Proteus

 

Medical need

Modern surgery aims to progressively less invasive procedures oriented to the development of ambulatory surgical procedures in order to reduce hospitalization expenses to private and public health insurance companies and to the patients. Laparoscopy, a non-invasive widely used surgery procedure exemplifies this trend.

Generally, post-surgery pain is intense, with an average duration period –in its most critical phase- of 18 ± 6 hours. Among most used anesthetics stands out Bupivacaine, which produces a post-surgery analgesic effect of about 6 hours as an average, after being topically administered.

Neosaxitoxin 0.002%, the product developed by PROTEUS, corresponds to the medical dose of the drug substance, purified and biotechnologically produced in industrial conditions for use as local anesthetic in human. It further produces a longer analgesic effect (demonstrated by clinical studies performed and published by the company’s research team), when concomitantly acting with bupivacaine.

The actual trend to widen the use of less invasive surgical techniques, allows us to foresee a very attractive demand for Neosaxitoxin as local anestethic. Its pharmaceutical characteristics, its wide spectrum of clinical applicability, its potential in therapeutic formulations (due to its chemical and physical stability) and the worldwide unique biotechnology developed for its production, endow it with a great clinical and commercial potential, making it a very appealing business opportunity in biotechnology, besides its already proven scientific and technological relevance.

 

Background

Neosaxitoxin represents an important advance over all commercially-available local anesthetics with regard to local and systemic safety as well as anticipated efficacy for treatment of postoperative pain.

All currently available local anesthetics (LA) have limitations and risks.

1.- Short duration of pain-relieving action
The longest acting LA last for no more than 6 – 10 hours after a single injection, but postoperative pain is often severe for 2 – 5 days. Currently, in order to provide longer duration of action, it is necessary to place indwelling catheters into the patient and give local anesthetics via an infusion pump. Indwelling catheters introduce additional expense, need for monitoring, risk of infection, and potential for migration of the catheters or misprogramming of pumps.

2.- Local toxicity
All of the existing LA are inherently toxic in some tissues. With prolonged exposure and with higher concentrations, histologic injury to cornea, cartilagous, nerve and muscle can be demonstrated. Epidemiologic studies suggest that after peripheral nerve blocks or plexus blocks, transient or longer term paresthesias or partial injuries to nerves are seen at frequencies ranging from 1:200 – 1:1000. Experts believe that, along with direct needle trauma and pressure-induced ischemia, direct chemical neurotoxic effects of the amino-amides are a major factor in peripheral nerve injuries after peripheral nerve blocks or plexus blocks. In addition, direct chemical neurotoxic effects of LA are regarded as prominent factors in the transient neurologic symptoms observed after spinal anesthesia.

3.- Systemic toxicity
If given in overdose, or if given inadvertently directly into a blood vessel, all LA can cause seizures, cardiac arrhythmias, cardiac depression, or cardiac arrest. Resuscitation after cardiac arrest following bupivacaine, in particular, can be quite difficult. Although ropivacaine and levo-bupivacaine were developed to reduce this cardiotoxicity slightly, they are only marginally safer.

Neosaxitoxin has unique advantages in terms of efficacy and safety.

1.- Prolonged duration of analgesia
The duration of analgesia from neosaxitoxin outlasts that of all existing LA. Moreover, in animal models, when neosaxitoxin is combined with low concentration of amino-amides or when it is combined with the vasoconstrictor epinephrine, its system safety is actually improved. In animals and in human volunteers, these combinations produce even longer durations of analgesic action.

2.- Very specific mechanism of action
The only known site of biological action of neosaxitoxin, tetrodotoxin and similar molecules is on site1 on the voltage gated sodium cannel (Nav Channel). More exactly, at the site 1 located at the external pore of the Nav Channel. In contrast, LA have a wide range of cellular actions, including actions on calcium channels, potassium channels, mitochondrial energetics, and assembly of filamentous proteins.
Neosaxitoxin’s high specificity of action will contribute to its safety and predictability.

3.- Lack of local tissue toxicity to nerve or muscles
All available studies have shown that the site 1 toxins have a remarkable absence of direct histologic injury to nerves or muscles.
Neosaxitoxin’s absence of local toxicity anticipate that widespread use of neosaxitoxin has the potential to reduce the frequency of paresthesias, partial numbness and other sequelae of peripheral nerve blocks.

4.- Absence of actions on cardiac sodium channels during systemic toxicity
Mammalian tissues have a number of subtypes of sodium channels. Some sodium channels subtypes are characterized by high sensitivity to blockade by site 1 toxins, other subtypes are highly resistant. The major sodium channel in cardiac tissues is known as Nav 1.5. Blockade of Nav 1.5 by bupivacaine and other currently available amino-amide local anesthetics contributes greatly to their cardiotoxicity. Nav 1.5 is profoundly resistant to blockade by neosaxitoxin and other site 1 toxins. In animal models of the site 1 toxins and in human cases of inadvertent overdose from contaminated seafood, there has been no evidence of any direct cardiotoxicity of this class of molecules.
Neosaxitoxin’s absence of cardiotoxicity is a major safety advantage over all available local anesthetics.

5.- Absence of actions on SNC sodium channels during systemic toxicity
Clinical and laboratory reports and studies supports that neosaxitoxin intoxication is not associated to the risk of seizures.
Neosaxitoxin’s absence of seizure induction potential is a major safety advantage over all available local anesthetics, because seizures can produce hypoxemia, acidosis and increased oxygen consumption, deteriorating the clinical condition of the affected patient.

6.- Manageable systemic effects on skeletal muscle and respiratory mechanics
Respiratory muscles paralysis and lithreaning ventilatory impairment after a neosaxitoxin intoxication, are very predictable risks, But, both are highly manageable situation.
But, neuromuscular blocking drugs (e.g. pancuronium, cis-atracurium, vecuronium, rocuronium, curare, succinylcholine) are used on a daily basis in operating rooms, as part of the current standar of care for diagnostic and therapeutic purposes. These drugs produce skeletal muscle relaxation, and their major mechanism of toxicity is the paralysis of the respiratory muscles, analogous to what would be seen with an systemic overdose of neosaxitoxin.
In all standar operating room, there is continuous monitoring of oxygenation and ventilation using pulse oximetry and capnometry. In addition, self inflating bag masks and modern anesthesia machines permit routine assessment and support of ventilation, and some equipments permits very sensitive measures of subclinical effects on respiratory muscle strength.
Neosaxitoxin’s systemic toxicity limited to muscular relaxation is a very strong safety characteristic of neosaxitoxin in the clinical enviroment, because of all anesthesiologists are fully trained to diagnose and treat in a timely manner the signs of muscular weakness produced by neuromuscular blocking drugs, so that there are established practices for assessing subclinical reductions in strength of respiratory muscles.

 

Mechanism of action

Sodium channels consist of a highly processed α subunit (the pore-forming unit) associated with auxiliary β subunits (the auxiliary and modulating units).

The pore-forming α subunit defines the functional expression of each Nav channel; but the auxiliary β subunits modifies kinetics and voltage dependence of channel gating, as others characteristics.

The α subunits are organized in four homologous domains (I-IV), each of which contain six transmembrane α helices (S1-S6) and an additional pore loop located between the S5 and S6 segments. The pore loops line the outer, narrow entry to the pore, whereas the S5 and S6 segments line the inner, wider exit from the pore. The S4 segments in each domain contain positively charged amino acid residues at every third position. These residues serve as gating charges and move across the membrane to initiate channel activation in response to depolarization of the membrane. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate, folding into the channel structure and blocking the pore from the inside during sustained depolarization of the membrane.

The channel itself is made up of a single peptide chain with four repeating units with each unit consisting of six trans-membrane helices. The trans-membrane pore is formed when the four units fold into a cluster with the center of the cluster the pore.

The theory is that neosaxitoxin acts in a very specific manner on the outer pore of Nav Channel, inducing the inactivation gate located in the inner pore (the short intracellular loop connecting homologous domains III and IV), to “swings” shut, turning off the cannel.

 

 

Reference: William A. Catterall, Alan L. Goldin, Stephen G. Waxman. Voltage-gated sodium channels, introductory chapter. Last modified on 13/08/2012. Accessed on 01/12/2012. IUPHAR database (IUPHAR-DB).

http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=82