• INCLUSION CRITERIA:
• Patients will be between 18 and 75 years of age, male or female, with a diagnosis of asthma for at least one year.
• Patients must have reversible airflow obstruction as defined by a positive methacholine bronchoprovocation challenge or a positive response to inhaled bronchodilators.
• Patients must be treated with EPR-3 Step 5 therapy (high dose greater than 440 microcg/day) fluticasone inhaler or equivalent dose of another inhaled corticosteroid) with or without an inhaled long-acting beta 2-agonist) for at least 3 months.
• Patients must meet the EPR-3 criteria for not well controlled asthma. The EPR-3 definition for not well controlled asthma includes any of the following features in a week (unless otherwise indicated): daytime asthma symptoms greater than 2 days/week, limitation of activities, nocturnal symptoms or awakening greater than two times/month, need for reliever/rescue treatment greater than 2 days/week, PEF or FEV(1) less than 80 percent predicted.
• Pre-bronchodilator FEV1 greater than or equal to 55 percent of predicted and post-bronchodilator FEV1 greater than or equal to 60 percent of predicted.
• During the 6 weeks prior to enrollment, patients should have stable asthma as defined by the absence of unscheduled health care visits for asthma care and unchanged use of asthma maintenance therapy. Additional criteria for disease stability include the absence of hospitalization for asthma or the need for a course of oral corticosteroids during the preceding 3 months.
• Research subjects must have a positive skin test to a common aeroallergen, such as dust mite, cat, short ragweed, cockroach, or grass or a prior history of severe allergy or anaphylaxis.
• Chest radiograph without evidence of pulmonary disease, other than asthma.
• Left ventricular ejection fraction greater than or equal to 50 percent. by echocardiogram.
• For women of childbearing potential, negative pregnancy test within 2 weeks prior to study and willingness to adhere to reliable birth control methods during the study.
• Subjects with a history of dermatologic cancers may be included if they have been cancer-free for at least 5 years prior to enrollment.

EXCLUSION CRITERIA:

• A known history of hypersensitivity to pioglitazone.
• Maintenance asthma therapy with oral corticosteroids, xolair (anti-IgE), methotrexate, cytoxan, gold salts, or cyclosporine.
• Cigarette smoking within the past 3 months or a prior history of greater than 5 cumulative pack-years.
• Viral or bacterial upper respiratory tract infection within 6 weeks prior to the screening visit.
• Investigational therapy for any indication within 1 month prior to the screening visit.
• History of lung disease other than asthma (i.e., COPD, sarcoidosis).
• History of diabetes mellitus, insulin secreting tumor, or symptomatic hypoglycemia.
• HIV or other known immunodeficiency.
• History of heart disease, congestive heart failure, previously diagnosed mitral valve prolapse, or bacterial endocarditis.
• Preexisting edema (2-plus or greater).
• Hemoglobin less than 12 gm/dl for males and less than 11 gm/dl for females.
• History of liver disease or abnormal liver function tests greater than 2 X upper limit of normal.
• History of inflammatory bowel disease.
• History of cancer (other than dermatologic cancer) or colon polyps.
• History of drug or alcohol abuse.

• Use of the following medications, which can interact with pioglitazone:

  1. Gemfibrizol (Lopid)
  2. Atazanivir (Reyataz)
  3. Ritonavir (Norvir)
  4. Rifampin (Rifampicin)
  5. Carbamzepine (Tegretol)
  6. Phenobarbital (Luminal)
  7. Phenytoin (Dilantin)
  8. Rifapentine (Priftin)
  9. Secobarbital (Seconal)
  10. Amiodarone (Cordarone, Pacerone)
  11. Palitaxel (Taxol)
  12. Replaglinide (Prandine)
  13. Ketoconazole (Nizoral)
  14. Atorvastatin (Lipitor® (Registered Trademark))
  15. Nifedipine ER (Adalat CC)
• Allergy to lidocaine.
• Anti-coagulant medications.
• Any condition that, in the investigator's opinion, places the patient at undue risk for complications from pioglitazone therapy.
• Dexa bone scan (Tscore below -1 SD)