Cypros Pharmaceutical Corp.

Questcor Pharmaceuticals, Inc.

Anthony W Fox

Paul J Marangos

Angel K Markov

David Royston

Bernhard Riedel

Brian W Sullivan

Fructose-1,6-diphosphate (FDP) has been shown, in double-blinded controlled clinical trials on patients with sickle cell anemia, to substantially reduce the pain suffered by such patients during the recurrent ischemic crises that are caused by red blood cell sickling. Tests on patients who have been hospitalized for such crises demonstrated that when they received an intravenous injection of FDP, they reported substantially lower pain levels during their hospital stays than control groups that received identical treatment without any FDP. Apparently, FDP has never previously been used or even tested in human clinical trials, to treat sickle cell anemia. In addition, FDP has never previously been reported to have any analgesic (pain-reducing) activity.

Treatment of sickle cell anemia crises with fructose-1,6-diphosphate as an analgesic drug

Fructose-1,6-diphosphate (FDP) is used to treat patients who are undergoing coronary artery bypass grafting (CABG) surgery. Before cardiopulmonary bypass begins, a liquid that contains FDP is intravenously infused in the patient, preferably for about 10 to 30 minutes, to allow the FDP to enter the heart and lung tissue while the heart is still beating. FDP can also be added to cardioplegia solution; in addition, FDP can be injected after bypass is terminated, but if post-bypass injection is used, steps should be taken to avoid excess lactic acid accumulation, which appears to increase the risk of atrial fibrillation. To prevent or control lactic acidosis, a buffering or alkalizing agent, such as sodium bicarbonate, or an agent which reduces lactic acid formation, such as dichloroacetate, can be used. In double-blinded trials, this use of FDP substantially reduced heart damage and improved overall outcomes, as shown by lower levels of creatine kinase in blood, improvements in pumping performance, reduced requirements for vasodilator and inotropic drugs, and shorter stays in intensive care units. Certain dosages also reduced the likelihood of atrial fibrillation; however, FDP at high dosages increased the likelihood of A-fib. FDP also helped reduce pulmonary vascular resistance (PVR); this is an important finding, since pulmonary hypertension following cardiopulmonary bypass is a very difficult and often intractable problem, and is a contributing factor in nearly all deaths following CPB surgery.

Injection of fructose-1,6-diphosphate (FDP) prior to coronary artery

Treatment of sickle cell anemia crises with fructose-1, 6-diphosphate as

A method is disclosed for using fructose-1,6-diphosphate (FDP) to reduce and prevent two very serious problems caused by surgery that requires cardiopulmonary bypass. Before bypass begins, a liquid that contains FDP is intravenously injected into the patient, preferably over a period such as about 10 to 30 minutes, to allow the FDP to permeate in significant quantity into the heart and lungs while the heart is still beating. FDP can be added to the cardioplegia solution that is pumped through the heart to stop the heartbeat, and/or during bypass. This treatment was found to reduce two very important and serious problems that have unavoidably plagued CPB surgery in the past, which are: (1) elevated levels of pulmonary vascular resistance (PVR), which includes pulmonary hypertension; and (2) high occurrence rates for atrial fibrillation. Prior to this discovery, there has never been any satisfactory treatment which could reduce the severity and occurrence rates for these two major problems. FDP also can be co-administered in this manner, along with (1) a buffering or alkalizing agent that counteracts acidosis, such as sodium bicarbonate or THAM, and/or (2) a drug that reduces the formation of lactic acid, such as dichloroacetate.

Method of reducing pulmonary hypertension and atrial fibrillation after

When fructose-1,6-diphosphate (FDP) is used as an inotropic drug in patients who have undergone surgery involving cardiopulmonary bypass, it can increase the pumping strength of a struggling heart, without increasing the heartbeat rate. As such, FDP can reduce the dosages of (and in some some cases eliminate the need for) other inotropic drugs such as dobutamine, epinephrin, or amrinone lactate, which have undesired and potentially dangerous side effects, mainly involving increasing the heartbeat rate, which imposes substantial additional stresses on hearts that are struggling to regain strength after cardiopulmonary bypass surgery.

Use of fructose-1 6-diphosphate as an inotrope drug after

A method and device are disclosed which enable on-site pre-diagnostic emergency treatment of people suffering from life-threatening injuries (such as victims of auto accidents, shootings, stabbings, and near-drownings), or from a collapse or loss of consciousness that might be due to a heart attack, stroke, cardiac arrest, internal hemorrhage, or various other causes that cannot be diagnosed until after a physician or ambulance has arrived on the scene. This on-site pre-diagnostic emergency treatment involves intravenous injection of fructose-1,6-diphosphate (FDP, a naturally-occurring chemical which functions as an intermediate in glycolysis) into the patient. Such injections can be administered by police, firemen, military personnel, lifeguards, nursing home attendants, ambulance attendants, or anyone else who has been trained to administer intravenous injections. The FDP should be injected into the patient as soon as possible, without delaying until the patient can be diagnosed and treated by a doctor. When administered immediately, intravenously injected FDP can reduce ischemic or hypoxic damage to the internal organs, without having any adverse effects or posing any significant risks for patients who may not need it. Injection kits which include vials containing partially lyophilized FDP (which does not require refrigeration), sterile water for reconstitution of the freeze-dried FDP, and a syringe with hypodermic needles are also disclosed, in a hard-shell case that can withstand rough handling, as might occur in a police car or firetruck.

On-site emergency treatment of injured or unconscious patients, using

This invention discloses an improved method of reducing elevated lactic acid and lactate concentrations in patients suffering from ischemic or hypoxic crises as stroke, cardiac arrest, or heart attacks, or other conditions involving surgery, that generate unwanted increases in blood or tissue lactate concentrations. This improvement comprises administering dichloroacetate (DCA), as in the sodium salt form, less than three times daily, at suitable dosages which cause the beneficial effects of DCA to persist beyond the time when the DCA has been pharmacokinetically cleared from the blood circulating in the patient.

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Rancho LaCosta, CA, United States of America

Anthony W Fox