WO2017194609A1

WO2017194609A1 - Adsorber material for preventing or treating serious progressions of infectious diseases

Info

Publication number: WO2017194609A1
Application number: PCT/EP2017/061195
Authority: WO
Inventors: Dietrich Seidel
Original assignee: B. Braun Avitum Ag
Priority date: 2016-05-10
Filing date: 2017-05-10
Publication date: 2017-11-16
Also published as: DE102016208024A1; EP3454841A1; RU2018142031A3; CN109069445A; BR112018072237A2; ZA201807160B; RU2018142031A

Abstract

According to the invention, an anion exchange material is used as an adsorber material for use in the prevention or treatment of serious progressions of infectious diseases, in particular infectious diseases caused by viral infection, fungal infection, or parasitic infection. The adsorber material is preferably contained in an extracorporeal perfusion system and comprises cations or synthetic, semisythetic, or natural polycation chains, which are fixed to carrier materials, wherein polycation chains are in linear or branched form.

Description

Adsorber material for the prevention or treatment of severe disease of infectious diseases

description

The present invention relates to an adsorbent material for use in the prevention or treatment of severe infectious disease infectious diseases, particularly infectious diseases caused by viral infection, fungal infection or parasitic infection.

Under normal circumstances, the human immune system can adequately control infectious diseases caused by viruses, fungi or parasites. However, in most cases harmless infectious diseases can take a difficult course with complications to death due to many causes.

Especially with infections with certain viruses came and comes again and again to epidemics with a high number of deaths. The Ebola epidemic of 2014/2015, with more than 11,000 deaths and over 28,000 illnesses, claimed the highest number of victims of this virus so far, leading to worldwide anxiety and uncertainty. But other viral infections cause many thousands of deaths each year worldwide, and a threat of fungal or parasitic infections is not to be underestimated, especially in patients whose immune system has been weakened for one reason or another.

Patients whose immune system is weakened by existing infections or genetic or acquired defects are generally more susceptible to infections and the course of the disease is generally more severe and leads to death much more frequently than in "healthy" patients, ie patients without impairment The previous therapy approach of severe courses of infectious diseases exists in particular in viral infections in the Relief of symptoms and, if necessary, non-specific antiviral therapy. In spite of all efforts, however, a fatal outcome of the disease is frequently complained of, especially in the case of infection with viruses which cause a haemorrhagic fever. Older people, children and people with immune system defects are particularly likely to be among the fatalities. Examples of such viral infections besides Ebola are yellow fever, dengue fever, Lassa fever, Crimean Congo and Hanta fever. However, infections caused by influenza viruses, hepatitis virus, cytomegalovirus and others can pose a significant risk, especially in these patient groups.

In previous therapeutic approaches, a treatment of bacterial superinfections has been included and often a prophylactic or therapeutic antibiotic used. Nevertheless, the mortality could not be lowered satisfactorily, especially in the case of the major viral epidemics, but also in seemingly harmless viral infections.

The present invention was therefore based on the object to show a new therapeutic or prophylactic approach, especially in the context of viral epidemics, but also in normal clinical operation, to significantly reduce mortality and to minimize the burden on patients. Furthermore, a way should be provided to avoid or effectively treat complications associated with fungus or parasitic infections.

This object is achieved by an adsorber material for use in the prevention or treatment of severe disease of infectious diseases, wherein the adsorber material is an anion exchanger material.

The present invention is based on the finding that bacterial superinfections in many cases of the abovementioned viral infections, fungal infections or parasitic infections play a role for the lethality of patients, which has hitherto still not been recognized to this extent. Increasingly It can be seen that to a great extent the patients suffer from subsequent reactions of the body's immune response to components of bacteria and the resulting damage to vital organs is difficult or impossible to heal. In the context of the present invention, it has been found that bacterial superinfection leads to the invasion of bacteria into the bloodstream and so-called bacteremia occurs. Subsequent reactions are often much more serious than the actual (viral) infection. As a result of bacteremia in the bloodstream of humans ultimately even serious complications such as sepsis, septic shock and multi-organ failure arise with mostly fatal outcome.

Responsible for the pathogenicity of Gram-negative bacteria are mainly the so-called lipopolysaccharides, LPS. These are constructed as components of the outer membrane of Gram-negative bacteria from three structurally different regions. The carrier of the toxic properties is lipid A. This sub-region with a molecular weight of 2,000 daltons consists of a phosphorylated D-glucosamine disaccharide to which are bound several long-chain fatty acids in ester and amide form (Bacterial Endotoxic Lipopolysaccharides, Morrison, DC, Ryan, JL eds., 1992, CRC Press)

Bacterial lipopolysaccharides are considered to be initiating mediators and key toxins in the pathogenesis of septic shock. The clinical picture of sepsis often correlates with the level of LPS concentration in the blood of the patients (Nitsche, D. et al., Intensive Care Med., 12 Suppl., 1986, 185ff). The lipopolysaccharides stimulate the phagocytes called macrophages in the organism for the production and release of inflammatory mediators such as TNF-α and interleukins.

However, not only the LPS of Gram-negative bacteria play a major role, but it can also cause infections by Gram-positive bacteria that contain no LPS, complications, in particular the dangerous hospital germs such as Staphylococcus au- Reus have proven to be particularly treacherous, since they are now often resistant to antibiotics. Almost 50% of septic patients have an infection with Gram-positive bacteria. About 30% of patients suffer from a mixed bacterial infection.

The toxins of the gram-positive bacteria, the lipoteichoic acids (LTA) are also located in the cell wall and are released during the lysis of the bacteria. The LTAs consist of glycerol or ribitol polymers which are linked to glycolipids or phosphatidyl glycolipids via 1-> 3 phosphodiester bonds. In addition, the polyglycerol or ribitol chains carry glucose and / or N-acetylglucosamine residues. The LTAs similarly stimulate monocytes and other immunocompetent cells to produce cytokine (Mattson, T., FEMS Immunol., Med. Microbiol. (1993) 7: 281-288) mediated in the circulation (Cleveland MG, Infect. Immun. (1996) 64: 1906-1921).

LTA flooded into the bloodstream binds to the cells of the monocyte-macrophage system and stimulates them to increase the production and release of mediators (cytokines). As an initial mediator and potent porinflammatory stimulus, the tumor necrosis factor α is first synthesized and secreted into the bloodstream. The subsequent biological signal amplification via interleukins, leukotrienes, prostaglandins and interferons (mediator cascade) can finally cause serious disturbances of the homeostasis of various biological control circuits and organ systems, such as the clinical picture of septic shock.

Thus, lipopolysaccharides as initiating toxins of Gram-negative bacteria and lipoteichoic acids as highly potent pyrogens of Gram-positive bacteria play a key role in the pathogenesis of sepsis. Essential in the context of the present invention, however, is the recognition that especially in patients suffering from an existing, in particular virus-induced infection, superinfections with both gram-negative and gram-positive bacteria pose a significant threat, since again on septic complications already by the Primary infection threatens weakened patients multi-organ failure with fatal outcome. Although, in contrast to massive bacterial infections, at least initially a small bacterial load is present in superinfections, in particular the treatment of such patients by antibiosis causes a release of the bacterial toxins into the bloodstream. Instead of improving the condition of the disease, complications and worsening of the general condition due to the initiation of an immune cascade, which otherwise only occurs in severe bacterial infections, often occur.

In addition, the non-critical and prophylactic use of antibiotics in non-bacterial infections leads to the formation of resistance and destruction of the physiological bacterial flora, for example in the intestine. Administration of antibiotics should therefore always be done wisely. Especially with serious viral infections and critically ill patients, it is desirable to combat a bacterial superinfection at an early stage, especially at a time when the nature of the bacteria has not yet been determined and thus not yet indicated each antibiotic can be determined. Prophylactic measures would be desirable, but are associated with considerable risks in this context.

By taking non-steroidal anti-inflammatory drugs, such as ibuprofen or paracetamol, which are often used to reduce fever, a granulocytopenia can be triggered, which further increases the risk of bacterial superinfection. In addition, intensive therapeutic measures, such as the use of venous catheters, bacteria and other pathogens, open up new and un- physiological entry ports at which under certain circumstances no adequate immune defense is available.

The adsorbents according to the invention act via the binding and thus the removal of the bacterial toxins LPS and LTA from body fluids, in particular from blood, blood plasma and blood serum. This can prevent the initiation of the defense cascade and the massive secretion of cytokines and other mediators of the immune system and prevent the often associated damage to organs. The adsorbents according to the invention have the significant advantage that they can be used both prophylactically and therapeutically in comparison to antibiotics treatment, but also to other drugs used to date for the relief or treatment of symptoms of bacterial superinfections. In both cases, there is no risk of resistance or a resulting burden on the patient. Rather, harmful effects of bacterial toxins entering the bloodstream can be absorbed at an early stage and the ensuing burden on the immune system can be avoided.

For this reason, the adsorber materials according to the invention can be advantageously used even in severe cases of infectious diseases, especially viral infections with incipient or manifest bacterial superinfections. A burden on the patient by massive release of toxic bacterial products, which is caused by antibiotic treatment and thereby killing off the bacteria, is not to be feared in the inventive use of Adsorbermaterialien. The possibility of avoiding the administration of antibiotics is also fundamentally advantageous since the formation of resistance today represents a major challenge for the healthcare system. The finding that with the adsorber materials according to the invention in their use for the prevention or treatment of severe courses of infectious diseases by the elimination of the trigger of the biological Mediatorkaskade that the above-described severe disorders of various Biological control circuits and organ systems leads to a fundamentally new approach in the treatment of affected patients. Whereas antibiotics in infectious diseases caused by viruses, fungi or parasites clearly do not permit satisfactory treatment, the adsorbent material according to the invention can be used to effect a gentle and extremely effective control of the harmful effects of bacterial superinfections on the patient.

The use of an adsorbent material according to the invention makes it possible in special cases in which a dose of antibiotics can not or should not be dispensed with without burdening the patients with LPS and LTA. Insofar as the adsorber materials are used simultaneously or directly following antibiotic administration, bacteria toxins entering the bloodstream are immediately captured and rendered harmless by killing the bacteria. In this way, a safe antibiotic administration can be made possible, so that the combined use of an adsorbent material according to the invention and one or more antibiotics represents a further preferred embodiment of the invention.

In preferred embodiments of the present invention, the adsorbent material is particularly provided for use in the treatment of infectious diseases caused by viral infection, fungal infection or parasite infection.

As mentioned, bacterial (super) infections with a low bacterial load for the immune system have to be mastered in principle without significant complications. However, under certain conditions, even a low level of bacterial load can overwhelm a patient's immune system and then lead to serious complications, including death. This is especially the case in patients with immunodeficiencies, which may be genetically determined on the one hand or also by a drug treatment for immunosuppression, for example after transplantation. Even such patients are already at trivial exposed to light or viral infections of increased risk. A slight infection can then lead to severe progression, this also applies to fungal or parasitic infections. Particularly at risk are those suffering from an immune deficiency patients, when it comes to infection by a dangerous virus. In such patients, for example, a prophylactic treatment with the adsorbent material according to the invention is already indicated at a time when no massive symptoms of illness are yet to be discerned. It must be remembered that due to the weakened immune system, disease courses are much faster and more severe than in persons with an intact immune system. In such patients, therefore, a severe disease course can be prevented by early prophylactic treatment.

Even an existing infection leads to a weakening of the immune system against further attacks by pathogens. Thus, in preferred embodiments of the present invention, the adsorbent material of the present invention is used for the prevention or treatment of severe infectious disease pathways, particularly viral infections, when immunodeficiency, immunodeficiency, or immunosuppression is underlying, and / or such ) Infection was triggered.

In a particular embodiment of the use according to the invention, the immunodeficiency is granulocytopenia, lymphocytopenia or an immunoglobulin defect. In the context of the present invention, such immunodeficiencies are manifested in particular by at least one of the following parameters:

(a) an absolute granulocyte count of the patient of <1500 per μΙ of blood, <500 per μΙ of blood, or / and

(b) an absolute number of CD4 + T helper cells of <500 per μΙ blood, preferably <200 per μΙ blood, again in particular with a simultaneously low proportion of naive T helper cells (CD4 + CD27 + CD45 RA +), or / and (c) a level of total IgG in the blood serum of <6 g / l, preferably <4 g / l, or / and

(d) an IgA deficiency (compared to norm values) or / and

(e) IgM deficiency (compared to norm values).

Granulocytopenia occurs transiently in viral infection or as a result of the use of non-steroidal anti-inflammatory drugs, but seriously in leukemia or cytostatic therapy or after bone marrow transplantation. In the presence of granulocytopenia, the absolute granulocyte count is usually less than 1500 per microliter of blood, preferably less than 500 per microliter of blood.

Lymphocytopenia predominantly occurs in HIV patients and as a result of the use of various immunosuppressants in autoimmune diseases or organ transplantation. In the presence of lymphocytopenia, the absolute number of CD4 + T helper cells in the blood is less than 500 and often less than 200, especially with a low proportion of naïve T helper cells (CD4 + CD27 + CD45 RA +).

Lymphocytopenia causes an increased risk for the reactivation of viral infections, for example the herpes group such as Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus (HSV) and cytomegalovirus ( CMV), intracellular bacteria such as tuberculosis or parasites such as toxoplasmosis.

Immunoglobulin defects may primarily occur, i. congenital, or acquired, such as in malignant diseases, by cytostatic therapy or protein loss. In the presence of an immune deficiency, the level of total IgG in the blood serum is <6 g / liter, in particular <4 g / liter or / and there is an IgA deficiency or / and an IgM deficiency.

An IgA deficiency is often primary and causes an increased risk of mucosal infections, whereas IgM deficiency is mostly acquired and an increased risk for infections caused by viruses and gram-negative bacteria.

When incipient inflammatory diseases such as viral infections with general symptoms such as fever, head and body aches, fatigue and organ-specific signs are often determined as inflammation markers, the level of C-reactive protein, the leukocyte count in the blood and other inflammatory markers. Severe courses of infectious diseases and in particular of viral infections are present in the context of the present invention if at least one inflammatory marker fulfills the following conditions or if one of the following physiological states is present:

(a) an increase in the level of C-reactive protein to> 0.5 mg / dl (5 mg / l), in particular> 1 mg / dl (10 mg / l), again in particular> 4 mg / dl (40 ml / l);

(b) a leukocyte count in the blood count of <4x10 ⁹ / L or> 9x10 ⁹ / L;

(c) a differential blood picture with lymphocytosis and / or granulocytosis, possibly with the formation of immature cell forms;

(d) an increase in the level of procalcitonin to> 0.5 ng / l, in particular> 1 ng / l, again in particular> 2ng / l;

(e) a sharp increase in the level of interleukin 6 versus the baseline value of 10 ng / l (10pg / ml);

(f) complement consumption, in particular a reduction in the level at C3 and C4;

(g) disseminated intravascular coagulation / consumption coagulopathy, in particular a reduction in platelet and antithrombin levels, abnormal quick and PTT values, or / and an increase in D-dimer.

The adsorber material according to the invention preferably deals with severe courses of infectious diseases, in particular viral infections, prophylactically or therapeutically, which are associated with complications such as systemic infections. associated with inflammatory response syndrome, sepsis, severe sepsis, septic shock and / or multiple organ failure.

Viral infections, which are based on a bacterial superinfection, can basically be triggered by viruses of any class or any type. Examples of such virus infections are those with influenza virus, cytomegalovirus, Epstein-Barr virus, hepatitis virus, herpesvirus, human immunodeficiency virus HIV or with a virus that causes a viral hemorrhagic fever, in particular selected from the group consisting of Lassa fever (Arenaviridae ), Rift Valley, Crimean Congo and Hanta fever (Bunyaviridae), Ebola and Marburg fever (Filoviridae), yellow fever and dengue fever (Flaviviridae) and Chikungunya fever (Togaviridae).

In a not inconsiderable proportion of patients with Ebola fever, comorbidities such as malaria, rickettsioses, typhoid fever and other non-typhoid Salmonella infections as well as HIV, HBV and HCV infections are present. Bacteria and bacterial pneumonia were also observed in Ebola. So it seems due to the caused by the Ebola virus organ damage to, inter alia, kidney, liver and intestine, and strong inflammatory reactions, for example, to a leak in the intestinal barrier. As a result, bacteria can enter the blood. For example, bacterial superinfections with Gram-negative or / and Gram-positive bacteria in Ebola infection can lead to further serious complications.

For the treatment of Ebola disease, so far essentially a symptomatic therapy is performed, which includes intensive medical care. Here are antipyretic measures, the balance of strong fluid and electrolyte loss due to diarrhea through intravenous fluid and electrolyte intake and parenteral nutrition to regulate the glucose balance in the center. In the early stages of the disease, there are occasional successes with convalescent serum. An effective antiviral, however, is not yet known. The Isolation of the patient is of great importance to prevent infection of the medical staff or other persons. Overall, however, so far there are no satisfactory treatment options and approaches for the treatment of Ebola infections and related complications. Rather, despite all efforts, about half of the affected patients die.

Surprisingly, it has now been found that especially with an Ebola infection by using the adsorber material according to the invention severe lethal courses of Ebola infections can be partially prevented or already manifested complications can be treated and thus a lethal outcome, often ultimately by sepsis or Septic shock caused by multiple organ failure can be prevented. The use of the adsorber material according to the invention for use in the prevention and / or treatment of severe courses of Ebola infections is therefore a particularly preferred subject of the present invention.

Apart from the dramatic epidemics caused for example by the Ebola virus, complications are also seen in other infections, especially viral infections, and it is the flu epidemic that causes a high death toll every year. For example, in Germany, for the winter season 2012/2013, influenza was attributed a mortality in about 29,000 cases (Epidemiological Bulletin, No. 3, 19 January 2015, pages 17-20). Also in this connection, the adsorbent material of the present invention can be used for prevention or treatment to just prevent the severe courses and to reduce the lethality.

The adsorber material according to the invention is described in another context in EP 1 602 387 B1. The disclosure of this patent is hereby incorporated by reference with respect to the design of the adsorber material. W

The adsorber material used in the context of the invention comprises anion exchange groups as functional groups. Cation or synthetic, semisynthetic or natural polycation chains can be used as anion exchanger groups. Polykationenket- th can be present in linear or branched form, more preferred are longer polycation with a variety of cationic charges, which are also referred to as tentacles.

The adsorber materials according to the invention are preferably present in an extracorporeal perfusion system. Patient blood or blood plasma or blood serum is passed through this system, thereby removing bacterial lipopolysaccharides and / or lipoteichoic acids. The adsorbent material according to the invention contains the anion exchanger groups, preferably fixed on a carrier material. Suitable support materials are porous glass and / or silica gel coated with organic polymers or copolymers, crosslinked carbohydrates and / or organic polymers or copolymers in the form of porous particles or microporous membrane and / or hollow fiber structures. Particularly preferably, the carrier material is a hollow fiber material.

To make this removal of LPS and LTA from the blood, plasma or serum as effective as possible, hollow fibers are used, which are chemically modified in such a way that the charged LPS and LTA molecules are particularly well bound and thus from the blood or plasma be removed.

The person skilled in the art knows hollow fiber materials suitable for the application. These consist in particular of polyamide, polysulfone, polyether, polyethylene, polypropylene, polyester or derivatives or / and mixtures of such polymers. In particularly preferred embodiments of the invention, the hollow fibers are made of nylon.

Particularly favorable for the modification of the support materials, a graft polymerization has been found in which the hollow fiber material Anion exchanger groupings are grafted. Such tentacle-like extensions on the base material are particularly suitable for binding large amounts of LPS or LTA molecules. As a result, the efficiency of the material can be optimally designed. For this modification of the hollow fiber material by means of tentacles synthetic or / and semi-synthetic and / or natural polycation chains are used, in particular those which have tertiary or and quaternary amines.

The adsorbent material according to the invention particularly preferably contains as anion exchange groups dialkylaminoalkyl, dialkylaminoaryl, diarylaminoalkyl, diarylaminoaryl, trialkylammoniumalkyl, triarylammoniumalkyl, triarylammoniumaryl or trialkylammoniumaryl radicals, polymers of positively charged or tertiary or quaternary amino-containing amino acids, such as polylysine , Polyarginine or polyhistidine, copolymers or derivatives thereof or polyethyleneimine.

Another adsorber material encompassed by the present invention is polymyxin B described in US 4,576,928 and DE 3932971.

In a further particularly preferred embodiment of the present invention, the adsorbent material comprises a diethylaminoalkyl- or diethylaminalkyl-modified polyamide-Hohlfasermatierial, in particular diethylaminoethyl-polyamide (DEAE-polyamide). Furthermore, DEAE-cellulose can be used as the adsorber material. This is a Adsorbermateiral, which not only comprises anion exchange groups, but additionally has hydrophobic properties. With such a DEAE cellulose adsorber (H.E.L.P heparin adsorber, B. Braun Melsungen), in particular, bacterial LPS can be eliminated with an adsorptive concentration from whole blood or / and blood plasma at a pH of 5.12 with high selectivity and capacity.

Especially when using modified hollow fiber materials according to the invention in known extracorporeal perfusion systems, as described in US Pat. Nos. 5,053,133, 5,766,908 and in WO 96/22316 are effectively modified adsorbent systems can be produced, which have such a high binding capacity and specificity that they can be used in filter cartridges with a low dead volume of less than 160 ml. This allows due to the lower required extracorporeal blood volume turn a gentle treatment of patients.

With the preferred materials according to the invention, even at physiological pH, LPS and LTA can be adsorptively eliminated from blood or plasma with high selectivity and capacity. Blood or plasma proteins, on the other hand, are adsorbed only in small amounts and harmless in their composition. In particular, the fibrinogen, which is important for the coagulation cascade, is removed from the patient's blood within the scope of the preferred adsorber materials according to the invention only in a very small way, so that the natural blood coagulation is not impaired.

The well-known use of disposable cartridges in such systems is advantageous and allows easy handling, but also safe use especially with regard to the necessary prevention of contagion.

While a variety of more or less successful treatments are currently used in severe infectious disease courses, the use of the adsorber materials of the present invention for the applications described herein has not yet been considered. Targeted application of the adsorptive materials, in particular well before the manifestation of serious effects of bacterial superinfections on the patients, will bring about a significant reduction in the severity of the disease and significantly reduce mortality among the affected patients.

Claims

claims

An adsorber material for use in the prevention or treatment of severe infectious disease courses,

characterized in that the absorber material is an anion exchange material.

2. Adsorber material for use according to claim 1, wherein the infectious diseases are caused by viral infection, fungal infection or parasitic infection, in particular by viral infection.

3. Adsorber material for use according to claim 1 or 2, wherein the adsorber material is used simultaneously with or directly following an antibiotic application.

Absorbent material for use according to claim 1, wherein the severe courses of infectious diseases, in particular viral infections, are associated with incipient or manifest bacterial superinfections.

5. Absorber material for use according to claim 1 or 2, wherein the severe courses of infectious diseases, in particular of viral infections, an immune defect or an immunosuppression is based or / and such was triggered by the infection.

6. The absorber material for use according to claim 3, wherein the immunodeficiency is a granulocytopenia, lymphocytopenia or an immunoglobulin defect.

7. Absorber material for use according to any one of the preceding claims, wherein the severe courses of infectious diseases, in particular of viral infections, are accompanied by complications selected from systemic inflammatory response. Syndrome, sepsis, severe sepsis, septic shock and / or multiple organ failure.

The absorber material for use according to any one of the preceding claims, wherein the viral infections are infections with influenza virus, cytomegalovirus, Epstein-Barr virus, hepatitis virus, herpesvirus, human immunodeficiency virus HIV, or viral hemorrhagic fever infections , in particular selected from the group consisting of Lassa fever (Arenaviridae), Rift Valley, Crimean Congo and Hanta fever (Bunyaviridae), Ebola and Marburg fever (Filoviridae), yellow fever and dengue fever (Flaviviridae) and Chikungunya fever (Togaviridae), especially Ebola fever or yellow fever.

The adsorber material for use according to any one of the preceding claims, wherein the adsorbent material is contained in an extracorporeal perfusion system.

10. adsorber material for use according to any one of the preceding claims, wherein as anion exchange material materials are used which contain fixed as anion exchange groups cations or synthetic, semi-synthetic or natural Polykationenket- th to support materials, wherein Polykationenketten present in linear or branched form.

1 1. Adsorber material for use according to one of the preceding claims, wherein a hollow fiber material is used as carrier material, onto which polycation tentacles have been grafted on, preferably by graft polymerization.

The adsorber material for use according to claim 8 or 9, wherein the anion exchange groups consist of cation or polycation chains which comprise tertiary or / and quaternary amines and / or where the anion exchanger groups comprise dialkylaminoalkyl-, Dialkylaminoaryl, Diarylaminoalkyl-, Diarylaminoaryl-, Trialkylammo- niumalkyl-, Triarylammoniumalkyl-, Triarylammoniumaryl-, or Tri- alkylammoniumaryl radicals, polymers of positively charged or tertiary or quaternary amino-containing amino acids such as polylysine, polyarginine or polyhistidine or copolymers or derivatives thereof or polyethyleneimine.