung disease, comprising:
(a) performing a denervation procedure to modulate nerve activity in an autonomic nervous system of the patient by preventing acetylcholine from influencing postjunctional activities to reduce obstruction in a distal airway in a lung of the patient, wherein the denervation procedure includes injuring, either temporarily or permanently, a nerve trunk extending along a wall of an airway or a bronchial branch of the vagus nerve; and
(b) subsequently administering a therapeutically effective dose of an inhaled anticholinergic drug while the obstruction is reduced in the distal airway such that the inhaled anticholinergic drug is delivered to the distal airway,
wherein steps (a) and (b) have a treatment efficacy greater than a reference efficacy of the inhaled anticholinergic drug, wherein the reference efficacy of the inhaled anticholinergic drug is defined as an efficacy of the inhaled anticholinergic drug after the inhaled anticholinergic drug has been administered as a second bronchodilator after administration of a first bronchodilator.

### Claim 3 (depends on 2)

The method of claim 2, wherein step (a) is performed without causing permanent damage to non-nerve tissue.

### Claim 4 (depends on 2)

The method of claim 2, wherein step (a) comprises attenuating nerve activity in a portion of a parasympathetic nervous system of the patient.

### Claim 5 (depends on 2)

The method of claim 2, wherein step (a) also comprises stimulating nerve activity in a portion of a sympathetic nervous system of the patient.

### Claim 6 (depends on 2)

The method of claim 2, wherein step (a) comprises modulating nerve activity along a first airway of the patient, the at least one obstructed airway is a higher generation airway of the first airway, and the modulating nerve activity includes modulating activity in a nerve which carries signals to or from the higher generation airway.

### Claim 7 (depends on 2)

The method of claim 2, wherein step (a) comprises modulating nerve activity of a pulmonary plexus.

### Claim 8 (depends on 2)

The method of claim 2, wherein step (a) comprises modulating nerve activity of a bronchial branch of the vagus nerve.

### Claim 9 (depends on 2)

The method of claim 2, wherein step (a) comprises damaging a bronchial branch of the vagus nerve.

### Claim 10 (depends on 2)

The method of claim 2, wherein step (a) also comprises stimulating the portion of the parasympathetic nervous system with electrical impulses to block nervous system signals from traveling past the portion of the parasympathetic nervous system.

### Claim 11 (depends on 2)

The method of claim 2, wherein the at least one obstructed airway results from smooth muscle contraction, thickening of airway wall, mucous accumulation, or a combination thereof.

### Claim 12 (depends on 2)

The method of claim 2, wherein the patient suffers from chronic obstructive pulmonary disease (COPD).

### Claim 13 (depends on 2)

The method of claim 2, wherein the patient suffers from asthma.

### Claim 14 (depends on 2)

The method of claim 2, wherein the patient suffers from cystic fibrosis.

### Claim 15 (depends on 2)

The method of claim 2, further comprising administering the inhaled anticholinergic drug to the patient prior to step (a), wherein steps (a) and (b) have a treatment efficacy greater than an efficacy of the inhaled anticholinergic drug delivered prior to step (a).

### Claim 16 (depends on 2)

The method of claim 2, wherein the denervation procedure prevents the acetylcholine from influencing postjunctional activities by inhibiting release and/or production of acetylcholine.

### Claim 17 (depends on 2)

The method of claim 2, wherein step (a) comprises damaging a portion of the parasympathetic nervous system.

### Claim 18 (depends on 17)

The method of claim 17, wherein damaging the portion of the parasympathetic nervous system comprises applying energy to the portion of the parasympathetic nervous system.

### Claim 19 (depends on 18)

The method of claim 18, wherein applying energy to the portion of parasympathetic nervous system comprises applying thermal energy, microwave, electrical energy, cryogenic energy, acoustic energy, radio frequency energy, pulsed high voltage energy, mechanical energy, ionizing radiation, or optical energy to the portion of the parasympathetic nervous system.

### Claim 20 (depends on 18)

The method of claim 18, wherein applying energy to the portion of parasympathetic nervous system does not cause permanent damage to any interior airway walls of the patient.

### Claim 21 (depends on 18)

The method of claim 18, further comprising protecting an interior airway wall of the patient from permanent damage while applying the energy.

### Claim 22 (depends on 2)

The method of claim 2, wherein the nerve trunk is damaged by delivering energy from an interventional device.

### Claim 23 (depends on 22)

The method of claim 22, wherein the energy is delivered from within the airway.

### Claim 24 (depends on 22)

The method of claim 22, wherein the energy is delivered from outside the airway.

### Claim 25 (depends on 2)

The method of claim 2, wherein the denervation procedure prevents the acetylcholine from influencing postjunctional activities by inhibiting binding of acetylcholine to receptor sites in nerve cells.

### Claim 26 (depends on 25)

The method of claim 25, wherein the receptor sites comprise muscarinic (M) receptors.