NNRTI BBP153 has been sold under a secrecy agreement. As a consequence bbPharma will no longer develop BBP153 in HIV or related conditions.
Edwin ten Winkel, CEO
Wednesday, 28 May 2008
Friday, 2 May 2008
Effect of BBP 418, a chemically synthetised tetrodotoxin derivative, in pain therapy
Pritsana Khamchaew, Edwin ten Winkel, bbPharma
BBP418 is chemically synthetised but identical to one of the main compounds of tetrodotoxin, the toxin of the pufferfish or blowfish (Tetraodontidae). BBP418 is a sodium channel blocker, that selectively blocks off the voltage-sensitive sodium channels of excitable tissues and neuronal transmission in skeletal muscles. It is being developed as a potent pain-killer and is currently undergoing Phase II trials in 30 patients. Administration of a few microgram appear to be effective in about 75% of subjects.
Tetradotoxin is complex in structure by small molecule standards and contains a guanidinium moiety. The guanidinium ion is able to enter cells via the voltage sensitive Na+ channels, which are critical for cellullar signalling pathways (e.g. transmission of impulses and the mediation of many cell functions). It is likely that this imidazole ring is the part of the molecule that lodges in the channel leaving the rest of the molecule blocking its outer mouth. Their association and dissociation are independent of whether the channel is open or closed. When a neuron (nerve cell) is sending a message, tiny pores or channels in the neuron's membrane open up to let sodium ions enter the cell. Tetrodotoxin (puffer fish toxin) blocks these tiny pores, which in turn prevents any signalling in the nervous system. The result is rapid paralysis and possibly death.
BBP418 differs from other painkillers in that it doesn't have the same side effects as e.g. morphine and its derivatives, there are no known significant interactions with other medicines and is not addictive. It is up to 3,200 times stronger than morphine.
Effects in similar compounds (Tectin®) have shown initial promising but ultimately disappointing effects in the treatment of cancerpatients. BBP418 however is not identical to Tectin® and is believed to hold promise for the treatment of cancerpain as well.
Note: Tetradotoxin is also found in other animals e.g., the California newt and the eastern salamander
Effects of low concentrations of tetradotoxin on rat trigeminal ganglion neurons
Field J. Puffer Fish Poisoning. Journal of Accident & Emergency Medicine.15: (5) 334-336 Sep 1998
Fuchi Y, Hoashi K, Akaeda H, Makino Y, Noguchi T. Anatomical Distribution and Seasonal Variation of Toxicity of Puffer Fish, "Hoshifugu" Arothron firmamentum specimens collected from the Bungo Channel, Oita. Journal of The Food Hygienic Society of Japan. 39: (6) 421-425 DEC 1998
Lin SJ, Chai TJ, Jeng SS, Hwang DF.Toxicity of the puffer Takifugu rubripes cultured in northern Taiwan.Fisheries Science. 64: (5) 766-770 Oct 1998
Malpezzi ELA, deFreitas JC, Rantin FT. Occurrence of toxins, other than paralysing type, in the skin of tetraodontiformes fish. Toxicon. 35: (1) 57-65 Jan 1997
Matsui T, Taketsugu S, Kodama K, Ishii A, Yamamori K, Shimizu C. Studies on the Toxification of Puffer Fish .1. Production of Tetrodotoxin by the Intestinal Bacteria of a Puffer Fish, Takifugu niphobles. Nippon Suisan Gakkaishi. 55: (12) 2199-2203 Dec 1989
Matsumura K.A. Monoclonal-Antibody Against Tetrodotoxin That Reacts to The Active Group For the Toxicity. European Journal of Pharmacology-Environmental Toxicology and Pharmacology Section.293: (1) 41-45 May 26 1995
Matsumura, K.Tetrodotoxin concentrations in cultured puffer fish, Fugu rubripes. Journal of Agricultural and Food Chemistry. 44: (1) 1-2 Jan 1996
Matsumura K. Production of tetrodotoxin in puffer fish embryos. Environmental Toxicology and Pharmacology.6: (4) 217-219 Dec 1998
Nagashima Y, Hamada Y, Ushio H, Nishio S, Shimakura K, Shiomi K. Subcellular Distribution of Tetrodotoxin in Puffer Fish Liver. Toxicon. 37: (12) 1833-1837 Dec 1999.
Saito T, Noguchi T, Shida Y, Abe T, Hashimoto K. Screening of Tetrodotoxin and Its Derivatives in Puffer-Related Species. Nippon Suisan Gakkaishi. 57: (8) 1573-1577 Aug 1991
Sun K, Wat J, So P. Puffer Fish Poisoning. Anaesthesia and Intensive Care. 22: (3) 307-308 Jun 1994
Sun K O. Management of Puffer Fish Poisoning. British Journal of Anaesthesia. 75: (4) 500-500 Oct 1995
Yang C C, Han K C, Lin T J, Tsai W J, Deng J F. An Outbreak of Tetrodotoxin Poisoning Following Gastropod Mollusk Consumption. Human & Experimental Toxicology. 14: (5) 446-450 May 1995
Yu CF, Yu PHF. A Preliminary Study of Puffer Fishes And Their Toxins Found in Hong Kong Waters. Journal of The Food Hygienic Society of Japan 38: (6) 460-463 Dec 1997
BBP418 is chemically synthetised but identical to one of the main compounds of tetrodotoxin, the toxin of the pufferfish or blowfish (Tetraodontidae). BBP418 is a sodium channel blocker, that selectively blocks off the voltage-sensitive sodium channels of excitable tissues and neuronal transmission in skeletal muscles. It is being developed as a potent pain-killer and is currently undergoing Phase II trials in 30 patients. Administration of a few microgram appear to be effective in about 75% of subjects.
Tetradotoxin is complex in structure by small molecule standards and contains a guanidinium moiety. The guanidinium ion is able to enter cells via the voltage sensitive Na+ channels, which are critical for cellullar signalling pathways (e.g. transmission of impulses and the mediation of many cell functions). It is likely that this imidazole ring is the part of the molecule that lodges in the channel leaving the rest of the molecule blocking its outer mouth. Their association and dissociation are independent of whether the channel is open or closed. When a neuron (nerve cell) is sending a message, tiny pores or channels in the neuron's membrane open up to let sodium ions enter the cell. Tetrodotoxin (puffer fish toxin) blocks these tiny pores, which in turn prevents any signalling in the nervous system. The result is rapid paralysis and possibly death.
BBP418 differs from other painkillers in that it doesn't have the same side effects as e.g. morphine and its derivatives, there are no known significant interactions with other medicines and is not addictive. It is up to 3,200 times stronger than morphine.
Effects in similar compounds (Tectin®) have shown initial promising but ultimately disappointing effects in the treatment of cancerpatients. BBP418 however is not identical to Tectin® and is believed to hold promise for the treatment of cancerpain as well.
Note: Tetradotoxin is also found in other animals e.g., the California newt and the eastern salamander
Effects of low concentrations of tetradotoxin on rat trigeminal ganglion neurons
Field J. Puffer Fish Poisoning. Journal of Accident & Emergency Medicine.15: (5) 334-336 Sep 1998
Fuchi Y, Hoashi K, Akaeda H, Makino Y, Noguchi T. Anatomical Distribution and Seasonal Variation of Toxicity of Puffer Fish, "Hoshifugu" Arothron firmamentum specimens collected from the Bungo Channel, Oita. Journal of The Food Hygienic Society of Japan. 39: (6) 421-425 DEC 1998
Lin SJ, Chai TJ, Jeng SS, Hwang DF.Toxicity of the puffer Takifugu rubripes cultured in northern Taiwan.Fisheries Science. 64: (5) 766-770 Oct 1998
Malpezzi ELA, deFreitas JC, Rantin FT. Occurrence of toxins, other than paralysing type, in the skin of tetraodontiformes fish. Toxicon. 35: (1) 57-65 Jan 1997
Matsui T, Taketsugu S, Kodama K, Ishii A, Yamamori K, Shimizu C. Studies on the Toxification of Puffer Fish .1. Production of Tetrodotoxin by the Intestinal Bacteria of a Puffer Fish, Takifugu niphobles. Nippon Suisan Gakkaishi. 55: (12) 2199-2203 Dec 1989
Matsumura K.A. Monoclonal-Antibody Against Tetrodotoxin That Reacts to The Active Group For the Toxicity. European Journal of Pharmacology-Environmental Toxicology and Pharmacology Section.293: (1) 41-45 May 26 1995
Matsumura, K.Tetrodotoxin concentrations in cultured puffer fish, Fugu rubripes. Journal of Agricultural and Food Chemistry. 44: (1) 1-2 Jan 1996
Matsumura K. Production of tetrodotoxin in puffer fish embryos. Environmental Toxicology and Pharmacology.6: (4) 217-219 Dec 1998
Nagashima Y, Hamada Y, Ushio H, Nishio S, Shimakura K, Shiomi K. Subcellular Distribution of Tetrodotoxin in Puffer Fish Liver. Toxicon. 37: (12) 1833-1837 Dec 1999.
Saito T, Noguchi T, Shida Y, Abe T, Hashimoto K. Screening of Tetrodotoxin and Its Derivatives in Puffer-Related Species. Nippon Suisan Gakkaishi. 57: (8) 1573-1577 Aug 1991
Sun K, Wat J, So P. Puffer Fish Poisoning. Anaesthesia and Intensive Care. 22: (3) 307-308 Jun 1994
Sun K O. Management of Puffer Fish Poisoning. British Journal of Anaesthesia. 75: (4) 500-500 Oct 1995
Yang C C, Han K C, Lin T J, Tsai W J, Deng J F. An Outbreak of Tetrodotoxin Poisoning Following Gastropod Mollusk Consumption. Human & Experimental Toxicology. 14: (5) 446-450 May 1995
Yu CF, Yu PHF. A Preliminary Study of Puffer Fishes And Their Toxins Found in Hong Kong Waters. Journal of The Food Hygienic Society of Japan 38: (6) 460-463 Dec 1997
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