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Gloydius Blomhoffii) Japan, Tel: 81 97 569 3121; Email: Ookamoto@ Central Journal of Pharmacology & Clinical Toxicology Bringing Excellence in Open Access Review Article *Corresponding author Osamu Okamoto, Department of Dermatology, Oita City Medical Association’s Almeida Memorial Hospital, Mamushi (Gloydius blomhoffii) Japan, Tel: 81 97 569 3121; Email: ookamoto@ Submitted: 07 April 2018 Snake Bites in Japan –Current Accepted: 26 April 2018 Published: 28 April 2018 Problems and Clues to a ISSN: 2333-7079 Copyright Solution © 2018 Okamoto et al. OPEN ACCESS Osamu Okamoto1*, Rui Suzuki2, Manami Kusatsu2, Ryuta Nakashima3, Nobuhiro Inagaki3, Yoshitaka Kai4, and Hiroyuki Keywords Hashimoto2 • Mamushi bite • Gloydius blomhoffii 1 Department of Dermatology, Oita City Medical Association’s Almeida Memorial Hospital, • Prediction of severity Japan • Chelator 2Department of Plastic Surgery unit, Oita City Medical Association’s Almeida Memorial Hospital, Japan 3Department of Emergency Medicine, Oita City Medical Association’s Almeida Memorial Hospital, Japan 4Department of Dermatology, National Hospital Organization Beppu Medical Center, Japan Abstract Venomous snakes of the genus Gloydius are distributed in eastern Asia. Bites from one species, known as Japanese Mamushi, Gloydius Blomhoffii, are common in Japan. Some patients develop severe symptom, represented by rhabdomyolysis and acute renal failure, and in extreme cases, death has resulted mainly due to intestinal bleeding/necrosis and perforating peritonitis. The mortality rate is estimated to be about 1 death/300 bites. The lethal cases presented with severe abdominal symptoms, including melena and ileus, and the severe cases including the lethal cases present with higher creatinine kinase values and white blood cell counts. Therefore, it was found that these are reliable indicators predicting the severity of envenomation. The severe and non-severe cases can often be distinguished by the rate of elevation of these laboratory values. At present, mamushi-specific antivenom is recognized as the sole effective medicine against a mamushi bite; however, the clinical results might fail to meet expectations. In this review, we discuss problems associated with treating cases of mamushi bite, our recent trials, and perspectives regarding solutions to the clinical problems encountered. INTRODUCTION with treating bitten patients and discuss ways to solve these There are several venomous terrestrial snakes in Japan with and outcome. We also highlight the current problems associated these, Habu (Protobothrops flavoviridis) is restricted to the south- problems.GENERAL DESCRIPTION OF MAMUSHI SPECIES westerntwo species islands, considered while ofanother, extreme Japanese medical significance.Mamushi (Gloydius One of blomhoffii, formerly Agkistrodon blomhoffii) is distributed widely taxonomical position is as follows: Mamushi is a viper that is widely distributed in Japan [1]. Its might expect, with its much wider distribution, the frequency of in Japan, except for the south-western islands [1,2]. As one a common event in Japan, with an estimated 3,000 people being Family: Viperidae, Subfamily: Crotalinae, Genus: Gloydius, mamushi bites significantly exceeds the other species, making it Species: blomhoffii G. tsushimaensis,Some other G. brevicaudus,closely related G. ussuriensisGloydius species are also whichbitten andis the 10 only dying medicine from the that bite can [3]. theoretically Mamushi-bitten neutralize patients the Mamushidistributed is ina pit the viper eastern with areasadults of between Asia and 40-80 these cm include in length, mamushiare often venom, treated however with mamushi-specificthe clinical effectiveness antivenom of this serum,serum usually pale to dark brown in color with dark-edged [4]. The Japaneseblotches is obscure. In addition, the causes of the envenomated victim’s (for photographs, see [5]). It is mainly active at night during the death are poorly known. Furthermore, to date, there have not Mamushi inhabits the wet, weedy areas typically around rice summer, so most of bites occur at that time and early morning. been available quantitative indicators that reflect the severity of a mamushi bite. so unsuspecting farmers are commonly bitten when maintaining that resulted in death and discuss some bite severity indicators paddies. It does not jump, and only bites when victim draws near, thatIn can this help review, physicians we describe recognize the and clinical predict progression the clinical in course cases their rice paddies and farms. Seventy percent of patients are bitten on the extremities [6]. Cite this article: Okamoto O, Suzuki R, Kusatsu M, Nakashima R, Inagaki N, et al. (2018) Mamushi (Gloydius blomhoffii) Snake Bites in Japan –Current Prob- lems and Clues to a Solution. J Pharmacol Clin Toxicol 6(1):1103. Okamoto et al. (2018) Email: Central Bringing Excellence in Open Access CHARACTERISTICS OF MAMUSHI VENOM estimated to be 1.32 mg/kg in the same study [16]. In contrast, in humans, deaths within 24 h have not been known, and lethal Like in other vipers, mamushi venom is comprised of outcomes generally take more than several days to develop a mixture of many different enzymes and non-enzymatic [19,20]. Therefore, the actual LD50 of the venom in humans is components (Table 1) [7,8]. These include phospholipase A2, expected to be much lower than that reported in mice. hyaluronidase, L-amino acid oxidase, phosphodiesterase, and 5’ nucleotidase, which are reported to be the most common When intravenously injected into mice, HR-1 induces drastic components of the venoms found in viper species [7,8]. intestinal hemorrhaging, whereas subcutaneous hemorrhaging Phospholipase A2 in Clotarinae subfamily has molecular weight is mild [7]. The intestinal hemorrhaging closely resembles that between 11-31 kDa [8]. This enzyme in habu venom is supposed seen in human lethal cases, as described in the section “Causes to cause rhabdomyolysis, hemorrhaging, and local swelling of deaths by mamushi bite”. In contrast, the hemorrhaging [8], and the toxic effects are similar in another Crotalinae induced by HR-2 is largely subcutaneous and intramuscular member [9]. Hyaluronidase does not have poisonous action [7]. The hemorrhagic activity of HR-1 is estimated to be 30- by itself, but it breaks down mucopolysaccharides, facilitating 50 times as potent as that of HR-2 [7,16]. Chelators such as diffusion of the venom components into the connective tissue. ethylenediaminetetraacetic acid (EDTA) and cysteine, which bind Particularly, hyaluronidase enhances hemorrhaging effects of and deplete the environmental divalent cations, cancel the lethal hemorrhagic factors (HR) mentioned below [7]. L-amino acid activities of HR-1, HR-2, and crude mamushi venom [16,21]. oxidase of venomous snake is quite potent among L-amino acid Importantly, the inhibition of these hemorrhagic factors is oxidase homologues found in other animals. It is a 60 kDa acidic irreversible. Thus, these hemorrhagic factors essentially require glycoprotein and it induces apoptosis of the vascular endothelial divalent cations to maintain their functional conformation. This cells, and inhibits factor IX function and platelet aggregation observation may be useful for treating patients suffering from [10,11]. These biochemical functions of the L-amino acid oxidase mamushi bites. would contribute to the subcutaneous hemorrhage usually seen in Apart from the components above, mamushi venom mamushi-bitten patients. Phosphodiesterase, and 5’ nucleotidase contains a platelet aggregation protein, mamushigin [22]. are nucleic acid-degrading enzymes and it is supposed that they It is a heterodimeric 30 kDa protein and it can bind platelet are potentially cytotoxic. However, their harmful in vivo effects glycoprotein-I, but it can also directly aggregate platelets [22]. have not ever been concerned. The unique function of the mamushigin is believed to cause Aside from these common components of venoms, arginine thrombocytopenia via platelet aggregation [23,24]. However, ester hydrolase is highlighted in all Gloydius species as well as this symptom is not often seen in mamushi-bitten human in the Crotalinae subfamily. Arginine ester hydrolase comprises victims. Here, mamushigin induces platelet aggregation whereas at least three enzymes: “bradykinin releasing enzyme”, “clotting L-amino acid oxidase inhibits platelet aggregation, thus their enzyme”, and “permeability increasing enzyme” which were functions are opposite. Considering from the frequency of named in the original publication [12]. These three enzymes have the thrombocytopenia and subcutaneous hemorrhaging, it is molecular weight of 30 kDa [8]. The bradykinin releasing enzyme supposed that the effect of the L-amino oxidase is normally releases bradykinin from plasma kininogen and thus induces predominant, and the effects of mamushigin appear in a special condition, such as direct intravascular injection of the venom, as kallikrein [13]. The clotting enzyme induces blood coagulation by hypotension. This enzyme was later identified as mamushi salivary mamushi venom. Alpha-toxin binds postsynaptic acetylcholine enzyme induces vascular hyperpermeability, resulting in swelling (ACh)described receptor below. Neurotoxinsand blocks (α-the and nerve β-toxins) conduction, are also whereasfound in [7,converting 12]. Further fibrinogen characterization to fibrin; and of the these permeability Japanese increasingmamushi enzymes could not be found in the following publications. conduction [25,26]. These neurotoxins are thought to contribute
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