Bio Balance Corporation

Improving Medications Using Cost-Effective Processes

Building a Broad and Flexible Technology

Enhancing the safety and efficacy of existing pharmaceuticals

&Creating new pharmaceuticals

G Protein-Coupled Receptors(GPCRs)

• It is conservatively estimated that 30-50% of all pharmaceuticals interact with GPCRs.

• These receptors are widely distributed within our bodies and are integral to our senses, thoughts and sensations.

• They all desensitize to continued stimulation by agonists.

Some Common GPCRs -Their Distribution and Effector Systems

• Gs – Heart, brain,lung, neurons, kidney, liver, adrenal gland

• Gi – Brain, olfactory, heart, all tissues

• Activate Ca2+ channels, cardiac positive inotropy, contractile proteins

• Regulate K+, Ca2+ channels, inhibit cAMP and Ca/CaM actions

Distribution: Effects:

The Problem of Desensitization

Terminology

• Desensitization• Fade• Autoinhibition• Tachyphylaxis

• Tolerance• Down-regulation• Resistance

The History of Desensitization

Interesting and Historical Points:

1957 – First detailed experimental observations of receptordesensitization by del Castillo & Katz Proc.Roy. Soc. Lond.146, 369-381.

1972 – From search - one paper titled “receptor desensitization by lobeline and nicotine”

1988 – The Rose patent # 5,316,759 (May 31, 1994) refers to work dating back to 1988 on the agonist-antagonist combinationof nicotine with mecamylamine.

1991 – Geoffroy, et al. “Reduction of Desensitization of aGlutamate Ionotropic Receptor by Antagonists” MolecularPharmacology 39, 587-591.

Patents Combining Agonists with Antagonists

USP# Inventor Date Comments4,769,372 Kreek 9/6/88 opioids5,316,759 Rose 5/31/94 nicotine5,352,680 Portoghese 10/4/94 opioids5,472,943 Crain 12/5/95 1:10-10005,580,876 Crain 12/3/96 10,000,0005,597,699 Lanzara 1/28/97 All GPCRs5,767,125 Crain 6/16/98 <100th6,096,756 Crain 8/1/00 method

Scientific Objective:Preventing Desensitization

MethodologyMedication

(“agonist” – e.g., isoproterenol, morphine)

+Antagonist to prevent desensitization

(“antagonist” – e.g., metoprolol, naloxone)

= New & Improved Medication

The Heart of Bio Balance’s Technology

The determination of the optimal ratio of agonist and antagonist by our patented method. This method is based upon a biophysical model for the receptor response.

This allows Bio Balance to create patentable compositions using the “best mode” of practice.

A Representation of the two-state model showing 5-HT binding

Experimental vs. Theoretical curves for various receptor responses

Applications of Bio Balance’s Technology

• Extend the patent protection of existing drugs

• Create new drugs as combinations of generic drugs

• Assist in drug development by salvaging previously discarded drug candidates because of excessive desensitization or fade

Advantages of Bio Balance’s Technology

• Better control of the therapeutic response. • Cheaper to develop• Multiple therapeutic areas can be targeted• Can combine generic drugs• Potentially quick acceptance by physicians as a

technically superior design of previously accepted drugs.

• Multiple new drugs can be created as compositions within several therapeutic areas such as cardiovascular, pain, pulmonary, brain/memory, tocolytic, etc.

Heart

Pain

Asthma

Premature Labor

Memory

Other GPCRs

Bio Balance’s

Therapeutic Targets

Conclusion

Bio Balance has a broad and flexible technology to enhance existing

pharmaceuticals and to create new pharmaceuticals that work better with

fewer side-effects.