Biguanide Groups Research Articles

Elastic and Self-Healing Copolymer Coatings with Antimicrobial Function.

The revolutionary self-healing function for long-term and safe service processes has inspired researchers to implement them in various fields, including in the application of antimicrobial protective coatings. Despite the great advances that have been made in the field of fabricating self-healing and antimicrobial polymers, their poor transparency and the trade-off between the mechanical and self-healing properties limit the utility of the materials as transparent antimicrobial protective coatings for wearable optical and display devices. Considering the compatibility in the blending process, our group proposed a self-healing, self-cross-linkable poly{(n-butyl acrylate)-co-[N-(hydroxymethyl)acrylamide]} copolymer (AP)-based protective coating combined with two types of commercial cationic antimicrobial agents (i.e., dimethyl octadecyl (3-trimethoxysilylpropyl) ammonium chloride (DTSACL) and chlorhexidine gluconate (CHG)), leading to the fabrication of a multifunctional modified compound film of (AP/b%CHG)-grafted-a%DTSACL. The first highlight of this research is that the reactivity of the hydroxyl group in the N-(hydroxymethyl)acrylamide of the copolymer side chains under thermal conditions facilitates the "grafting to" process with the trimethoxysilane groups of DTSACL to form AP-grafted-DTSACL, yielding favorable thermal stability, improvement in hydrophobicity, and enhancement of mechanical strength. Second, we highlight that the addition of CHG can generate covalent and noncovalent interactions in a complex manner between the two biguanide groups of CHG with the AP and DTSACL via a thermal-triggered cross-linking reaction. The noncovalent interactions synergistically serve as diverse dynamic hydrogen bonds, leading to complete healing upon scratches and even showing over 80% self-healing efficiency on full-cut, while covalent bonding can effectively improve elasticity and mechanical strength. The soft nature of CHG also takes part in improving the self-healing of the copolymer. Moreover, it was discovered that the addition of CHG can enhance antimicrobial effectiveness, as demonstrated by the long-term superior antibacterial activity (100%) against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria and the antifouling function on a glass substrate and/or a silica wafer coated by the modified polymer.

Profile of the Use of Type II Antidiabetic Drugs in RSUD Dr. Husni Thamrin Natal Medan, North Sumatra

The pancreas does not produce enough insulin or the body cannot use the insulin it produces effectively. Insulin is a hormone that regulates the balance of blood sugar levels. (hyperglycemia). This research was conducted with a non-experimental descriptive method with a cross-sectional design that was carried out every month. Sampling was carried out in the internal medicine section of RSUD by Dr. Husni Thamrin Natal. Samples were taken retrospectively every month using secondary data, namely medical records of patients using oral antidiabetics (drugs) in the period from January to June 2019. The data obtained was presented in the form of table proportions and graphs. The results showed that the largest percentage of use of antidiabetic drugs was male, as many as 67 people (57.26%), over 50 years old, as many as 97 people (82.91%), and the type of work was self-employed for as many as 47 people (40, 17%). The most widely used antidiabetic drug groups are the biguanide groups (75.17%), the combination type of drug with a combination of metformin and glimepiride (93.33%), and the frequency of use of the drug metformin (74.15%). Based on the results of the study, it can be concluded that the highest prevalence is in the male sex, and the average age is over 50 years. The pattern of prescribing antidiabetic drugs based on the most widely used drug class is the biguanide group, which is a combination of metformin and glimepiride types of drugs, and the frequency of drug use is metformin.

The passively sensitized mast cell activation test is a reliable diagnostic for chlorhexidine allergy

Chlorhexidine (CHX) is a synthetic cationic biguanide that harbors 2 biguanide groups both linked to a terminal 4-chlorophenyl group with the resultant chlorguanide structures connected by a hexamethylene bridge. Chlorhexidine can cause life-threatening anaphylaxis due to specific immunoglobulin E (sIgE) antibody–mediated activation of basophils and mast cells (MCs) and is generally associated with mucosal or parenteral exposure. Although it was originally thought to be very rare, in some countries, CHX has now become an important—often hidden and overlooked—cause of perioperative hypersensitivity (POH).

Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study.

Polyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due to the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study, we show by the means of atomistic molecular dynamics (MD) simulations that, while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favorable electrostatic interactions between the phospholipid headgroups and the biguanide groups and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively "bind" to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.

A biodegradable poly(amido amine) based on the antimicrobial polymer polyhexamethylene biguanide for efficient and safe gene delivery

Inspired by the excellent membrane affinity of antimicrobial polymers, we synthesized a novel biodegradable poly(amino amine) polymer with pendent side chains that mimic the widely used biocide polyhexamethylene biguanide (PHMB) for gene delivery. Michael addition polymerization was utilized to form the polymer scaffold between N,N′-cystaminebisacrylamide (CBA) and N-Boc-1,6-diaminohexane (Boc-DAH) followed by N-Boc deprotection. Then the exposed primary amino groups were partly (about 75%) transformed into biguanide by an addition reaction with dicyandiamide to obtain the final product CBA-DAH-biguanide (CBA-DAH-BG). The polymer CBA-DAH-BG was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>35 mV) polyplexes that were well resistant to heparin and DNase I. Rapid DNA release was observed in the presence of dithiothreitol (DTT), indicating that CBA-DAH-BG was equipped with biodegradability by the cleavage of disulfide bonds, which was helpful for unpacking DNA and decreasing cytotoxicity. CBA-DAH-BG/pDNA polyplexes were characterized by efficient cellular uptake efficacy, extremely low cytotoxicity, and high transfection efficiency in two cell lines (i.e., NIH/3T3 and U87 MG), compared to 25 kDa polyethyleneimine (PEI) and the intermediate product CBA-DAH that were both devoid of biguanide groups. Of note, clathrin-mediated endocytosis and lipid rafts played an important role in the internalization of the polyplexes. Taken together, this strategy described herein may represent an innovative avenue for the design of more advanced nonviral gene vectors with high transfection efficiency and biocompatibility.

Unexpected Like-Charge Self-Assembly of a Biguanide-Based Antimicrobial Polyelectrolyte.

Polyelectrolyte chains dissolved in good solvent are expected to collapse in compact configurations in the presence of multivalent ions. Here, we show that a weakly charged, hydrophilic polyelectrolyte containing biguanide groups self-assembles in water also in the presence of monovalent counterions, even at low salt concentrations. The polymer assembles in a compact, ordered, hairpin-like shape that, with increasing the ionic strength of the solution, can collapse further in three- or five-folded structures. Neither water nor ions mediate the self-assembly which, instead, is driven by the like-charge pairing of the biguanide units. The thermodynamics of the self-assembly show that the self-association is enthalpically driven, is isodesmic (at least at low aggregation number), and is favored by increasing salt concentration. This unique self-assembly behavior may be linked to the well-known polymer's antimicrobial properties and could help in rationalizing its biological activity.

PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery.

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.

Characteristics of patients with type 2 diabetes mellitus grouped by 5 classes of oral hypoglycemic agents based on assessment of treatment satisfaction

We analyzed data on treatment satisfaction of patients with type 2 diabetes mellitus (T2DM) treated with one oral hypoglycemic agent (OHA) and examined characteristics of the patients grouped by 5 classes of OHAs, i.e., sulfonylurea (SU), biguanide (BG), α-glucosidase inhibitor (αGI), thiazolidine insulin sensitizer (TZD), and dipeptidyl peptidase IV (DPP-4) inhibitor. Treatment satisfaction was assessed by the Oral Hypoglycemic Agent Questionnaire (OHA-Q) and Diabetes Treatment Satisfaction Questionnaire (DTSQ). Out of 597 enrolled patients, we excluded 73 and included 524 (SU 107, BG 120, αGI 99, TZD 99, DPP-4 inhibitor 99) for statistical analyses. There were some significant between-group differences in background factors, such as age, duration of diabetes mellitus, body mass index (BMI), etc. After adjusting the factors using a multivariate model, there was a significant between-group difference only in treatment convenience out of three OHA-Q subscale scores. Relatively low treatment convenience was reported in the BG and αGI groups. Out of 20 OHA-Q item scores, there were significant between-group differences in six items, and the result was consistent with known side effects of each drug class, i.e., bodily swelling in the TZD group, hypoglycemia in the SU group, etc. Meanwhile, with regard to DTSQ, there was a significant between-group difference only in the hypoglycemia subscale out of the three subscales. These results showed the possibility of the treatment satisfaction scale to characterize OHAs from the patient’s standpoint. Therefore, treatment satisfaction scales, such as the OHA-Q, are expected to help each T2DM patient to choose the best OHA (or combination of OHAs) according to his/her condition and preference.

Salt tolerant membrane adsorbers for robust impurity clearance

Clearance of impurities such as viruses, host cell protein (HCP), and DNA is a critical purification design consideration for manufacture of monoclonal antibody therapeutics. Anion exchange chromatography has frequently been utilized to accomplish this goal; however, anion exchange adsorbents based on the traditional quaternary amine (Q) ligand are sensitive to salt concentration, leading to reduced clearance levels of impurities at moderate salt concentrations (50-150 mM). In this report, membrane adsorbers incorporating four alternative salt tolerant anion exchange ligands were examined for impurity clearance: agmatine, tris-2-aminoethyl amine, polyhexamethylene biguanide (PHMB), and polyethyleneimine. Each of these ligands provided greater than 5 log reduction value (LRV) for viral clearance of phage phiX174 (pI approximately 6.7) at pH 7.5 and phage PR772 (pI approximately 4) at pH 4.2 in the presence of salt. Under these same conditions, the commercial Q membrane adsorber provided no clearance (zero LRV). Clearance of host-cell protein at pH 7.5 was the most challenging test case; only PHMB maintained 1.5 LRV in 150 mM salt. The salt tolerance of PHMB was attributed to its large positive net charge through the presence of multiple biguanide groups that participated in electrostatic and hydrogen bonding interactions with the impurity molecules. On the basis of the results of this study, membrane adsorbers that incorporate salt tolerant anion exchange ligands provide a robust approach to impurity clearance during the purification of monoclonal antibodies.

Hydrogen-bonded networks in crystals built from bis(biguanides) and their salts

Biguanide groups and biguanidinium cations incorporate multiple sites that can donate or accept hydrogen bonds. To assess their ability to associate and to direct the formation of extended hydrogen-bonded networks, we examined the structure of crystals of four compounds in which two neutral biguanide groups or the corresponding cations are attached to the 1,4- and 1,3-positions of phenylene spacers. As expected, all four structures incorporate extensive networks of hydrogen bonds and reveal other reliable features. In particular, (1) neutral biguanide groups favor a roughly planar conformation with an intramolecular hydrogen bond, and they associate as hydrogen-bonded pairs, (2) despite coulombic repulsion, biguanidinium cations can also associate as hydrogen-bonded pairs, and (3) the 1,3-phenylenebis(biguanidinium) dication favors a pincerlike conformation that allows chelation of suitable counterions. However, the precise patterns of hydrogen bonding in the structures vary substantially, limiting the usefulness of biguanide and biguanidinium as groups for directing supramolecular assembly.Key words: bis(biguanide), bis(biguanidinium), structure, hydrogen-bonded network, noncovalent interaction, supramolecular chemistry, crystal engineering.

Sorption of Poly(hexamethylenebiguanide) on Cellulose: Mechanism of Binding and Molecular Recognition

Antimicrobial agents such as poly(hexamethylene biguanide) (PHMB) find application in medical, apparel, and household textile sectors; although it is understood that certain concentrations need to be applied to achieve suitable performance, there has been very little work published concerning the interactions of the polymer and its adsorption mechanism on cellulose. In this paper, such physical chemistry parameters are examined and related to computational chemistry studies. Adsorption isotherms were constructed: at low concentrations, these were typical Langmuir isotherms; at higher concentrations, they were more indicative of Freundlich isotherms, attributed to a combination of electrostatic and hydrogen-bonding forces, which endorsed computational chemistry proposals. At lower concentrations, electrostatic interactions between PHMB and carboxylic acid groups in the cellulose dominate with a contribution to binding through hydrogen bonding; as the concentration of PHMB increases, hydrogen bonding with cellulose becomes increasingly dominant. At high PHMB concentrations, observations of increasing PHMB adsorption are attributed to monolayer aggregation and multilayer stacking of PHMB through electrostatic interactions with counterions and hydrogen bonding of biguanide groups.

Bis{N′-[(E)-amino(imino)methyl]morpholinocarboximidamido}copper(II)

The title complex of a deprotonated form of morpholine biguanide with CuII, namely bis(2-morpholinobiguanido)copper(II), [Cu(C6H12N5O)2], was characterized crystallographically. The Cu2+ ion, on a centre of symmetry, is coordinated by four N atoms from two bidentate morpholine biguanide monoanions; the biguanide groups of the two ligands and the copper ion are coplanar. The two morpholine rings of the ligands are in a trans configuration and have a chair conformation.

Antibacterial and Bacterium Adsorbing Macromolecules

Currently studies on antibacterial macromolecules, i. e., bactericidal and bacteriostatic ones, have been made to develop a new utilization field of polymeric materials. In these studies, there are immobilizations of iodine to quaternary ammonium salts, antibiotics, antibacterial groups to macromolecular substances, as well as syntheses of polymers with quaternary ammonium salts, biguanide groups, quaternary pyridinium salts, sulphonium salts, phosphonium salts, and other antibacterial groups. On the other hand, studies have been made of bacterium adsorbing macromolecules, which can remove by adsorbing bacterial cells in water. The macromolecules are the ones based on poly(4-vinylpyridine-co-divinylbenzene), crosslinked poly(3- and 4-chloromethylated styrene-g-amine), and poly(glycidyl methacrylate-g-amine), as well as filters and microporous membranes are covered with a macromolecule based on quaternized poly(4-vinylpyridine-co-styrene). Here, a review is made of the syntheses and preparation of the respective macromolecules, as well as of their antibacterial activities and the bacterium adsorbing activities.

Antibacterial and Bacterium Adsorbing Macromolecules

Currently studies on antibacterial macromolecules, i. e., bactericidal and bacteriostatic ones, have been made to develop a new utilization field of polymeric materials. In these studies, there are immobilizations of iodine to quaternary ammonium salts, antibiotics, antibacterial groups to macromolecular substances, as well as syntheses of polymers with quaternary ammonium salts, biguanide groups, quaternary pyridinium salts, sulphonium salts, phosphonium salts, and other antibacterial groups. On the other hand, studies have been made of bacterium adsorbing macromolecules, which can remove by adsorbing bacterial cells in water. The macromolecules are the ones based on poly(4-vinylpyridine-co-divinylbenzene), crosslinked poly(3- and 4-chloromethylated styrene-g-amine), and poly(glycidyl methacrylate-g-amine), as well as filters and microporous membranes are covered with a macromolecule based on quaternized poly(4-vinylpyridine-co-styrene). Here, a review is made of the syntheses and preparation of the respective macromolecules, as well as of their antibacterial activities and the bacterium adsorbing activities.

Self-Sterilizing Materials. 1. Controlled Release of Biguanide Biocides from Polymeric Materials

An acrylate monomer with a pendant biguanide, N'-4-(2-acryloyl- oxyethyl)phenyl-N5-4-chlorophenylbiguanide hydrochloride (2), when incor porated covalently into cross-linked polyacrylamide matrices was found to hydrolyzed in water to release N1-4-(2-hydroxyethyl)phenyl-N5-chlorophenylbi guanide hydrochloride (1). When the degree of cross-linking was high, the release was approximately zero-order at least over a period of one week. In con trast to 2, methacrylate and acrylamide monomers with pendant biguanide groups were strongly resistant to hydrolysis. Detailed release profiles from various cross-linked polyacrylamide films containing covalently or non- covalently bound biguanide compounds indicate that the rate of release can be tailored to specific delivery needs.

New polymeric biocides: synthesis and antibacterial activities of polycations with pendant biguanide groups.

Acrylate monomers with pendant biguanide groups were successfully synthesized, and their homopolymers and copolymers were prepared with acrylamide. These cationic disinfectants of polymeric forms exhibited high antibacterial activity against gram-positive bacteria, whereas they were less active against gram-negative bacteria. It was found that the activity of the polymeric disinfectants was much higher than that of the monomeric species, and the difference in activity between the polymers and the monomers was discussed on the basis of their contributions to each elementary process of the lethal action.

Interaction of biologically active molecules with phospholipid membranes: I. Fluorescence depolarization studies on the effect of polymeric biocide bearing biguanide groups in the main chain

Interaction of poly(hexamethylene biguanide hydrochloride) (PHMB), which is a polymeric biocide bearing biguanide groups in its main chain, with phospholipid bilayers was studied by the fluorescence depolarization method. A strong interaction of PHMB with negatively charged bilayers composed of phosphatidylglycerol(PG) alone or of PG and phosphatidylcholine (PC) was observed, whereas neutral PC bilayers were not affected. On adding PHMB, the fluorescence polarization of diphenylhexatriene embedded in the negatively charged bilayers was reduced to a great extent, especially in the gel phase. This was interpreted in terms of PHMB-induced expansion and fluidization of the bilayer, which enables the probe molecule to undergo less-hindered torsional motion. Similarity between PHMB and polymyxin B in the structure, the mode of action against bacteria and the interaction with lipid membranes is discussed.