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
Showing posts with label Edwin ten Winkel. Show all posts
Showing posts with label Edwin ten Winkel. Show all posts
Friday, 2 May 2008
Monday, 3 March 2008
Effects of Coccinia indica and tolbutamide on human bloodsuger values
Pritsana Khamchaew, Edwin ten Winkel, bbPharma
Abstract. Coccinia indica (Climbing ivy gourd) is a herb used in traditional and Ayurvedic medicine in India where it is often combined with Abroma augusta.
100 patients with confirmed type II Diabetes mellitus were rondomized over two groups. One group received 2dd 200mg/kg of Coccinia indica (in watery extract, freeze dried and encapsulated), wheras the other group recieved Tolbutamide 2dd 200mg/kg. Treatment results were determined after 45 days.
Both Coccinia Indica and Tolbutamide caused a statistical and clinically significant lowering of bloodsuger values in comparison to base values. There were no statistically significant differences between patients treated with Coccinia Indica and patients treated with tolbutamide.
Abstract. Coccinia indica (Climbing ivy gourd) is a herb used in traditional and Ayurvedic medicine in India where it is often combined with Abroma augusta.
100 patients with confirmed type II Diabetes mellitus were rondomized over two groups. One group received 2dd 200mg/kg of Coccinia indica (in watery extract, freeze dried and encapsulated), wheras the other group recieved Tolbutamide 2dd 200mg/kg. Treatment results were determined after 45 days.
Both Coccinia Indica and Tolbutamide caused a statistical and clinically significant lowering of bloodsuger values in comparison to base values. There were no statistically significant differences between patients treated with Coccinia Indica and patients treated with tolbutamide.
Thursday, 13 December 2007
In vivo activity of NNRTI BBP153 against wildtype HIV-1
Pritsana Khamchaew, Edwin ten Winkel, bbPharma
BBP153, is shown to have potent in vitro activity, high genetic barrier to resistance development and favorable pharmacokinetics.
In Vitro Activity
BBP153, a new NNRTI, exhibits potent in vitro anti-HIV activity with an EC50 against wild-type HIV-1 of 0.5 nM, and little or no loss of activity against HIV-1 variants having key NNRTI resistance mutations.
This might be a result of the adaptability of the interaction between BBP153 and the NNRTI binding site of HIV-1 reverse transcriptase which allows the compound to bind in different modes and adjust in case of RT mutations.
BBP153, is shown to have potent in vitro activity, high genetic barrier to resistance development and favorable pharmacokinetics.
In Vitro Activity
BBP153, a new NNRTI, exhibits potent in vitro anti-HIV activity with an EC50 against wild-type HIV-1 of 0.5 nM, and little or no loss of activity against HIV-1 variants having key NNRTI resistance mutations.
This might be a result of the adaptability of the interaction between BBP153 and the NNRTI binding site of HIV-1 reverse transcriptase which allows the compound to bind in different modes and adjust in case of RT mutations.
Wednesday, 12 December 2007
Male preputium eversion in Biomphalaria straminea caused by fluoxetine
Lam Hoi-ka, Edwin ten Winkel, bbPharma
Reference
Yapp, J.: Distribution of the Schistosome Vector Snail Biompholaria straminea: J. Mollus. Stud. 1990; 56: 47-55
Fluvoxamine (=Fluvox®), a selective serotonin reuptake inhibitor (SSRI) was tested for its ability to induce preputium eversion in Biomphalaria straminea in order to clarify the physiological mechanism of eversion. Biomphalaria straminea is a snail species that was accidentally introduced to Asia in recent years। Methioheptin and serotonin were added as controls. Fluvoxamine was found to have an MED of 10-50μM (p<0.0001). The receptor antagonist methiothepin was found to have an MED of 1 -10 μM (p <0.0001). Serotonin did not induce eversion and did not block methiothepin-induced eversion. This suggests that fluvoxamine is not acting as SSRI, but possibly as a receptor ligand.
Reference
Yapp, J.: Distribution of the Schistosome Vector Snail Biompholaria straminea: J. Mollus. Stud. 1990; 56: 47-55
Schistosomiasis
Schistosomiasis (also known as Bilharzia) is a disease caused by a fluke worm (trematode) of the genus Schistosoma.
Schistosomiasis is the second most prevalent tropical disease in Africa after malaria and is therefore a great impact on public health and socio-economic developmentin the developing world. There are five major species of schistosomiasis that infect man. One is found in Africa and in South America, two are confined to Africa, and the other two are found only in the Far East in China and the Philippines.
Schistosoma mansoni – which causes intestinal bilharzia – originated in Africa (but might have come from Asia even earlier) but was carried to South America through the slave-trade, where, because a suitable and very productive snail host (Biomphalaria glabrata) existed, it became established, particularly in Brazil and initially the Caribbean. Snails of the genus Biomphalaria, are aquatic snails that live in irrigation canals, and along lake shores.
It has since spread into other neotropical Biomphalaria species and mammalian hosts. The distribution of S. mansoni is in a state of flux. In Egypt, S. mansoni has nearly completely replaced S. haematobium in the Nile Delta, and has spread to other regions of the country. A susceptible host snail, B. straminea, has been introduced into Asia and there are reports of S. mansoni transmission in Nepal. Dam and barrage construction has lead to an epidemic of S. mansoni in Senegal. Because of competition with introduced aquatic species and environmental changes, B. glabrata and consequently S. mansoni have become less abundant on the Caribbean islands.
Schistosoma haematobium – which causes urinary bilharzia – is transmitted by snails of the species Bulinus, which inhabit less permanent water bodies, because during their life cycle they prefer a period of hibernation in mud, during a dry season.
Schistosoma japonicum, is transmitted by amphibious snails of the species Oncomelania. It used to be widespread in the Far East and caused widespread morbidity and mortality. It affects not only man but also domestic and wild animals. As a result of effective control measures in Japan during the 1940’s and 1950’s S. Japonicum has been eradicated in Japan. Stringent snail control as well as socio-economic development in China, has reduced the prevalence in most areas, and this species is now found only in isolated areas in China and some islands in the Philippines.
Two other species of schistosoma exist; S. intercalatum which is confined to West Africa, and lives in mesenteric vessels in man causing abdominal pain and bloody diarrhoea, S.mekongi, which is another form of intestinal schistosoma is found predominantly in Southeast Asia. The main reservoir for this species is dogs.
Life Cycle
The schistosome life cycle is simple; It goes from human to water to snail to water and back to human. The adult worms live in the blood vessels of the human host, and the eggs that the female worms lay break from the blood vessels into the bladder or intestine of the host. These eggs then leave the human body in the feaces of an infected person. They hatch on contact with water and release microscopic larvae called miracidia. These larvae penetrate a specific fresh water snail. Once inside the snail host, the miracidium undergoes an asexual reproduction cycle to produce thousands of new parasite larvae (cercariae), which leave the snail to go into the water.
People are infected with these cercariae during contact with infested water during their normal daily activities such as washing or recreation but also through farming by irrigation.
The cercariae are capable of penetrating an individual's unbroken skin within a few seconds, and having done so they continue their biological cycle by migrating through the lungs to reach the liver. It takes about 45 days from penetration before the worms are adult and mature in the liver, and they then pair off. The male transports his mate to their final site in the human host blood vessel where they can live for several years producing many eggs every day.
Control Measures
Control measures focus on both the parasite as well as the snails, through molluscicides and helminticides. Biological controls have included control of the vegetation on which snails prosper through fish, the introduction of snail eating fish and competing species of snails and flushing of channels. Application of SSRI type anti-depressants seems to prevent copulation of snails, thus opening a new way of control.
Schistosomiasis is the second most prevalent tropical disease in Africa after malaria and is therefore a great impact on public health and socio-economic developmentin the developing world. There are five major species of schistosomiasis that infect man. One is found in Africa and in South America, two are confined to Africa, and the other two are found only in the Far East in China and the Philippines.
Schistosoma mansoni – which causes intestinal bilharzia – originated in Africa (but might have come from Asia even earlier) but was carried to South America through the slave-trade, where, because a suitable and very productive snail host (Biomphalaria glabrata) existed, it became established, particularly in Brazil and initially the Caribbean. Snails of the genus Biomphalaria, are aquatic snails that live in irrigation canals, and along lake shores.
It has since spread into other neotropical Biomphalaria species and mammalian hosts. The distribution of S. mansoni is in a state of flux. In Egypt, S. mansoni has nearly completely replaced S. haematobium in the Nile Delta, and has spread to other regions of the country. A susceptible host snail, B. straminea, has been introduced into Asia and there are reports of S. mansoni transmission in Nepal. Dam and barrage construction has lead to an epidemic of S. mansoni in Senegal. Because of competition with introduced aquatic species and environmental changes, B. glabrata and consequently S. mansoni have become less abundant on the Caribbean islands.
Schistosoma haematobium – which causes urinary bilharzia – is transmitted by snails of the species Bulinus, which inhabit less permanent water bodies, because during their life cycle they prefer a period of hibernation in mud, during a dry season.
Schistosoma japonicum, is transmitted by amphibious snails of the species Oncomelania. It used to be widespread in the Far East and caused widespread morbidity and mortality. It affects not only man but also domestic and wild animals. As a result of effective control measures in Japan during the 1940’s and 1950’s S. Japonicum has been eradicated in Japan. Stringent snail control as well as socio-economic development in China, has reduced the prevalence in most areas, and this species is now found only in isolated areas in China and some islands in the Philippines.
Two other species of schistosoma exist; S. intercalatum which is confined to West Africa, and lives in mesenteric vessels in man causing abdominal pain and bloody diarrhoea, S.mekongi, which is another form of intestinal schistosoma is found predominantly in Southeast Asia. The main reservoir for this species is dogs.
Life Cycle
The schistosome life cycle is simple; It goes from human to water to snail to water and back to human. The adult worms live in the blood vessels of the human host, and the eggs that the female worms lay break from the blood vessels into the bladder or intestine of the host. These eggs then leave the human body in the feaces of an infected person. They hatch on contact with water and release microscopic larvae called miracidia. These larvae penetrate a specific fresh water snail. Once inside the snail host, the miracidium undergoes an asexual reproduction cycle to produce thousands of new parasite larvae (cercariae), which leave the snail to go into the water.
People are infected with these cercariae during contact with infested water during their normal daily activities such as washing or recreation but also through farming by irrigation.
The cercariae are capable of penetrating an individual's unbroken skin within a few seconds, and having done so they continue their biological cycle by migrating through the lungs to reach the liver. It takes about 45 days from penetration before the worms are adult and mature in the liver, and they then pair off. The male transports his mate to their final site in the human host blood vessel where they can live for several years producing many eggs every day.
Control Measures
Control measures focus on both the parasite as well as the snails, through molluscicides and helminticides. Biological controls have included control of the vegetation on which snails prosper through fish, the introduction of snail eating fish and competing species of snails and flushing of channels. Application of SSRI type anti-depressants seems to prevent copulation of snails, thus opening a new way of control.
References
Ibrahim, Mohamed: Population dynamics of Chaetogaster limnaei (Oligochaeta: Naididae) in the field populations of freshwater snails and its implications as a potential regulator of trematode larvae communityParasitology Research, Volume 101, Number 1, June 2007 , pp. 25-33(9,), Springer
Kenawy, El-Refaie; El-Maghraby, Azza: New Polymeric Formulation for the Control of Biomphalaria Alexandrina Based on Pharmaceutical Waste Gelatin, Journal of Biobased Materials and Bioenergy, Volume 1, Number 2, August 2007 , pp. 215-219(5), American Scientific Publishers
Remais, J.; Hubbard, A., et al.Weather-driven dynamics of an intermediate host: mechanistic and statistical population modelling of Oncomelania hupensis: Journal of Applied Ecology, Volume 44, Number 4, August 2007 , pp. 781-791(11)
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