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PubMedDate not supplied

The effect of protamine on antibiotic action against Staphylococcus epidermidis biofilms.

Infection associated with medical devices may involve bacterial biofilms, a possible cause of antibiotic resistance. Protamine, a basic polypeptide, depresses the metabolic activity of Staphylococcus epidermidis in a standardized biofilm assay. The resistance of the biofilm preparations to many antibiotics, with the sole exception of rifampin, was confirmed. Rifampin produced predominant lysis and killing with foci of genetically programmed resistance. The combination of protamine with antibiotics produced no change, except the combination with rifampin where clear classic synergism with a totally bactericidal outcome was demonstrated. Protamine is a member of the larger family of charged polycations, some of which possess membrane potential altering properties, possibly interfering with the protective nature exhibited by the negatively charged bacterial biofilm matrix.

Anti-Bacterial Agents↗
PubMed1975

Complement activation by interaction of polyanions and polycations. I. Heparin-protamine induced consumption of complement.

Interactions of heparin and protamine in fresh human serum, in amounts far below those required for complement depletion by either agent alone, were found to induce virtually complete depletion of total hemolytic complement activity. This depletion was dependent on time, temperature, pH, divalent cations, and serum concentration. The predominant complement component hemolytic activity depleted was C1; under appropriate reaction conditions C4 and C2 were depleted as well. Equivalent amounts of heparin along induced lesser but substantial depletion of C3-9, whereas equivalent amounts of protamine had no effect upon complement component activities. We conclude that interaction of heparin with protamine, like interaction of antibody with antigen, markedly enhances its ability to interact with the first component of complement and activate the classical complement pathway. It is suggested that complement activation by interactions between certain polyanions and polycations, like interactions between antigens and antibodies, may have a role in the initiation of inflammatory reactions.

Adult↗
PubMedDate not supplied

Cardiorespiratory effects of protamine sulphate in man: intra-aortic vs intra-right atrial rapid administration after cardiopulmonary bypass.

The effects of protamine sulphate on several cardiorespiratory variables were studied under clinical situations in twenty patients following cardiopulmonary bypass. Because recent reports suggest that there may be advantages of intra-aortic versus intra-venous administration we prospectively evaluated cardiorespiratory features 1 and 10 minutes after rapid administering of protamine sulphate either into the aortic arch (through a catheter percutaneously inserted via the radial artery for monitoring purposes) or into the right atrium. Significant variations in some parameters were found in the patients receiving the drug via the aorta, such as a drop of systemic vascular resistances (p less than 0.05), of coronary perfusion pressure (p less than 0.05), of aortic systolic pressure (p less than 0.01), of diastolic (p less than 0.01) and mean blood pressure (p less than 0.05) and a rise in the respiratory quotient (p less than 0.05). It is concluded that the results do not confirm the superior safety of intra-aortic administration of protamine particularly when replenishment of intravascular volume is not provided.

Analysis of Variance↗
PubMedDate not supplied

[Thrombotic complications in the blocking effect of protamine sulfate on nonenzymatic fibrinolysis in the blood of animals during activation of the anticoagulation system].

Protamine-sulfate blocked non-enzymatic fibrinolysis not only in vitro but also in vivo through binding of heparin and dissociation of its complexes, which are of great importance as humoral components of the anticoagulation system. Almost complete blocking of humoral agents of the anticoagulation system, caused either by a single intravenous administration of protamine-sulfate at large doses or by repeated administration of the substance at moderate doses within 14 days, led to death of the animals as a result of thrombotic complications related to appearance of additional thrombin in blood circulation. In these cases thrombosis occurred into coronary blood vessels. The non-enzymatic fibrinolytic effect was not observed in extracts from lungs, auricula atrii and liver tissue of experimental animals, treated with protamine-sulfate, as compared with the controls, administered with physiologic solution.

Animals↗
PubMed1984

Glomerular albumin leakage and morphology after neutralization of polyanions. II. Discrepancy of protamine induced albuminuria and fine structure of the glomerular filtration barrier.

Changes in the fine structure of the glomerular filtration barrier were studied by perfusion of isolated rat kidneys with varying doses of protamine: 1) at low doses (110-150 micrograms/ml) ultrastructural changes were only detectable after prolonged recirculation (90-120'), 2) at high doses (250-330 micrograms/ml) profound epithelial foot process lesions were observed even after a short perfusion time, 3) at any concentration protamine particles were distributed in the laminae rarae of the GBM, thus visualizing neutralization of fixed negative charges. Reduction of glomerular anionic sites caused pronounced albuminuria even before podocyte morphological alterations were detectable. The effects of protamine on structure and function of the glomerular capillary wall are dose and time dependent. Besides intact morphology of the epithelial cells regular distribution of negative charges is necessary to maintain glomerular barrier function to macromolecules. Foot process alterations are not the primary reason for increased proteinuria but rather a secondary phenomenon.

Albuminuria↗
PubMedDate not supplied

[Conformational properties of protamines].

Conformational peculiarities of protamines in a wide range of various conditions have been studied by the CD and X-ray analysis. Characteristic peculiarities of CD-spectra and position of diffraction maximum in X-ray diagrams of protamines argue in favor that their conformation is similar to that of the extended left handed helix of poly(L)-proline II. Though conformation parameters of this structure are very sensitive to temperature or pH variations, to specific action of different ions, alcohols, and detergents the structure itself is rather stable and is destroyed under extreme conditions only. This conformation seems to be optimal for protamines to interact with DNA and necessary for cross-linking of DNA molecules and for the more dense packing of chromatin.

Circular Dichroism↗
PubMed1982

Anaphylactic shock following protamine administration.

A severely debilitating anaphylactic reaction occurred in a diabetic when protamine was injected following carotid endarterectomy. The patient had been taking neutral protein Hagedorn (NPH) insulin for several months. Neural and humoral pathways have been well documented as being responsible for its cardiovascular effects; however, little attention has been given to the immunologic mediations of protamine action. On the basis of this report, we suggest that caution is warranted when protamine is administered to patients who may have been sensitized by previous injections. This applies to diabetics, certain blood donors, and previous cardiac surgery patients. Skin testing and specific premedications may be indicated to avoid disastrous consequences.

Anaphylaxis↗
PubMed1981

Reversal of protamine of the prolonged response to intrapulmonary heparin.

A single large dose of heparin (2000 units/kg) was administered to dogs by intratracheal instillation. Whole blood clotting times and plasma heparin concentrations were measured at intervals. At each interval the calculated dose of protamine required to neutralize the circulation heparin was given intravenously and the measurement of plasma heparin concentration repeated. The authors found that the whole blood clotting time was prolonged for 24 to 48 hours and there was a detectable concentration of heparin in the plasma for 96 hours. On each occasion the protamine eliminated the circulation heparin, but more heparin continued to enter the circulation. It is hypothesized that after rapid absorption from the lung, heparin is stored temporarily in a cellular pool throughout the body and then released into the circulation. At any given time the anticoagulant effect can be reversed by intravenously administered protamine sulfate if this should become necessary, but repeated administration would be required. Intrapulmonary heparin may have useful clinical applications but further clinical and laboratory investigations are required.

Animals↗
PubMed1981

[Cardiac arrest following protamine sulphate administration (author's transl)].

This study presents the case history of a patient who suffered from recurrent pulmonary embolism, despite heparinisation, after a car accident and who died during preparation for caval ligature. We feel that the protamine sulphate given for neutralization of the heparin effect played an important role, since no signs of massive pulmonary embolism were found at autopsy. Protamine sulphate is known to possess a significant cardiovascular depressive action. On the basis of a survey of the literature the possible potentiation of circulatory insufficiency by changed haemodynamics following pulmonary embolism, induction of anaesthesia, and protamine sulphate is discussed. Proposals for improved management of such case are made.

Acute Disease↗
PubMed1980

Clinical experience with the activated clotting time for the control of heparin and protamine therapy during cardiopulmonary bypass.

The clinical experience with the activated clotting time (ACT) for the control of heparin and protamine therapy during cardiopulmonary bypass in 70 patients (50 adults and 20 children) is reviewed. After a standard dose of 2 mg/kg of body weight of heparin, the patient's ACT ranged from 210 to more than 600 seconds. The heparin dose required to accomplish an ACT of 500 seconds ranged from 1.3 to 4.7 mg/kg for adults and from 2 to 4.5 mg/kg for children. At the termination of bypass, the assessment of the patient's heparin level with the ACT allowed a more accurate reversal with protamine and markedly reduced the protamine requirements. Although the postoperative drainage was not significantly decreased, the total amount of blood transfusion and fresh-frozen plasma and platelet requirements were reduced by 30%, 20%, and 20% respectively. The simple, easy-to-use protocol is presented in detail.

Adult↗
PubMed1980

The determination of the heparin neutralising capacity of protamine using acridine orange fluorescence.

A new method to estimate the heparin neutralising capacity of protamine has been investigated. The technique has been applied to two commercial heparin preparations tested against the W.H.O. 1st International Reference preparation of protamine. The technique is based on the fluorescence of acridine orange dye and the selective binding of heparin with protamine. A titration procedure has been devised and the two variations of the assay are compared and evaluated. The titration is rapid, accurate and convenient.

Acridine Orange↗
PubMed1980

Kinetics and in vivo redistribution of (111)Indium-labelled human platelets after intravenous protamine sulphate.

The pathogenesis of thrombocytopenia induced by intravenous protamine sulphate was studied in six patients who underwent cardiopulmonary bypass surgery, and in three normal volunteers. Autologous platelets were labelled with (111)Indium-oxine. Platelet lifespan was determined. In vivo (111)In-platelet localization, organ redistribution and sites of destruction were quantitated with a scintillation camera and a computer-assisted imaging system. Protamine induced a transient thrombocytopenia, maximal 5-10 min after injection, and 30-40 min in duration. . The thrombocytopenia was accompanied by a transient accumulation of platelets in the liver. The splenic platelet pool remained unaltered and no platelets accumulated in the lungs. Platelet survival, measured in two volunteers, was slightly longer than normal and fitted a linear function best. There was a severe transient neutropenia during the period of thrombocytopenia. We conclude that protamine-induced thrombocytopenia is caused by hepatic accumulation of "activated" platelets or platelet aggregates, the process is reversible, and in the two normal volunteers studied, platelet survival was not affected.

Blood Platelets↗
PubMed1993

Analysis of synthetic DNAs and DNA-protamine complexes with the scanning tunneling microscope.

Three duplex DNAs 22, 47, and 100 base-pairs in length have been imaged with the scanning tunneling microscope (STM) after deposition on highly oriented pyrolytic graphite (HOPG). Images of the 47 base-pair (bp) molecules are resolved sufficiently to identify the two phosphodiester strands, the direction of helical coiling (this molecule contains three turns of left-handed helix), and single-stranded ends. Length measurements indicate that all three DNA sequences have adopted an "A-like" conformation. DNA-protamine complexes were also prepared and imaged under similar conditions. Length measurements of the complexes demonstrate that the binding of bull protamine 1 to the 47-mer stabilizes the DNA in a B conformation and prevents the B to A transition that has been shown to occur as the DNA molecules dehydrate on the surface. Measurements of the diameter of the complex (3 nm) were also obtained and were found to be only slightly larger than the DNA molecule. This observation is consistent with the binding of the protamine molecule inside one of the grooves.

Base Sequence↗
PubMed1993

Protamine and other polycationic drugs inhibit calcium leak in cardiac cells during metabolic inhibition and free radical exposure.

We studied the effect of the polycationic compounds protamine, polybrene and gentamicin on the calcium leak induced by metabolic inhibition and free radical exposure in cultured neonatal rat cardiac cells. All of the drugs tested inhibited the calcium leak. The potency of the compound in this respect was related to the magnitude of the positive charge borne by the molecule. Protamine was the most potent drug tested. None of the drugs tested had more than a small effect on lactate dehydrogenase release. The physicochemical properties of these compounds lead us to predict that they are acting at negatively charged sites on the outer surface of the sarcolemma. We conclude that polycationic compounds, exemplified by protamine, are able to inhibit calcium overload. It is anticipated that this group of compounds may be effective as cardioprotective agents.

Animals↗
PubMed1993

Intraarterial protamine sulfate reduces the magnitude of streaming potentials in living canine tibia.

Using previously described techniques, transcortical streaming potentials were measured at two middiaphyseal sites on one tibia of each of nine anesthetized canines during sinusoidal bending (approximately 0 to -200 mu epsilon periosteal surface strain) at 2 Hz. Measurements were made for 60 minutes prior to and up to 180 minutes following bolus injection of protamine sulfate (42-126 mg/kg) dissolved in Hanks Balanced Salt Solution, directly into the femoral artery without interrupting circulation. Shortly after injection, the protamine sulfate caused a clear reduction in the magnitude of streaming potentials. Subsequent injections of additional protamine sulfate resulted in further reductions, and in several instances, voltage sign reversals. This study represents the first observation that circulating proteins may alter electromechanical transduction in living bone, and suggests the possibility that specific agents, which are known to affect bone remodeling, may do so, in part, by altering these endogenous electrical potentials.

Animals↗
PubMed1993

Phosphorylation and activation of protamine kinase by two forms of a myelin basic protein kinase from extracts of bovine kidney cortex.

Two myelin basic protein kinases designated MBPK-1 and MBPK-2 were purified to apparent homogeneity from extracts of bovine kidney cortex. The purified preparations exhibited an apparent M(r) approximately 40,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and approximately 42,000 (MBPK-1) and 45,000 (MBPK-2) by gel permeation chromatography. Up to 0.4 and 1.8 mol of phosphoryl groups were incorporated per mol of MBPK-1 and MBPK-2, respectively, on threonines following incubation with ATP. Autophosphorylation, incubation with protein phosphatase 2A2 (PP2A2), CD45, or T-cell protein tyrosine phosphatase did not affect MBPK-1 activity. Autophosphorylation increased by about 3-fold MBPK-2 activity. This autophosphorylation and activation was reversed by PP2A2 but not by CD45 or T-cell protein tyrosine phosphatase. MBPK-1 and MBPK-2 displayed a positive reaction with an antibody to mitogen-activated protein kinase. Purified preparations of protamine kinase were activated by about 1.5-6-fold and, after inactivation with PP2A2, were reactivated by about 30% by MBPK-1 and MBPK-2. Activation and reactivation correlated with the incorporation, respectively, of 0.1-0.5 and 0.5 mol of phosphoryl groups/mol of the protamine kinase on serines. The results show that MBPK-1 and MBPK-2 are protamine kinase-activating kinases and suggest that MBPK-1 and MBPK-2 may be related to mitogen-activated protein kinase.

Amino Acid Sequence↗
PubMed1995

[Anaphylactic reaction to protamine in cardiovascular surgery].

The authors describe a serious anaphylactic reaction after protamine administration and its successful control. In cardiovascular surgery protamine a basic peptide, is used as a matter of routine to eliminate the anticoagulation effect of heparin. The use of this drug is associated with a number of negative haemodynamic reactions, most of them not serious, the incidence of which varies from 0 to 100%. The incidence of serious reactions associated with a life threatening drop of the blood pressure is reported to be between 0.13% to 4%, depending whether a retrospective or prospective study is involved. The pathogenesis of this anaphylactic reaction is not quite clear. Prevention in patients with known risk factors is problematic. Treatment of the allergic reaction to protamine is still symptomatic. In the authors' patient the condition was coped with by administration of colloid solutions, adrenaline and solumedrol.

Aged↗
PubMed1995

Protamine reaction in a patient undergoing coronary artery bypass grafting.

The neutralization of heparin anticoagulation is accomplished by the administration of protamine. While the administration of protamine is generally uneventful, allergic reactions can occur. This article describes such a reaction in a patient having cardiac surgery. Classification of protamine reactions and signs and symptoms are discussed. Treatment and management of high risk patients is highlighted.

Aged↗