METHOD OF TREATING LOW BLOOD PRESSURE

Abstract

A method for treating a patient suffering from one of septic shock, acute kidney injury, severe hypotension, cardiac arrest, and refractory hypotension, but not from myocardial infarction, is provided. The method includes administering a therapeutically effective dose of Angiotensin II, or Ang II, to the patient.

Claims

1.-29. (canceled)

30. A method of treating severe hypotension in a human subject, comprising administering Angiotensin II to the human subject by intravenous infusion at an initial rate of about 20 ng/kg/min.

31. The method of claim 30, further comprising titrating the rate up to about 30 ng/kg/min.

32. The method of claim 30, further comprising titrating the rate up to about 40 ng/kg/min.

33. The method of claim 30, wherein the rate is titrated up one or more times by about 10 ng/kg/min.

34. The method of claim 30, wherein the Angiotensin II is administered to the human subject over a period of about 0.25 hours to about 120 hours.

35. The method of claim 34, wherein the Angiotensin II is administered to the human subject over a period of about 1 hour to about 7 hours.

36. The method of claim 30, wherein the rate of administration of Angiotensin II is titrated to achieve a mean arterial pressure of about 65 mmHg.

37. The method of claim 30, wherein the rate of administration of Angiotensin II is titrated to achieve a mean arterial pressure of 65 mmHg.

38. The method of claim 36, wherein the mean arterial pressure is maintained at about 65 mmHg for about 0.25 hours to about 120 hours.

39. The method of claim 38, wherein the mean arterial pressure is maintained at about 65 mmHg for about 1 hour to about 7 hours.

40. The method of claim 30, wherein the subject has septic shock.

41. The method of claim 30, wherein the severe hypotension is refractory hypotension.

42. The method of claim 30, wherein the human subject is undergoing treatment with one or more vasopressors.

43. The method of claim 42, wherein the one or more vasopressors is selected from the group consisting of norepinephrine, vasopressin, epinephrine, and dopamine.

44. The method of claim 43, wherein the one or more vasopressors is norepinephrine.

45. The method of claim 43, wherein the one or more vasopressors is vasopressin.

46. The method of claim 42, further comprising titrating the rate up to about 30 ng/kg/min.

47. The method of claim 42, further comprising titrating the rate up to about 40 ng/kg/min.

48. The method of claim 42, wherein the rate is titrated up one or more times by about 10 ng/kg/min.

49. The method of claim 42, wherein the Angiotensin II is administered to the human subject over a period of about 0.25 hours to about 120 hours.

50. The method of claim 49, wherein the Angiotensin II is administered to the human subject over a period of about 1 hour to about 7 hours.

51. The method of claim 42, wherein the rate of administration of Angiotensin II is titrated to achieve a mean arterial pressure of about 65 mmHg.

52. The method of claim 42, wherein the rate of administration of Angiotensin II is titrated to achieve a mean arterial pressure of 65 mmHg.

53. The method of claim 51, wherein the mean arterial pressure is maintained at about 65 mmHg for about 0.25 hours to about 120 hours.

54. The method of claim 53, wherein the mean arterial pressure is maintained at about 65 mmHg for about 1 hour to about 7 hours.

55. A method of treating severe hypotension in a human subject, comprising administering Angiotensin II to the human subject by intravenous infusion at a rate of from about 20 ng/kg/min to about 40 ng/kg/min.

56. The method of claim 55, wherein the Angiotensin II is administered at a rate of about 30 ng/kg/min.

57. The method of claim 55, wherein the Angiotensin II is administered at a rate of about 40 ng/kg/min.

58. The method of claim 55, wherein the subject has septic shock.

59. The method of claim 55, wherein the severe hypotension is refractory hypotension.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Ang II is degraded to angiotensin III in a patient, having a half life of a few minutes. Ang II is a direct vasoconstrictor by activating angiotensin I receptors, enhancing peripheral noradrenergic neurotransmission, increasing sympathetic discharge (CNS), and releasing catecholamines from the adrenal medulla.

[0014] Administration of Ang II to patients suffering from at least one of septic shock, acute kidney injury, severe hypotension, cardiac arrest, and refractory hypotension can have adverse side effects, including ischemia, such as, for example, mesenteric ischemia, that damage internal organs. The present teachings disclose a therapeutic regimen of Ang II at doses below that where adverse side effects, such as ischemia, are seen. Furthermore, the therapeutic regimen of Ang II disclosed in the present teachings can act as an adjuvant and lower the effective doses of other therapies, including administration of vasopressin and catecholamine.

[0015] The therapeutic regimen disclosed herein can be started within, for example, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours after onset of acute symptoms.

EXAMPLE I

[0016] A dose study was designed to determine the feasibility of Ang II as a treatment for sepsis related hypotension.

[0017] A 20 patient randomized blinded study in the treatment of sepsis related hypotension was proposed. Patients suffering from septic shock receiving >15 mcg/min of norepineprhine are eligible. Patients are randomized to Ang II or norepinephrine in a blinded fashion. There are 10 patients in each arm. Norepinephrine is used as a control instead of a true placebo, because the blood pressure rising effects of Ang II would defeat the blinding intent.

[0018] All patients have the treatment of vasopressors titrated to a mean arterial pressure (MAP) of 65 mm of Hg. Patients are then randomized to a control group or arm, or an interventional group or arm treated with Ang II. Patients randomly assigned to the control group are administered with norepinephrine starting at 5 mcg/min, and can be titrated up to 7.5 mcg/mink, and then to 10 mcg/min. Patients in the interventional arm are administered Ang II starting at a dose of about 20 ng/kg/min. Additionally, the dose can then be titrated up to about 30 ng/kg/min. Furthermore, the dose can then be titrated up to about 40 ng/kg/min. The intervention can last for about 4 hours.

[0019] Each patient in the interventional group is started with the assigned starting dose. After the first hour, if the patient is still requiring standing norepinephrine, the dose of the control and interventional drugs can be increased 50%. After the second hour, if the patient is still requiring a standing dose of norepinephrine, the control and interventional drugs can be increased again to twice the initial dose. At the end of 4 hours, the study drug will be titrated off over 30 minutes.

[0020] In the two hours before the initiation of the study drug, all urine is collected. The urine collections are continued for a total duration of nine (9) hours. Blood is drawn at the initiation of the study, four (4) hours thereafter, and then seven (7) hours after. This involves a total of three (3) blood draws of 7 cc of blood per draw for a total of 21 cc of blood. Blood is examined for serum chemistry and serum lactate. In this same time period, demographic and clinical data are collected. Creatinine clearance will be calculated for the pre-study, study, and post-study periods.

[0021] Blood pressure of each patient is monitored continuously from about two (2) hours before initiation of the control and interventional drugs for about seven (7) hours after initiation of the control and interventional drugs.

[0022] Results:

[0023] At the conclusion of the study, 30 day mortality is assessed.

[0024] According to an embodiment of the present teachings, a method of treating a patient suffering from low blood pressure is provided. The patient can suffer from one of septic shock, acute kidney injury, severe hypotension, and refractory hypotension, but not from myocardial infarction. The method can comprise administering a therapeutically effective dose of Angiotensin II (Ang II) to the patient.

[0025] The dose of Angiotensin II can be administered at a rate of between about 5 ng/kg/min to about 100 ng/kg/min. The dose of Angiotensin II can be administered at a rate of between about 10 ng/kg/min to about 50 ng/kg/min. The dose of Angiotensin II can be administered at a rate of between about 20 ng/kg/min to about 40 ng/kg/min.

[0026] The dose administration can last from about 0.25 hours to about 120 hours. The dose administration can last from about 1 hour to about 7 hours. The dose administration can last from about 2 hour to about 6 hours. The dose administration can last from about 3 hours to about 5 hours.

[0027] Those skilled in the art can appreciate from the foregoing description that the present teachings can be implemented in a variety of forms. Therefore, while these teachings have been described in connection with particular embodiments and examples thereof, the true scope of the present teachings should not be so limited. Various changes and modifications may be made without departing from the scope of the teachings herein.

[0028] The following publications are herein incorporated by reference in their entireties: [0029] 1. Bagshaw S M, George C, Dinu I, Bellomo R: A Multi-Centre Evaluation of the Rifle Criteria for Early Acute Kidney Injury in Critically Ill Patients. Nephrol Dial Transplant Oct 25 (Epub): 2007 [0030] 2. Uchino S, Kellum J A, Bellomo R, Doig G S, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294:813-818, 2005 [0031] 3. Heringlake M, Knappe M, Vargas H O, et al: Renal dysfunction according to the ADQI-RIFLE system and clinical practice patterns after cardiac surgery in Germany. Minerva Anestesiol 72:645-654, 2006 [0032] 4. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V: Acute renal failure after cardiac surgery: evaluation of the RIFLE classification. Ann Thorac Surg 81:542-546, 2006 [0033] 5. Lopes J A, Jorge S, Resina C, et al: Prognostic utility of RIFLE for acute renal failure in patients with sepsis. Crit Care 11:408, 2007 [0034] 6. Wilson C T, Fisher E S, Welch H G, Siewers A E, Lucas FL: U.S. trends in CABG hospital volume: the effect of adding cardiac surgery programs. Health Aff 26:162-168, 2007 [0035] 7. Angus D C, Linde-Zwirble W T, Lidicker J, Clermont G, Carcillo J, Pinsky M R: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303-1310, 2001