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The applicability of the comparative molecular field analysis (CoMFA) approach to describe the nonlinear dependence of biological activity on lipophilicity in 3D quantitative structure-activity relationships (QSAR) has been demonstrated. The results indicate that the CoMFA approach is appropriate for describing nonlinear effects in 3D QSAR studies.
We have studied the motor response to ethylenediamine (EDA), a well known releaser of endogenous GABA, on the longitudinal muscle of the rat isolated proximal duodenum in presence of atropine (3 microM) and guanethidine (3 microM). EDA produced a concentration-(0.03-3 microM)-dependent relaxation which was potentiated when the preparations were exposed to GABA during the equilibration period. The GABA-induced potentiation of the response to EDA was prevented by nipecotic acid, an inhibitor of GABA uptake. The response to EDA was partially inhibited by 3-mercaptopropionic acid, a known inhibitor of GABA release. However, contrary to the relaxant response produced by exogenous GABA, the EDA-induced relaxation was picrotoxin-(0.1 microM)-resistant. In preparations pre-exposed to GABA, the response to EDA was partially tetrodotoxin-(1 microM)-sensitive. By contrast, in preparations not exposed to GABA, the EDA-induced relaxation was totally tetrodotoxin resistant. The response to EDA was abolished or largely inhibited in preparations excised from rats in which the proximal duodenum was chemically denervated by exposure (2 weeks before), to benzalkonium chloride (BZK). Likewise, the indirect relaxations produced by electrical field simulation. DMPP, capsaicin or GABA were abolished by BZK pretreatment while noradrenaline was still effective. These findings indicate that the relaxant response to EDA is neurogenic in origin, while being largely tetrodotoxin-resistant. A GABAergic mechanism could be involved but also other inhibitory transmitter(s) should be taken into account. EDA appears a useful tool to study the inhibitory non-adrenergic non-cholinergic innervation of the rat proximal duodenum.
Epithelial permeability and autofluorescence of the cornea were determined by fluorophotometry in 21 patients with open-angle glaucoma or ocular hypertension using timolol medication with the preservative benzalkonium chloride (BAC) and 2 weeks after changing to timolol medication without BAC. The investigation was performed to determine whether removal of BAC would reduce toxic effects on the cornea and complaints of sensations of burning or dry eye. Corneal epithelial permeability decreased significantly after changing medication (mean decrease per patient 27%, P = 0.025). Corneal autofluorescence increased significantly after changing medication suggesting an alteration in corneal metabolism (mean increase per patient 6%, P = 0.003). Timolol without BAC was found to be as effective as timolol with BAC in reducing intraocular pressure (P = 0.4). Removal of BAC from timolol resulted in an improvement of corneal epithelial barrier function and in a reduction of complaints. The improvement was found to be proportional to the duration of the preceding BAC-containing therapy.
A new method of evaluating quantitative cytotoxicity in cell culture was demonstrated using Chang's cultured human conjunctival cells. Time-dependent cytotoxicity of some beta-adrenergic blocking agents was shown and expressed by exposure time, causing 50% cell damage (50% cell damage time CDT50). Pure timolol maleate maleate of 0.25% and 0.5% concentration caused no cytotoxicity within a 64-min exposure. Pure befunolol hydrochloride of 0.25%, 0.5% and 1% inhibited 10%-30% of cell growth at 64-min exposure. Pure bupranolol of 0.125%, 0.25%, 0.5% and 1% showed evident cytotoxicity and CDT50 at 66 min 48 s, 38 min 54 s, 3 min 46 s and 1 min 18 s, respectively. Commercial preparations, which contained benzalkonium chloride as a preservative, indicated more rapid cytotoxicity. Timolol preparations of 0.25% and 0.5% showed CDT50 at 48.1 s and 2 min 4 s, respectively. Befunolol preparations of 0.25%, 0.5% and 1% showed CTD50 at 43.4% s, 4 min 38 s and 58 s, respectively, Bupranolol preparations of 0.125%, 0.25%, 0.5% and 1% demonstrated CDT50 at 1 min 11 s, 3 min 24 s, 22.3 s and 13.7 s, respectively.
The objective of this study was to examine the effects of two different denervation procedures on the distribution of nerve fibers and neurotransmitter levels in the rat jejunum. Extrinsic nerves were eliminated by crushing the mesenteric pedicle to a segment of jejunum. The myenteric plexus and extrinsic nerves were eliminated by serosal application of the cationic surfactant benzyldimethyltetradecylammonium chloride (BAC). The effects of these two denervation procedures were evaluated at 15 and 45 days. The level of norepinephrine in whole segments of jejunum was initially reduced by more than 76% after both denervation procedures, but by 45 days the level of norepinephrine was the same as in control tissue. Tyrosine hydroxylase (noradrenergic nerve marker) immunostaining was absent at 15 days, but returned by 45 days. However, the pattern of noradrenergic innervating axons was altered in the segment deprived of myenteric neurons. Immunohistochemical studies showed protein gene product 9.5 (PGP 9.5)-immunoreactive fibers in whole-mount preparations of the circular smooth muscle in the absence of the myenteric plexus and extrinsic nerves. At 45 days, the number of nerve fibers in the circular smooth muscle increased. Vasoactive intestinal polypeptide (VIP)-immunoreactive fibers, a subset of the PGP 9.5 nerve fibers, were present in the circular smooth muscle at both time points examined. Choline acetyltransferase (CAT) activity and VIP and leucine enkephalin levels were measured in separated smooth muscle and submucosa-mucosal layers of the denervated jejunum. VIP and leucine-enkephalin levels were no different from control in tissue that was extrinsically denervated alone. However, the levels of these peptides were elevated two-fold in the smooth muscle 15 and 45 days after myenteric and extrinsic denervation. In the submucosa-mucosa, VIP and leucine enkephalin levels also were elevated two-fold at 15 days, but comparable to control at 45 days. CAT activity was equal to control in the smooth muscle but elevated two-fold in the submucosa-mucosa at both times. These results provide evidence for innervation of the circular smooth muscle by the submucosal plexus. Moreover, these nerve fibers originating from the submucosal plexus proliferate in the absence of the myenteric plexus. Furthermore, the myenteric neurons appear to be essential for normal innervation of the smooth muscle by the sympathetic nerve fibers. It is speculated that the sprouting of the submucosal plexus induced by myenteric plexus ablation is mediated by increased production of trophic factors in the hyperplastic smooth muscle.
The toxic side-effects of 0.4% Novesine and Chibro-Kerakain were investigated by scanning- and transmission electron microscopy in 15 rabbit corneae each in intervals of 3, 6, 10, 15 and 60 mins. The lesions following Kerakain were larger and occurred earlier. After 60 mins, the specimens after Novesine application showed an almost complete repair process, whereas after Kerakain the epithelial surface appeared to be functionally impaired.
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We studied the time course of the regeneration of the jejunal mucosa of the rat after it was damaged by exposure to the surfactant, benzalkonium chloride. We placed particular emphasis on assessing the morphology of the nerve fibers within the villi during and after regeneration. The application of benzalkonium chloride resulted in virtually complete loss of villi within the treated segment; however, the crypts were only partially damaged. The mucosa began to regenerate within 6 hr of the insult. The villus lengths and crypt depths returned to pretreatment values within two to four days. The mucosal innervation was assessed through immunohistochemistry for vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and neuron-specific enolase (NSE). At all stages of regeneration, VIP, NPY, and NSE immunopositive fibers within the lamina propria extended to the tips of the villi. The density of the immunopositive fibers in the lamina propria at four days after mucosal insult was similar to that in control tissues regardless of the neuronal marker visualized. We conclude that the nerve fibers innervating the small intestinal mucosa grow at a rate of approximately 100 microns/day and that the entire length of each villus contains nerve fibers throughout the regeneration process. The innervation of the regenerated mucosa appears identical to that of control mucosa.
DNA recovered from a condom found at a crime scene appeared undigestible with restriction enzymes, preventing characterization by Southern blot and polymorphic probe hybridization. Several chemical substances used in the processing and treatment of condoms were tested for inhibitory action of restriction enzymes. In particular dibenzalkonium chloride appeared to promote enzyme inhibition at very low concentrations. The effectiveness of treatments to restore cleavage of sample DNA in the presence of such contaminants is discussed.
Alterations in smooth muscle responsiveness and neural pathways in adjacent tissue may occur after local myenteric denervation. The in vitro contractile responses of both longitudinal and circular muscle to the mixed muscarinic and nicotinic cholinergic agonist carbachol were determined 15, 30, and 45 days after localized myenteric plexus ablation. Denervated longitudinal muscle exhibited decreased responsiveness to carbachol at all times examined. Denervated circulated muscle was initially supersensitive, but with time became subsensitive. These changes probably reflect the loss of the nicotinic (neuronal) component of the action of carbachol. Muscle orad to the site of denervation appeared subsensitive, while muscle caudad to the lesion was supersensitive (circular) or unaffected (longitudinal). These results suggest that there are changes in ascending and descending neural pathways. Alterations in the cholinergic responsiveness of intestinal smooth muscle, both at and beyond the site of myenteric plexus ablation, may result in altered intestinal motility that could lead to functional obstruction.
Intestinal aganglionosis produced by serosal application of 0.1% benzalkonium solution to the colon of the rat was studied electronmicroscopically, and it was concluded that a higher susceptibility to the agent and a lower recovering ability of the nerve elements might be responsible for the phenomenon.
Eye drop formulations containing indometacin and benzalkonium salt often show an opalescence as a result of ion-pair formation. The insoluble ion pair was isolated and characterized by infrared and ultraviolet spectroscopy and thin layer chromatography. This ion pair is also responsible for the bad assay results of benzalkonium using the ion-pair extraction method with bromothymol blue as counterion. The distribution constant (KD = 1O4) of indometacin and the extraction constant (Kex = 3 X 1O4) of the ion pair indometacin-benzalkonium in a water-chloroform system at various pH values were determined. A discussion on the preservation of indometacin eye drop formulations with benzalkonium salt in view of this chemical incompatibility is presented.
A close resemblance in fine structure was observed between the aganglionic colon, produced in rats by serosal application of 0.1% benzalkonium chloride solution, and the aganglionic descending colon, or more proximal segments, of Hirschsprung's disease. The pathogenesis of the disease is discussed.
Bradykinin, kallidin (Lys-bradykinin) and [Thi 5,8, D-Phe7]-bradykinin, a functional B2 antagonist, induce histamine release from rat peritoneal mast cells. The histamine release is dependent upon added calcium when mast cells are placed in calcium-free medium 30 min before being triggered with the kinins. Histamine release was dose-dependently inhibited by pertussis toxin (1-100 ng/ml) and by benzalkonium chloride (0.1-3 micrograms/ml). The efficiency of ionophore A23187 on histamine release was affected neither by pertussis toxin nor by benzalkonium chloride. The parallel response of rat peritoneal mast cells to kinins and to substance P suggest that these peptides have the same mechanisms of action i.e. activation of a pertussis toxin-sensitive G protein and of phospholipase C defining a peptidergic triggering pathway of mast cells.
The efficacy of an antimicrobial catheter for the prevention of bacterial colonisation was investigated. The catheter was hydrophilic coated (Hydrocath) and impregnated with the quaternary ammonium antimicrobial agent, benzalkonium chloride (BZC). Microbial colonisation of this central venous catheter was compared to that of polyurethane catheters with or without a hydrophilic coating. Adherence of five strains of Staphylococcus epidermidis to the three catheter types was determined with a microbial colonisation model. Adherence of three strains of Staphylococcus epidermidis to Hydrocath catheters was significantly reduced in comparison to polyurethane catheters (p < 0.01). BZC-impregnated Hydrocath catheters prevented bacterial colonisation of both the internal and external catheter surfaces (p < 0.01). These results were confirmed by scanning electron microscopy. The findings demonstrate that hydrophilic-coated Hydrocath catheters can inhibit bacterial adherence in vitro. Bacterial colonisation was further restricted by the addition of BZC to these coated catheters.
The incubation of neuropeptide Y (NPY) or of NPY C-terminal fragments with rat peritoneal mast cells resulted in a dose-dependent histamine secretion (10(-9)-10(-5) M). A linear correlation between the number of net positive charges of the peptides and histamine release potencies was obtained. The histamine secretion induced by NPY fragments was inhibited by the treatment of mast cells with benzalkonium chloride and pertussis toxin indicating the involvement of G proteins.
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The corneal epithelium of patients with dry-eye syndrome is stressed by both tear film insufficiency and the frequent use of eye drops (artificial tears). In order to quantify corneal epithelial damage, the permeability of corneal epithelium to sodium fluorescein was determined in 40 consecutive patients with dry eyes (BST less than 10 mm), who did not exhibit visible corneal lesions upon slit-lamp examination. The corneal epithelial permeability of dry-eye patients was shown to be 2.8 times greater than that of individuals without ocular disease. Corneal epithelial permeability of patients using artificial tears containing benzalkonium chloride was increased 3.1 times and that of patients using drops preserved with chlorobutanol only 1.7 times.