Antidotes: Principles and Clinical Applications

Designing Drugs And Their Antidotes Together Improves Patient Care
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Hemophilia treatment improved in the late s by the introduction of partly purified, human plasma-derived concentrates of either factor VIII or factor IX. Due to the presence of the other vitamin K-dependent coagulation factors in partly purified factor IX concentrates, its use was also recognized for the treatment of congenital factor VII and factor X deficiencies, as well as for acquired deficiencies in vitamin K-dependent coagulation factors due to liver disease [ 14 ]. And last but not least, partly purified factor IX concentrates appeared extremely useful in rapid reversal of anticoagulation by vitamin K antagonists like warfarin [ 15 , 16 ].

Nowadays, partly purified factor IX concentrate is referred to as prothrombin complex concentrate PCC. In various countries outside the US, 4F-PCC is indicated for emergency as well as prophylactic reversal of VKA anticoagulation and for replacement therapy in patients with congenital or acquired factor deficiencies. Given their composition, 4F-PCCs may provide an off-label alternative for treatment of acute bleeds in patients with liver disease and in patients with trauma-induced coagulopathy [ 17 ].

Its off-label use as reversal agent for VKA-induced coagulopathy seems obvious because of its composition presence of all procoagulant vitamin K-dependent factors, with factor VII in its activated form. The clinical usefulness of activated PCC in emergency reversal of vitamin K antagonists has been demonstrated in a limited number of clinical studies [ 10 , 22 ].

Development of universal antidotes to control aptamer activity

Vitamin K-dependent coagulation proteins. Vitamin K-dependent procoagulant factors VII, IX, X, prothrombin and vitamin K-dependent anticoagulant proteins C and S are depicted as bars illustrating their different domains as well as globular structures based on current knowledge of their three dimensional configuration [55—65].

The Gla domain is essential for binding to negatively charged phospholipids, e. The enzymatic activity of vitamin K-dependent clotting factors resides in the catalytic domain. In pro-enzymes, the site that is responsible for the proteolytic activity is masked. The active site becomes exposed upon proteolytic cleavage of the so-called activation peptide AP. In factor VIIa and thrombin, the cleaved activation peptide remains attached. In factor IXa, factor Xa, and activated protein C, the activation peptide is cleaved out. Thrombin has lost its Kringle domains and its Gla domain and therefore is not able to bind to negatively charged phospholipids.

Thrombin, in most cases, exerts its activity in solution and independent of a phospholipid membrane. Protein S does not contain an activation peptide and catalytic domain, and therefore cannot exhibit enzymatic activity. This factor concentrate was originally developed for the treatment of bleeding in patients with hemophilia who developed antibodies to factor VIII. Off-label use of recombinant factor VIIa has been documented in a number of bleeding conditions including cardiovascular surgery, trauma, and intracranial hemorrhage [ 23 ]. Some case-control studies have suggested a beneficial effect of a factor VIIa concentrate in the treatment of VKA-associated bleeds [ 24 — 27 ].

The idea behind the treatment of hemorrhages with recombinant factor VIIa is the delivery of a sufficient amount of already activated factor VII to exposed tissue factor at sites of vessel injury Figure 1. In an alternative model, recombinant factor VIIa interacts with the GPIb-IX-V complex on platelets and this interaction enhances tissue factor-independent thrombin generation mediated by recombinant factor VIIa on the activated platelet surface [ 29 ].

When employing recombinant factor VIIa concentrate, one should keep in mind that sufficient plasma levels of other essential vitamin K-dependent coagulation factors are still needed Figure 1. This notion is underscored by the absence of a significant correcting effect of recombinant factor VIIa concentrate in carefully controlled bleeding models in rats tail injury , mice tail injury , and human volunteers punch biopsy subjected to VKA anticoagulation [ 30 — 32 ]. Interestingly, correction of bleeding did occur in incomplete anticoagulated rats [ 30 ]. On the other hand, two studies reported recombinant factor VIIa to be effective in reducing VKA-associated experimental intracerebral hemorrhage in mice [ 33 , 34 ].

Studies employing bleeding models in animals and healthy human volunteers have revealed that all PCCs as well as recombinant factor VIIa are potentially applicable in the treatment of NOAC-associated bleeds [ 36 ]. Activated PCC was shown to reduce dabigatran- as well as rivaroxaban-associated bleeds in various bleeding models [ 32 , 45 , 48 , 50 ].

Results with factor VIIa concentrate were less conclusive, showing positive outcome in about half of the reported bleeding models [ 32 , 43 — 49 ]. Several reasons may underlie the variability in study outcome, including the bleeding model used, plasma concentration of the NOAC at the time of intervention, and the type and dosage of reversal agent administered. The composition of the PCC, that differs from brand to brand, may also be of influence. There is currently no strong clinical evidence e. See legend Table 2 for analytical details.

PCC is a mixture of partly purified vitamin K-dependent coagulation proteins Figure 2.

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PCCs are prepared from human plasma and are supplied as freeze-dried products. Some of the earlier PCCs available until the mids were associated with an increased risk of thrombosis [ 66 ].

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Data published by Grundman et al. An appropriate balance in the levels of coagulation factors may therefore have significant influence on the safety of PCC [ 68 ]. Most desirable are relative clotting factor quantities similar to that in plasma. In Figure 3 , molar quantities of the different clotting factors relative to factor IX are shown for some of the currently available PCCs.

As can be appreciated, relative quantities of all procoagulant vitamin K-dependent clotting factors in PCC are almost identical to that in plasma. This is also true for the vitamin K-dependent coagulation inhibitor protein C. For protein S, however, levels are considerably lower than in plasma.

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Prothrombin is the most abundant vitamin K-dependent coagulation factor, while only trace amounts of factor VII are present in both plasma and PCC. PCCs not only contain vitamin K-dependent coagulation proteins. Mass spectrometric analysis revealed the presence of a variety of common plasma proteins such as fibrinogen, vitronectin, inter-alpha-trypsin inhibitor, complement, albumin, ceruloplasmin, C4b-binding protein, and apolipoprotein [ 69 , 70 ].

The amount of co-purified plasma constituents may vary between the different PCC brands. Copper-containing ceruloplasmin is responsible for the bluish colour of some PCCs. From each product, a single lot was analyzed at Sanquin laboratories. Factor IX activity clotting assay was determined against the European Pharmacopoeia reference standard for factor IX concentrates. Total protein was determined according to Bradford [ 71 ]. Heparin was determined against the 6th international standard for unfractionated heparin [ 73 ].

Content may vary from lot to lot. Data obtained are in good agreement with values from the literature, as can be appreciated from the data between parentheses that were taken directly from reports by Kalina et al. Specific activity is a measure of purity. Total protein is determined spectrophotometrically employing a protein dye and the levels are calculated using a calibration curve of an albumin solution with known protein content [ 71 ].

Specific activities of some currently available PCCs are listed in Table 2. Dissimilar specific activities of the different PCCs are indicative for differences in composition and purity.

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Specific activity based on factor IX coagulant activity, however, does not take into account therapeutic vitamin K-dependent coagulation factors other than factor IX. In the early days of PCC utilization, clinicians were facing an increased incidence of thrombosis in PCC-treated patients [ 66 ].

To minimize thrombogenicity, heparin and antithrombin were advised as supplements in PCC [ 68 ].

Antidotes Principles and Clinical Applications

The rationale behind heparin and antithrombin supplementation is to inactivate any activated coagulation factor in the final PCC product. Levels of heparin and antithrombin supplement, however, vary considerably between different PCC brands Table 2. The ability of heparin and antithrombin supplement to inhibit any active coagulation factor in PCC can be demonstrated, e. The level of antithrombin appeared to have greater impact on thrombin inhibition than either heparin content or the ratio of antithrombin to heparin [ 74 ]. The presence of antithrombin and heparin supplement may have influence on the procoagulant potential of the PCC, i.

A negative effect of anticoagulant supplement can be easily demonstrated in the so-called thrombin generation test. In this test, thrombin generation in a plasma sample is initiated by the addition of calcium-ions and a trigger of coagulation, usually tissue factor. A fluorogenic, thrombin-sensitive substrate is present in the incubation mixture, allowing to monitor in time the generation and subsequent inhibition of thrombin [ 78 ]. The area under the thrombin generation curve endogenous thrombin potential, ETP , one of the parameters that can be derived from the curve, is frequently used as a measure for the amount of thrombin generated.

When PCC is added to normal plasma, an increase in ETP is to be expected because of an increase in level of all essential coagulation factors. A correlation between ETP and the quantity of antithrombin supplement seems absent. Several reports have pointed to a potential negative effect of heparin supplement on the procoagulant efficacy of PCC [ 73 , 76 , 79 — 81 ]; though all of these are in vitro studies, a clinical effect should not be ruled out.

Clinicians thus should be aware of the possibility that during PCC infusions and depending on the PCC brand administered, levels of co-administered heparin may be within the heparin therapeutic window [ 83 ]. It is therefore to be expected that co-infused heparin may only transiently counteract the prohemostatic efficacy of administered clotting factor concentrate.

Additional complicating aspect when treating emergency bleeds in patient on rivaroxaban or any other NOAC, is the fact that co-infused heparin supplement will enhance the anticoagulant effect of the NOAC see Figure 4 and reference [ 73 ]. Thus, an inhibitory effect of heparin during and shortly after infusion of heparin-containing PCC should be taken into account, especially when treating emergency bleeds associated with NOAC anticoagulation.

PCC brands containing no or low heparin do not have this side effect. Heparin intensifies NOAC anticoagulation. Coagulation enzymes are inhibited by antithrombin AT , a process significantly enhanced by heparin. Rivaroxaban, apixaban, and edoxaban are direct Xa inhibitors.

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Dabigatran is a direct thrombin inhibitor. It would therefore be more beneficial to treat emergency bleeds in NOAC-anticoagulated individuals with PCCs containing no or low dose heparin than with PCCs containing high dose heparin. Coagulation cofactors are not depicted in this schematic representation. Release tests, among others, include solubility, sterility, bacterial endotoxins, coagulation factor II, VII, IX, X, and activated coagulation factors. Heparin, if present in the PCC, must be neutralized when performing coagulation factor and activated coagulation factor release tests.

Thrombin is measured by mixing prescribed volumes of PCC and fibrinogen solution.

If thrombin is present, fibrin will be formed. For comparison, coagulation occurs within 30 s in a reference tube containing a prescribed mixture of fibrinogen and thrombin instead of PCC. The absence of thrombin in currently available PCCs was recently confirmed by immunological techniques [ 75 ]. A second test for activated clotting factors that must be performed according to the European Pharmacopoeia is the so-called non-activated partial thromboplastin time NAPTT.

Prescribed dilutions of PCC, phospholipids blood platelet substitute , and calcium chloride are added to plasma anticoagulated with citrate and the time to clot formation is recorded. The test is valid when clotting time in the reference sample with buffer instead of PCC ranges between and s. Stable suspension system for microencapsulated flowable formulations, and method of preparing stable suspension of microcapsules. Divisible, multi-compartment, doseindicating, separately-releasing blister package.

USB1 en. CAC en. Administrative and dosage from drug active agents, reagents or the like and process for the preparation thereof. USA1 en. EPB1 en. Racioppi et al. Household bleaches based on sodium hypochlorite: review of acute toxicology and poison control center experience. USB2 en. Baker et al. Leape et al. In fact, the pregnancy was favourably resolved for both bitches, who gave birth to live puppies free from obvious abnormalities at birth. Furthermore, the puppies did not show any clinical signs of suffering, immaturity or underweight. The echographic check proved favourable at a week before the expected delivery date and the birth took place naturally.

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On the other hand, 95 patients Beard Professor of Surgery. In conclusion, dogs and 3 cats, brought for urgent examination following poisoning by snakebite, showed complete and lasting remission of the symptoms following administration of the composition which is the subject of the present invention. Molecular, Clinical and Environmental Toxicology pp Cite as. For all substances not only the compound itself but also the route of exposure is relevant for toxicity. The same bleeding model was used to demonstrate successful reversal of apixaban- as well as rivaroxaban-associated bleeds [ 37 , 40 ]. USB2 en.

In particular, the puppies of the second bitch, which had been bitten in a foetal period most susceptible to teratogenic effects on organ development, showed no clinical signs, congenital defects or abnormalities. She gave birth naturally. It seems obvious that cortisone treatment would have induced abortion or reabsorption or possibly secondary metritis. This metabolism, in the pregnant bitch, did not have the slightest effect on organs to which the tropism of the venom is linked.

In fact, in the case of the first bitch, her huge response to being bitten by the viper, which occurred in July among other things, with a snake of remarkable size and therefore presumably with a very toxic bite was of a predominantly neurological nature, with extreme lethargy, ataxia, general weakness, temporary blindness and the most extreme prostration for 72 hours. However, the classic hepatic and renal symptoms, the appearance of jaundice and myoglobinuria were almost or completely absent.

In the case of the second pregnant female also there was no foetal damage. The seven puppies did not display, either at birth or after 50 days, any alterations attributable to states of foetal distress or genetic abnormalities. In this case too the damage from the viper's bite, promptly treated, left only visible marks of a local type, with local swelling and oedema, slight lethargy and an absence of the organic symptoms which are typically reported in the statistics.

The best results in terms of general recovery, cessation of the state of shock, renal filtration capacity, appetite and absence of neurological symptoms, which occurred in the cases where intervention with the antidotes had been made earliest, were clinically manifested right from the first hour after the incident.

The rapidity and timeliness of the treatment with the composition of the invention shows how the effects of the venom are less and almost nonexistent when the treatment is administered promptly. From this it is clear that this therapeutic procedure has a particular place of its own as an emergency medicine for prompt use. A composition comprising at least venoms of venomous snake, characterized in that said venoms are diluted in an aqueous medium according to the Sequential Kinetic Activation method.

The composition according to claim 1 , comprising a mixture of venoms. The composition according to claim 1 , wherein said venoms are extracted from a venomous snake selected among Vipera aspis Asp viper , Lachesis mutus, Naja tripudians, Timber rattlesnake Crotalus horridus , Vipera ammodytes, Vipera russel, Agkistrodon anctarticus, Bungarus fasciatus, Botrops lanceolatus, Bitis gabonica, Dendroaspis sp, Elaps corallines, Bushmaster Surukuku or Trigonocephalus lachesis and Asian king cobra Naja tripudians. The composition according to claim 3 , wherein said venomous snake is preferably selected among Vipera Aspis Asp viper , Timber rattlesnake Crotalus horridus , Bushmaster Surukuku or Trigonocephalus lachesis or Asian king cobra Naja tripudians.

The composition according to claim 5 , wherein said protocol comprises serial of sequential steps of dilution of said venom in said aqueous medium and agitation succussion of said diluted solution. The composition according to claim 6 , wherein said sequential steps comprise a dilution from 9 to times. The composition according to claim 6 , wherein said sequential steps comprise a dilution from 9, 30 or times.

The composition according to any claim 1 , wherein said venom is diluted in an aqueous solution. The composition according to claim 9 , wherein said aqueous solution is an isotonic solution. An antidote comprising the composition according to claim 1. Method for the treatment of a poisoning caused by the bite of a venomous snake comprising the step of administering to an individual in need thereof an effective amount of the antidote according to claim Method according to claim 13 wherein the bite is of Vipera Aspis.

The composition according to claim 9 , wherein said aqueous solution is a physiological solution. Method according to claim 13 , wherein the composition is administered subcutaneously. Method according to claim 13 , wherein the composition is administered subcutaneously in the site where the snakebite is located. Method according to claim 13 , wherein the administration comprises consecutive doses of homeopathic composition, at intervals of minutes from each other. Method according to claim 13 , wherein the administration comprises doses of homeopathic composition per day for the days following the bite.

USA1 en. EPA1 en. JPA en. BRA2 en. ITB1 en. WOA1 en. Ahmed et al. Emergency treatment of a snake bite: Pearls from literature. J Emerg Trauma Shock, v1 2 , 20 pages. Ernst Homeopathy: what does the " best " evidence tell us? MJA, v 8 , p Garattini et al European Journal of Internal Medicine, v25 5 , page e Gutierrez et al. Pan-African polyspecific antivenom produced by caprylic acid purification of horse IgG: an alternative to the antivenom crisis in Africa. J Proteome Res.

Isbister epub Human anti-snake venom IgG antibodies in a previously bitten snake-handler, but no protection against local envenoming. Toxicon, v55, p ITMIA1 en. Swanson et al. Barbuio et al. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. Reid et al. Wingert et al.