Rapid identification of conditions, compounds, or compositions that inhibit, prevent, induce, modify, or reverse transitions of physical state

Abstract

The invention concerns arrays comprising hundreds, thousands, to hundreds of thousands of samples and methods for screening thereof. These methods are useful to optimize, select, and discover compounds, compositions, or conditions that prevent, inhibit, induce, modify, or reverse physical-state transitions, particularly in-vivo physical-state transitions relating to disease causing processes. Such compounds, compositions, or conditions can be exploited to treat (e.g., reverse) or prevent the disease itself, the cause of the disease, or the symptoms of the disease.

Description

1. RELATED APPLICATION[0001] This application incorporates by reference, and claims priority from, the U.S. provisional application number 60 / 253,629 filed on Nov. 28, 2000, entitled RAPID IDENTIFICATION OF CONDITIONS, COMPOUNDS, OR COMPOSITIONS THAT INHIBIT, PREVENT, INDUCE OR REVERSE TRANSITIONS OF PHYSICAL STATE.2. FIELD OF THE INVENTION[0002] The invention is directed to methods and systems for high through-put sample screening for optimization of conditions and discovery of new compounds and compositions. In particular, the invention is directed to methods and systems for high-throughput, rapid screening of large numbers of samples for identification of conditions, compounds, or compositions that inhibit, prevent, induce, modify, or reverse transitions of physical state, particularly, where the physical-state transition relates to a disease process.3. BACKGROUND OF THE INVENTION[0003] Many serious diseases of both humans and animals are caused by abnormal physical-state transit...

AI Technical Summary

Benefits of technology

0083] Patients with sickle cell disease can be treated with blood transfusions to reduce the concentration of abnormal hemoglobin in their circulation. However this is primarily an emergency procedure and has many disadvantages, such as transmission of infectious agents and high cost.

0084] No simple agent is known that would inhibit the phase transition that allows the abnormal polymerization of HbS when deoxygenated. The methods of this invention would allow the high-throughput screening of agents to determine if they can prevent or diminish this pathological phase transition and the resulting disease symptoms.

Problems solved by technology

Bio-precipitation processes can result in organic deposits, such as plaques, fats, and other undesirable amorphous-substance buildup in the body.

Both crystallization and precipitation result from the inability of a solution (e.g., body fluid) to fully dissolve the substance and can be induced by changing the state of the system in some way.

Another instance of unfavorable biocrystallization or bioprecipitation concerns physiologically low-solubility pharmaceuticals or pharmaceuticals that complex with tissue or other bodily substances.

Here they cause inflamation with pain and swelling and limitation of motion of the involved joint.

Acute attacks of pseudogout often occur in the knees and are incapacitating for days or weeks.

Unfortunately, no treatment is available to dissolve the crystal deposits.

An extremely destructive arthritis may occur at the shoulder, "Milwaukee shoulder," or at hips and knees in elderly people.

However, in most cases the cause of soft tissue apatide deposition is not known.

The acute arthritis or periarthritis can be treated with VSAIDS or colchicine but no agent capable of preventing this potentially destructive type of phase transition is known.

Monosodium urate crystals may deposit in joints and other connective tissue causing gout.

Crystals are often present in joint fluid even between attacks and may contribute to low-grade inflammation and joint damage.

The presence of uric acid crystals in the kidneys can cause renal failure.

Treatment options for gout are also limited with the effective treatment comprising administration of colchicine for acute gout notwithstanding its side effects of nausea, vomiting and diarrhea.

It is a major cause of morbidity in the United States and elsewhere.

As the table below shows, the treatment for many types of renal stones is imperfect and the occurrence of renal calculi continues to cause significant morbidity and high cost to the health care system associated with emergency room visits, etc.

The regulation of bone formation and removal is complex and involves both systemic and local regulation.

In addition there is a highly complex network of local controls.

The loss of bone density caused by osteoporosis results in fractures of the hip, pelvis, wrist, proximal humerus, proximal tibia and vertebral bodies.

In addition, many drugs can cause bone loss, such as heparin, ethanol, glucocorticoids and some anti-convulsants.

However, all forms of bone density loss are ultimately the result of the loss of mineralization of bone.

At present, few agents capable of stabilizing the solid phase of bone and preventing the phase change that results in loss of biomineralization are known.

First, a supranormal "calcium-phosphate solubility product" in extracellular fluid can cause "metastatic" calcification.

However metastatic calcification is a risk if significant hypercalcemia or hyperphosphatemia or both occur for any reason.

In addition there is a predilection for precipitation into certain tissues.

The lesions of calcinosis are small or medium sized hard nodules that can cause muscle atrophy, and contractions, and may produce significant disability.

Dental calculus is a distinct oral detriment because it is especially difficult to remove with dental floss and serves as a localized physical irritant to the gingival tissue.

However, no generally effective means to control the formation of dental calculus is known.

In addition, gallstone formation may be associated with impaired gallbladder motility resulting in impaired contractile response of the gallbladder muscle to cholecystokinin.

However, if the bile is supersaturated, vesicles fail to dissolve completely and instead fuse to form large, cholesterol-rich multilamellar liquid crystals from which excess cholesterol may precipitate as plate-like cholesterol monohydrate crystals.

This may account for the two-fold increase risk of cholesterol gallstones in women during their childbearing years.

In addition some hypocholesterolemic drugs such as the fibric acid derivatives clofibrate and gemfibrizol directly stimulate secretion of cholesterol into bile and are associated with increased risk of cholesterol gallstones.

Thus the formation of gallstones is a major medical problem associated with significant morbidity and mortality and expense.

This rigid deformation of the red blood cells, in turn, causes occlusion of the microvasculature.

However, when the mutant gene is inherited from both parents then sickle cell disease results and this is associated with chronic anemia and recurrent pain and the periodic occurrence of, possibly life threatening "sickle cell crisis".

Sickle disease can cause serious organ damage due to the reduction of blood flow in small vessels.

In addition, a common and extremely serious condition called osteonecrosis may occur because of the reduction of blood flow to the bones, resulting in painful bone infarctions.

Thus deoxygenation in the tissues causes rapid supersaturation with aggregation and polymerization of the abnormal hemoglobin and resulting large scale deformation of red blood cells containing such hemoglobin.

This deformation causes vaso-occlusion and the resulting decrease in blood supply causes the diverse symptoms of the disease.

However, the delay times usually exceed capillary transit times and so cells do not accumulate significant amounts of polymer until they are in a large vein where they cannot elicit vasoocclusion.

Unfortunately local vascular perturbations may cause unusual delay in the transit time and allow sickling to take place in the capillary, causing a potentially disastrous decrease in blood supply to the organ.

However this is primarily an emergency procedure and has many disadvantages, such as transmission of infectious agents and high cost.

They are the leading cause of blindness in the world and the leading cause of visual loss in Americans older than age 40.

However, it is known that exposure to ultraviolet light, trauma to the eye, Wilson's disease or systemic corticosteroid use may all cause cataract formation.

The normal protein matrix of the lens may cross link and precipitate over the course of time causing loss of transparency to visual light.

Although cataracts may be treated surgically by removal of the opacified lens, no agent capable of preventing the phase transition responsible for this tissue change is known.

No clinical classification of the amyloid diseases is entirely satisfactory.

But given the enormous variety of disorders due to physical-state changes in animals, it has been extremely tedious to perform the huge number of experiments to determine the conditions, compounds, or compositions that will prevent, inhibit, or reverse these undesirable physical-state changes or promote or induce desirable physical-state changes.

And because many factors influence crystallization, precipitation, deposition, and other physical-state changes of inorganic and organic substances, testing to find conditions, compounds, or compositions that can inhibit or reverse such processes or induce desirable physical state changes is an extremely tedious process.

At present, industry does not have the time or resources to test hundreds of thousands of combinations to find the right conditions, compounds, or compositions adverse to undesired physical-state changes.