Medicinal leech

The prototype of this class is hirudin, which was originally isolated from the salivary glands of the medicinal leech, Hirudo medicinalis. Hirudin itself is not commercially available, but recombinant technology has permitted production of hirudin derivatives, namely lepirudin and desirudin.29,38,41 Lepirudin has a short half-life of approximately 40 minutes after IV administration and 120 minutes when given SC. Elimination of lepirudin is primarily renal therefore, doses must be adjusted based on the patient s renal function. The dose should be monitored and adjusted to achieve an aPTT ratio of 1.5 to 2.5 times the baseline measurement. Lepirudin is currently approved for use in patients with HIT and related thrombosis. Up to 40% of patients treated with lepirudin will develop antibodies to the drug.29,38,41... 

The most potent thrombin inhibitor is hirudin, originally isolated from the salivary glands of the medicinal leech Hirudo medicinalis. Its inhibition constant is in the femtomolar (10-15 M) range (57). It is a 65-amino-acid tyrosine-sulfated single-chain polypeptide. Recombinant hirudin differs from native hirudin by the absence of the sulfate group on tyrosine 63 (Tyr-63) and is referred to as desulfato hirudin. The loss of this sulfate group reduces the thrombin inhibitory potency by 10-fold. 

Figure 8 Venomous animals with chemotherapeutic potential, (a) Vampire bat (Desmodus rotundas (http // www.Animalpicturesarchive.com)) (b) medicinal leech [Hirudo medicinalis)-, (c) oriental fire-bellied toad (Bombina orientalis)-, (d) phantasmal poison frog [Epipedobates tricolor), (e) solitary tunicate sea peach Halocynthia aurantium), (f) glia monster (Heloderma suspectum). Photos (b)-(f) by I. Boyd (Creative Commons Attribution ShareAlike License), H. Van (Public domain), L. Ghoul (Creative Commons Attribution ShareAlike License), A. Rode (Creative Commons Attribution ShareAlike License) and Arpingstone (Public domain), respectively. See website for photo credit (a).

In contrast direct-acting preparations have the ability to inhibit fibrin-bound thrombin and include hirudin derived from medicinal leeches but now produced by recombinant technology. Particular interest centres on ximelagatran which may be a possible... 

The oleosin fusion procedure was used for the purification of the commercially valuable plant-based blood anticoagulant hirudin in transgenic Brassica carinata and Brassica napus. Hirudin, a natural protein from the medicinal leech Hirudo medicinalis, is superior to other anticoagulants such as heparin. Recombinant hirudin was cleaved from oil-bodies using endoproteinase Factor Xa. Released hirudin was biologically active, as determined by a colorimetric thrombin inhibition assay. 

A. General description Lepirudin is a recombinant hirudin, a highly specific direct inhibitor of thrombin, derived from yeast cells. The polypeptide is composed of 65 amino acids and has a molecular weight of 7 kD. Natural hirudin is produced in trace amounts as a family of highly homologous isopolypeptides by the medicinal leech. Lepirudin is identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminal end... 

The saliva of the medicinal leech contains a battery of substances that interfere with the hemostatic mechanisms of the host. One of these compounds is hirudin, a potent anticoagulant, which maintains the fluidity of the ingested blood and is the most potent inhibitor of thrombin. Upon binding to thrombin, the cleavage of fibrinogen and subsequent clot formation are prevented. The potency and specificity of hirudin make it a useful antithrombin-III-independent alternative to heparin for the control of thrombosis. 

Collectively, the direct thrombin inhibitors are prototypically represented by hirudin, the antithrombotic molecule found in the saliva of the medicinal leech (Hirudo medicinalis), This protein is a 65 amino acid molecule that forms a highly stable but noncovalent complex with thrombin (7). With two domains, the NH2-terminal core domain and the COOH-terminal tail, the hirudin molecule inhibits the catalytic site and the anion-binding exosite in a two-step process. The first step is an ionic interaction that leads to a rearrangement of the thrombin-hirudin complex to form a tighter bond that is stoi-chiometrically I I and irreversible. The apolar-binding site may also be involved in hirudin binding. This complex and... 

Hirudin is a direct thrombin inhibitor marketed in a recombinant form (lepirudin). It is a protein derived from a salivary gland of the medicinal leech. It binds tightly to exosite I and the apolar site near the catalytic site. It is used as a substitute for... 

The polypeptide hirudin from the saliva of the European medicinal leech inhibits clotting of the leech s blood meal by blockade of the active center of thrombin. This action is independent of AT III and thus also occurs in patients with AT III deficiency. Lepirudin and desrudin are yeast-derived recombinant analogues. They can be used in patients with HIT II. 

Hirudin, a polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicalis, is now produced by recombinant technology. It is a potent and specific inhibitor of thrombin with which it forms an almost irreversible complex. It is cleared predominantly by the kidneys and has a of 40 minutes after i.v. administration. No antidote is available for a bleeding patient. It has been used successfully in patients with heparin-induced thrombocytopenia (HIT), thromboprophylaxis in elective hip arthroplasty, xmstable angina and myocardial infarction. 

G. L. Snider, P. J. Stone, E. C. Lucey, R. Breuer, J. D. Calore, T. Seshadri, A. Catanese, R. Maschler, and H. P. Schnebli. Eglin-c, a polypeptide derived from the medicinal leech, prevents human neutrophil elastase-induced emphysema and bronchial secretory cell metaplasia in the hamster. Am. Rev. Respir. Dis. 732 1155 (1985). 

Hirudin is a substance produced by medicinal leeches, which directly inactivates thrombin. Lepirudin is a synthetic version produced by recombinant DNA technology, which has to be given by injection. It is used specifically in patients that have developed hypersensitivity to heparin (see Chapter 3, page 35). 

The saliva of the medicinal leech contains a battery of substances that interfere with the hemostatic mechanisms of the host. One of these compounds is himdin, a potent... 

Lepirudin (Refludan) is a recombinant derivative (Leu -Thr -63-desulfohirudin) of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech. It is a 65-amino-acid polypeptide that binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin. Lepirudin is approved in the United States for treatment of patients... 

Jellies, J., Johansen, K. and Johansen, J. (1994). Specific pathway selection by the early projections of individual peripheral sensory neurons in the embryonic medicinal leech. 

Surgeons have used medicinal leeches Hirudo medicinalis) for years to prevent thrombosis in fine vessels of reattached digits. Hirudin is the potent, specific thrombin inhibitor isolated from the leech. Lepirudin is a rDNA-derived (recombinant yeast) polypeptide that differs from the natural polypeptide, having a terminal leucine instead of isoleucine and missing the sulfate group at Tyr 63 (115). 

Baskova, I.R., Aguejouf, O.M., Azougagh-Oualane, F. et al. 1995. Arterial antithrombotic effect of piyavlL the novel pharmacological preparation from the medicinal leech, and of its components, prostanoids and enzyme destabilase. Thromb Res. 77 483-492. 

Baskova, I.R., Korostelev, A.N., Chirkova, L.D. et al. 1997. Riyavit from the medicinal leech is a new orally active anticoagulating and antithrombotic drug. Clin Appl Thromb Hemost. 3 40-45. 

---