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PubMed1982

The effect of oral neomycin on the absorption of isoniazid, quinidine and sulphafurazole from the rat small intestine in situ.

The effect of oral neomycin (2 g/kg for 4 or 7 days) on drug absorption from the small intestine was studied in anaesthetized rats in situ. Neomycin did not greatly affect the small intestinal morphology. Only in some cases there were slightly edematous and low villi in the intestines of the rats treated for 7 days, and there was "nuclear debris" in the mucosal cells as a sign of neomycin toxicity. Neomycin did not modify isoniazid or quinidine absorption, nor did it have any effects on intestinal fluid absorption. Sulphafurazole absorption was retarded, but the change was significant only after a 7-day neomycin treatment. The mechanisms of neomycin-induced changes in absorption still remain largely speculative, but the findings support the concept of the rat being fairly resistant to oral neomycin with respect to eventual malabsorption.

Animals↗
PubMedDate not supplied

Neomycin inhibition of intestinal putrescine uptake.

Enhanced intestinal polyamine uptake was confirmed in tumor-bearing rats. Intestinal brush border membrane from rats bearing a Mat Lylu prostatic adenocarcinoma exhibited 46% increase in 14C putrescine uptake. After oral ingestion of 14C putrescine, radioactivity was recovered in the tumor (about 2% of total amount ingested) and was enhanced in liver and in blood. Radioactivity in tumor-bearing rat red blood cells (RBC) was two-fold higher than in healthy control rats indicating that polyamines originating in food can contribute to the enhancement of RBC polyamine levels observed after tumor development. Neomycin-induced inhibition of intestinal putrescine absorption was observed both in vitro and in vivo. In intestinal brush border membrane 500 microM neomycin inhibited putrescine uptake by 30-35%. In vivo, a single dose of neomycin given per os modified final 14C radioactivity distribution: a) The final accumulation of radioactivity in the tumor was reduced by 50%. b) Neomycin treatment lowered the high levels of radioactivity in the blood of cancerous animals. This reduction was correlated with a significant reduction of RBC polyamine levels. c) Radioactivity accumulated in the colon after neomycin treatment in both healthy and cancerous rats. The role of neomycin as an intestinal antibiotic and the presently described effect of this drug on intestinal polyamine uptake emphasize the importance of neomycin in polyamine deprivation treatments.

Adenocarcinoma↗
PubMed2004

Interactions of the antibiotics neomycin B and chlortetracycline with the hammerhead ribozyme as studied by Zn2+-dependent RNA cleavage.

We have investigated the interactions of two antibiotics, neomycin B and chlortetracycline (CTC), with the hammerhead ribozyme using two Zn(2+) cleavage sites at U4 and A9 in its catalytic core. CTC-dependent inhibition of Zn(2+) cleavage was observed in all cases. In contrast, we unexpectedly observed acceleration of A9 cleavage by neomycin under low ionic strength conditions similar to those used to study inhibition of hammerhead substrate cleavage by this antibiotic. This result provides evidence that the inhibitory mechanism of neomycin does not include competition with the metal ion bound to the A9/G10.1 metal-ion binding site, as previously proposed. Under high ionic strength conditions, optimized for Zn(2+)-dependent cleavage, we observed neomycin-dependent inhibition of cleavage at both A9 and U4. The ability of neomycin to both inhibit and accelerate Zn(2+) cleavage suggests that there is either more than one neomycin binding site or multiple binding modes at a single site in the hammerhead ribozyme. Furthermore, the accessibilities and/or affinities of disparate neomycin binding sites or binding modes are dependent on the ionic strength and the pH of the medium.

Anti-Bacterial Agents↗
PubMedDate not supplied

Improved liquid chromatographic determination of neomycin B in bovine kidney.

An improved liquid chromatographic (LC) method was developed for the determination of neomycin B in bovine kidney tissue. The tissue is homogenized twice in phosphate buffer; homogenate is centrifuged, and the supernatant is deproteinated by heat. The extract is acidified and mixed with ion-pair concentrate, and neomycin B is determined by an LC system consisting of an ion-pairing mobile phase, a reversed-phase ODS column, postcolumn derivatization with o-phthalaldehyde reagent, and fluorometric detection. Average recoveries of neomycin B from kidney tissues spiked at 3, 6, and 12 ppm were 103, 99, and 104%, with 9.7, 7.9, and 3.7% intralaboratory coefficients of variation, respectively, using a standard curve prepared in buffer. The method was used to determine neomycin B in kidney tissue obtained from a calf killed 14 days after intramuscular dosing with neomycin (5 mg/lb). The tissue was found to contain about 3 ppm neomycin B. The LC conditions were also used to assay control samples of muscle, liver, milk, plasma, and urine. No interfering peaks were noted at the elution position of neomycin B.

Animals↗
PubMed1964

INFLUENCE OF NEOMYCIN AND INGESTED ENDOTOXIN IN THE PATHOGENESIS OF CHOLINE DEFICIENCY CIRRHOSIS IN THE ADULT RAT.

Two groups of adult rats fed a choline-deficient diet supplemented with neomycin in their drinking water for 250 or 350 days were protected against the development of liver fibrosis and cirrhosis. At the termination of the study these animals weighed more than others not receiving neomycin. This difference in weight did not appear to be caused by a growth-promoting effect of neomycin but rather reflected the increased severity of liver disease and a resultant weight loss in animals not receiving neomycin. Protection by neomycin was cancelled when Salmonella typhosa endotoxin was added to the drinking water. It was concluded that the protective effect of neomycin was mediated by an alteration in the intestinal microflora resulting in a reduction in the numbers of organisms contributing to intraluminal endotoxin. In the presence of choline deficiency, absorption of intraluminal endotoxin may contribute to the development of fibrosis and cirrhosis.

Animals↗
PubMed1993

PDGF and neomycin induce similar changes in the actin cytoskeleton in human fibroblasts.

The addition of platelet-derived growth factor (PDGF) to serum-starved fibroblasts induces increased motility, formation of lamellipodia, increased ruffling activity, and actin ring structures associated with dorsal ruffles. Involvement of the phosphatidylinositol cycle (PI-cycle) in these morphological changes was investigated by observing the effects of neomycin, an inhibitor of the PI-cycle, on cultured human foreskin fibroblasts. The role of actin in the changes was investigated by using cytochalasin D (CD). Actin in detergent-extracted cells was labelled with TRITC-phalloidin and examined with fluorescence microscopy. Using PDGF and neomycin simultaneously potentiated lamellipodia formation, ruffling activity, as well as the number of cells with actin rings. Furthermore, neomycin by itself induced morphological changes similar to those induced by PDGF. Quantitation of actin rings showed dose and time dependency for PDGF and neomycin respectively, with a maximal number of cells containing rings after 15 min of exposure to either 3.5 mM neomycin or 10 ng PDGF/ml. Comparing the two substances, PDGF induced ring formation in a greater number of cells. These processes were inhibited by the presence of CD. PDGF- and neomycin-induced changes in the actin cytoskeleton were also observed in human embryonic lung fibroblasts, human glial cells, and embryonic mouse fibroblasts, all of which are known to express PDGF-receptors. In conclusion, the present study indicates that an increased turnover of the PI-cycle is not essential for the changes in actin organization induced by PDGF.

3T3 Cells↗
PubMed1998

Distribution of cytoskeletal proteins in neomycin-induced protrusions of human fibroblasts.

The organization of actin, tubulin, and vimentin was studied in protruding lamellae of human fibroblasts induced by the aminoglycoside antibiotic neomycin, an inhibitor of the phosphatidylinositol cycle. Neomycin stimulates the simultaneous protrusion of lamellae in all treated cells, and the lamellae remain extended for about 15-20 min, before gradually withdrawing. The pattern and distribution of actin, tubulin, and vimentin during neomycin stimulation were analyzed by fluorescence and electron microscopy. F-actin in the newly formed lamellae is localized in a marginal band at the leading edge. Tubulin is colocalized with F-actin in the marginal band, but the newly formed lamellae are initially devoid of microtubules. Over a period of 10 to 20 min after the addition of neomycin, microtubules grow into the lamellae from the adjacent cytoplasm, while the intensity of tubulin staining of the marginal band decreases. Distribution of vimentin remains unchanged in neomycin-treated cells and vimentin filaments do not enter the new protrusions. Treatment of cells with colchicine and Taxol do not inhibit neomycin-induced protrusion but protrusions are no longer localized at the ends of cell processes and occur all around the cell periphery. We conclude that actin filaments are the major component of the cytoskeleton involved in generating protrusions. Microtubules and, possibly, intermediate filaments control the pattern of protrusions by their interaction with actin filaments.

Actins↗
PubMed1987

Effects of neomycin on calcium channel currents in clonal GH3 pituitary cells.

Membrane Ca currents were recorded from voltage-clamped clonal (GH3) pituitary cells under conditions where currents through Na and K channels were abolished. Two Ca currents, with distinct kinetics and voltage dependence for activation and inactivation, were identified. Neomycin, an aminoglycoside polycation, inhibited both the "transient" (ICa,t) and the "slowly-inactivating" (ICa,s) Ca currents in a dose-dependent manner (100-1,000 microM). The blockade was reversible and ICa,s was more sensitive to neomycin than ICa,t. The inhibition of ICa,s was frequency and time-independent, and was not affected by changes in the holding membrane potential (-35 to -100 mV). Neomycin did not affect the voltage dependence for inactivation of ICa,t. The blockade of both Ca currents by neomycin is ascribed to the general property of aminoglycosides to compete with, and displace Ca ions from membrane binding sites that determine the currents and selectivity of Ca channels. Because comparable concentrations of neomycin were required for blocking the currents conveyed by Ca or, in the absence of external divalent cations, by Na ions through the slowly-inactivating Ca channels, we suggest that the neomycin binding sites are distinct from the high-affinity transition sites within the Ca channel path.

Cells, Cultured↗
PubMed1982

Effect of neomycin sulphate alone and in combination with D-thyroxine on serum lipoproteins in hypercholesterolaemic subjects.

Treatment with neomycin sulphate 1.5 g/d for 8 weeks significantly lowered total serum cholesterol by an average of 19% in 15 out of 19 patients with primary hypercholesterolaemia and LDL-cholesterol by 21%, without significantly changing the corresponding triglyceride and HDL-cholesterol concentrations. Combined treatment with neomycin sulphate 1.5 g/d and d-thyroxine 6 mg/d for 8 weeks lowered total serum cholesterol in the same patients by an average of 30%, LDL-cholesterol by 27% and serum triglycerides by 18%, without significantly changing the HDL-cholesterol concentration. Continued treatment for 10 patients with neomycin sulphate 1.5 g/d for up to 13 months did not further change the reduced serum cholesterol level. 10 of 19 patients complained of side effects after 4-8 weeks of treatment with neomycin: 8 of recurrent diarrhoea, abdominal pain or poor appetite, and 4 of acute attacks of vertigo with nystagmus. All side effects were reversed a few days after stopping the neomycin treatment. No additional serious side effects due to d-thyroxine were observed. These serious side effects of neomycin sulphate limit its use to selected high risk patients with hypercholesterolaemia, who have failed to respond successfully to other LDL-cholesterol-lowering drugs. They stress the necessity for frequent monitoring for the side effects described.

Adult↗
PubMedDate not supplied

Neomycin inhibits K+-induced force and Ca2+ channel current in rat arterial smooth muscle.

The techniques of small vessel isometric myography and patch clamp were used to investigate the action of neomycin on K+-induced isometric force and voltage-gated Ca2+ channel currents in rat arterial smooth muscle. Neomycin and the dihydropyridine (DHP) Ca2+ channel antagonist (-)202-791 concentration-dependently and reversibly inhibited 40 mM K+-induced isometric force in rings of rat mesenteric and basilar arteries (IC50 values of 70 microM and 1. 2 nM, respectively, n = 10 and 4). Elevation of [Ca2+]o by a factor of 2 significantly reduced the IC50 values for inhibition of K+-induced force for both neomycin and (-)202-791 (192 microM and 3. 7 nM, respectively, n = 6 and 4), but did not affect the Hill coefficient of the concentration/effect relationships. In patch-clamp experiments using freshly isolated basilar arterial myocytes, the voltage-gated inward current carried by Ba2+ was reversibly and concentration-dependently inhibited by neomycin (IC50 32 microM, n = 3). The concentration/effect curve for inhibition of the inward Ba2+ current by neomycin was significantly shifted to the right when [Ba2+]o was raised from 1.8 mM to 10 mM (IC50 144 microM, n = 8). Our findings suggest that neomycin relaxes high-K+-induced force in rat isolated mesenteric and basilar arteries largely by inhibition of voltage-dependent and DHP-sensitive Ca2+ channels.

Animals↗
PubMed1985

Effects of combination cholestyramine-neomycin treatment on plasma lipoprotein concentrations in type II hyperlipoproteinemia.

Recent prospective clinical trials have established that cholesterol reduction in patients with elevated (upper 90th percentile) concentrations of low-density lipoproteins (LDL) reduces the incidence of myocardial infarction and sudden death. Because the level of protection from these cardiovascular sequelae is directly related to the degree of LDL reduction, combination therapy using different hypolipidemic agents has been used in patients with type II hyperlipoproteinemia (HLP). Neomycin is as effective as cholestyramine in reducing LDL levels and combination neomycin-niacin treatment normalizes the plasma lipoproteins in 92% of patients with type II HLP. Because neomycin could theoretically ameliorate some of the gastrointestinal side effects of cholestyramine in addition to further affecting cholesterol levels, the effects of combination cholestyramine-neomycin treatment on the plasma lipoprotein were assessed in 18 patients with type II HLP in a 9-month clinical trial. Compared with diet-only treatment, cholestyramine reduced total and LDL cholesterol levels by 77 mg/dl (22%) and 78 mg/dl (31%), respectively. In addition to relieving cholestyramine-induced constipation, neomycin further reduced the total cholesterol level by 20 mg/dl (6%). However, this further reduction in total cholesterol concentration was the result of a decrease in the concentration of high-density lipoprotein cholesterol. These findings indicate that combination therapy does not have an additive LDL cholesterol-lowering effect and that neomycin and cholestyramine is not a useful drug combination. In addition, these results illustrate the importance of determining the high-density lipoprotein cholesterol concentration to fully interpret the effects of hypolipidemic treatment.

Cholesterol, HDL↗
PubMed1980

Comparison of the action of streptomycin and neomycin on the structure of the bacterial ribosome.

The influence of streptomycin and neomycin upon the conformation of the ribosome has been investigated using spin-labeled and fluorescent analogs of the sulfhydryl reagent, N-ethylmaleimide. Changes in the electron paramagnetic resonance spectra or in the polarization of fluorescence of labeled ribosomes reveal that streptomycin alters the mobility of labels bound to the sulfhydryl group of protein S18 while neomycin affects the mobility of labels bound to the sulfhydryl groups of proteins S1, S21 and/or L10. It is also observed that both streptomycin and neomycin interfere with changes in the mobility of labels induced by storage under inactivating conditions. From these results, it is concluded that: 1. streptomycin and neomycin distort the conformation of the ribosome at different sites, streptomycin disturbing preferentially the area around the sulfhydryl group of protein S18 while neomycin affects the environment of the sulfhydryl groups of proteins S1, S21 and/or L10; 2. streptomycin and neomycin interefere with the ability of the ribosome to undergo conformational changes.

Edetic Acid↗
PubMed2006

Determination of neomycin and bacitracin in human or rabbit serum by HPLC-MS/MS.

The method for the simultaneous determination of neomycin and bacitracin in human or rabbit serum was developed by using ion pairing reversed phase chromatography and tandem mass spectrometry (MS/MS) detection with electrospray (ESI) in positive mode. Both substances elute under these conditions at the same time and also kanamycin as internal standard elutes almost at the same time. The sample preparation was simple-only using 0.1 mL serum by protein precipitation with acetonitrile. Neomycin and bacitracin were detected as two-fold charged ions as well as the internal standard. The calibration range of these quite difficult detectable substances was 0.2-50 microg/mL of serum. The method was validated for both human or rabbit serum. The inter batch precision of quality control samples in human serum for neomycin ranged from 4.46% to 8.99% and for bacitracin from 6.85% to 11.17%. The inter batch accuracy for neomycin ranged from 98.7% to 100.7% and for bacitracin from 99.2% to 103.0%. At lower limit of quantitation (LLOQ) level of 0.2 microg/mL inter batch precision in human serum for neomycin was 12.05% and for bacitracin 11.91%, whereas accuracies were 99.9% for neomycin and 102.7% for bacitracin. Bench top stability in human or rabbit serum was given over three freeze thaw cycles and 4h at room temperature. The method can be considered to be specific and recoveries for sample preparation were high.

Animals↗
PubMed1987

Neomycin inhibits agonist-stimulated polyphosphoinositide metabolism and responses in human platelets.

The effect of neomycin on agonist-induced changes in polyphosphoinositide metabolism was studied in human platelets. Neomycin induced no changes in the 32P-labeled phospholipids of unstimulated cells. Between 1 and 5 mM of neomycin the initial thrombin-induced decrease in [32P]phosphatidylinositol-4,5-bis-phosphate and production of [32P]phosphatidic acid were gradually inhibited. In contrast, the production of [32P]phosphatidylinositol-4-phosphate was increased. The thrombin-induced decrease in mass of phosphatidylinositol was completely inhibited at 5 mM of neomycin. Collagen- and PAF acether-induced changes in platelet phosphoinositide metabolism as well as aggregation and dense granule secretion induced by all three agonists were inhibited by neomycin. The results indicate that neomycin inhibit platelet responses by selective interference with the interconversions and hydrolysis of polyphosphoinositides upon thrombin stimulation.

Blood Platelets↗
PubMed2002

Block of the ryanodine receptor channel by neomycin is relieved at high holding potentials.

In this study we have investigated the actions of the aminoglycoside antibiotic neomycin on K+ conductance in the purified sheep cardiac sarcoplasmic reticulum (SR) calcium-release channel (RyR). Neomycin induces a concentration- and voltage-dependent partial block from both the cytosolic and luminal faces of the channel. Blocking parameters for cytosolic and luminal block are markedly different. Neomycin has a greater affinity for the luminal site of interaction than the cytosolic site: zero-voltage dissociation constants (Kb(0)) are respectively 210.20 +/- 22.80 and 589.70 +/- 184.00 nM for luminal and cytosolic block. However, neomycin also exhibits voltage-dependent relief of block at holding potentials >+60 mV when applied to the cytosolic face and a similar phenomenon may occur with luminal neomycin at high negative holding potentials. These observations indicate that, under appropriate conditions, neomycin is capable of passing through the RyR channel.

Animals↗
PubMed2002

Ryanodine-induced structural alterations in the RyR channel suggested by neomycin block.

In Mead and Williams, (Biophys. J. 82:1953-1963, 2002) we have reported that neomycin is a potent partial blocker of single purified sheep cardiac SR calcium release channels. Neomycin is unusual in that it is capable of blocking when applied to either the cytosolic or the luminal face of the channel. Block at either aspect of the channel is both concentration- and voltage-dependent, but exhibits different blocking parameters. In this study we have investigated the actions of neomycin on ion handling in the ryanodine-modified channel. Neomycin is more effective at the cytosolic face, having a Kb(0) value of 534.9 +/- 35.17 nM compared with a Kb(0) value of 971.5 +/- 66.62 nM for the luminal face. The voltage dependence also differs at the two sites. Values of zdelta for cytosolic and luminal neomycin are 1.09 +/- 0.04 and -0.57 +/- 0.03, respectively. The interaction of neomycin with the ryanodine-modified channel differs notably from that in the unmodified channel. Voltage-dependent relief of block is not observed after ryanodine modification, and the luminal blocking characteristics are altered. This suggests that ryanodine induces changes at the luminal mouth of the channel and may confer increased rigidity to the channel protein.

Animals↗
PubMed2001

Neomycin blocks capsaicin-evoked responses in rat dorsal root ganglion neurons.

Small dorsal root ganglion (DRG) neurons are characterized by sensitivity to capsaicin. In acutely isolated rat DRG neurons, the effect of neomycin, one of the aminoglycoside antibiotics, on capsaicin-evoked current and voltage responses was examined using whole-cell patch-clamp recording. We showed for the first time that neomycin dose-dependently inhibited capsaicin-evoked currents with half-maximal inhibitory concentration at 130.60 microM (n=70). Under current-clamp condition, depolarization and firing rate evoked by capsaicin became weakened when neomycin was perfused to the neurons (n=10). Neomycin had no significant effect on the resting potentials of DRG neurons. These results suggest that neomycin could inhibit capsaicin-sensitive responses in small DRG neurons, which may contribute to neomycin-induced peripheral analgesia.

Analgesics↗
PubMed1995

Neomycin inhibition of the hammerhead ribozyme involves ionic interactions.

To investigate the properties of the neomycin-hammerhead interaction, inhibition of hammerhead activity was measured as a function of magnesium concentration and pH. The data are consistent with a simple competition between magnesium and neomycin with about five magnesium ions required to displace neomycin from the hammerhead. The pH dependence of the inhibition of hammerhead cleavage by neomycin and two related aminoglycosides was also determined. The data indicate that at least three of the five positively charged ammonium ions present on neomycin are critical for inhibiting hammerhead function. Taken together, these results suggest that the neomycin-hammerhead interaction is mostly ionic in character.

Base Sequence↗