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PubMed2004

Surfactant-mediated dissolution: contributions of solubility enhancement and relatively low micelle diffusivity.

The objective of this study was to assess the contributions of surfactant-mediated solubility and micellar diffusivity on the ability of surfactant to enhance drug dissolution. The following model was derived to predict the degree to which surfactants enhance griseofulvin dissolution: phi = 1 + (fm/ff).((D(D-M)2/3)/(DD2/3)) where phi is the degree of surfactant-mediated dissolution enhancement, fm is the fraction of the drug in micelle, and ff is the fraction of free drug, and DD and D(D-M) are the diffusivities of free drug and drug-loaded micelles, respectively. The Wood apparatus was used to measure the dissolution of griseofluvin in the presence of the anionic surfactant sodium dodecyl sulfate (SDS), the cationic surfactant cetyl trimethyl ammonium bromide (CTAB), and the neutral surfactants Tween 80 and Cremophor EL. DD was estimated using the Levich equation. D(D-M) was measured using dynamic light scattering. Griseofulvin solubility was evaluated in SDS, CTAB, Tween 80, and Cremophor EL at the surfactant concentrations used in the dissolution studies. DD was 11.0 x 10(-6) cm2/s. D(D-M) was 1.29 x 10(-6) cm2/s, 0.956 x 10(-6) cm2/s, 0.569 x 10(-6) cm2/s, and 0.404 x 10(-6) cm2/s for griseofulvin-loaded micelles of SDS, CTAB, Tween 80, and Cremophor EL, respectively. At the highest surfactant concentrations studied, griseofulvin solubility increased 107-fold, 31-fold, fourfold, and threefold for SDS, CTAB, Tween 80, and Cremophor EL. Dissolution into SDS and CTAB were markedly enhanced, but only about one-third as much as solubility enhancement. Dissolution enhancement in the presence of SDS and CTAB were in excellent agreement with model predicted values, with prediction error less than 12%. The model predicted dissolution into Tween 80 and Cremophor EL to be minimally enhanced, as was observed, although the model underpredicted dissolution into these two neutral surfactants. The derived model predicted surfactant-mediated dissolution and reflects dissolution enhancement to be promoted by surfactant-enhanced solubility, but limited by the relatively slow diffusion of drug-loaded surfactant micelles.

Diffusion↗

PubMed1991

Enhancing effect of pyrrolidone derivatives on transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen.

The enhancing effects of pyrrolidone derivatives on the transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen were studied by using an in vitro technique and full-thickness rat skin. The enhancers included 1-methyl (1), 1-hexyl (2), and 1-lauryl-2-pyrrolidone (3). Penetrants with various physicochemical properties were used. Flurbiprofen penetrated through skin rapidly after application alone. 5-Fluorouracil, triamcinolone acetonide, and indomethacin showed little penetration. Pyrrolidone derivatives enhanced the penetration of penetrants, especially the lipophilic compounds 2 and 3, which showed a great enhancing effect on the penetration of 5-fluorouracil and indomethacin. Pyrrolidone derivatives also enhanced the solubility of these penetrants in isopropyl myristate. Compounds 2 and 3 showed greater enhancing effects on the solubility and penetration of hydrophilic penetrants than those of lipophilic penetrants. These results suggest that the pyrrolidone derivatives enhance the flux of penetrants in skin by increasing the solubility of penetrants in the stratum corneum. Compounds 1 and 2 were detected in the receptor phase. All enhancers accumulated to a great extent in the skin. These derivatives also enhanced the skin retention of drug. It is concluded that these pyrrolidone derivatives are useful for transdermal drug delivery, although further studies are necessary before they could be used clinically.

Administration, Topical↗

PubMed1995

Transdermal delivery of drugs with differing lipophilicities using azone analogs as dermal penetration enhancers.

Six model drugs were selected for this study based on their degree of lipophilicity as represented by their log P values (range = -0.95 to 3.51). They included 2,4-dihydroxy-5-fluoropyrimidine (5-fluorouracil); 1,3,7-trimethylxanthine (caffeine); [(2-hydroxybenzoyl)amino]-acetic acid (salicyluric acid); 2-hydroxybenzoic acid (salicylic acid); 9 alpha-fluoro-16 alpha-hydroxyprednisolone 16 alpha, 17 alpha-acetonide (triamcinolone acetonide); and alpha-methyl-4-[2-methylpropyl]benzeneacetic acid (ibuprofen). Six dermal penetration enhancers [Azone or 1-dodecylhexahydro-2H-azepin-2-one (1), N-dodecyl-2-pyrrolidinone (2), N-dodecyl-2-piperidinone (3), N-dodecyl-N-(2-methoxyethyl)acetamide (4), N-(2,2-dihydroxyethyl)dodecylamine (5), and 2-(1-nonyl)-1,3-dioxolane (6)] were tested in vitro across full-thickness hairless mouse skin with each of the drugs. The relationship between lipophilicity (log P) and efficacy (represented by the enhancement ratio of flux) of the drugs when coadministered with the enhancers was examined using linear regression. The three cyclic enhancers (1-3) exhibited linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs R2 = 0.8997 for 1, 0.8801 for 2, and 0.804 for 3) when evaluating all the model drugs except triamcinolone acetonide (TA). The two acyclic enhancers (4 and 5) showed a similar relationship, but their correlation coefficients were lower at 0.6463 for 4 and 0.6213 for 5. Studies with the dioxolane (6) yielded no relationship between the lipophilicity of the drug and the efficacy of the enhancer, with an R2 of 0.002. Overall, 6 was the least effective enhancer studied. The steroid TA was not included in the linear regression analysis. Of the six model drugs studied, TA exhibited the largest increase in transdermal delivery when enhancers 1-6 were used.

Animals↗

PubMed1996

Detection and characterization of primary liver cancer in rats by MS-264-enhanced MRI.

A new MR contrast agent, MS-264 (Gd(1RS)-1-(p-butylbenzyl)-DTPA), was developed to achieve hepatobiliary specificity and its potential evaluated for detecting and characterizing liver tumors in rats with chemically induced hepatocellular carcinoma (HCC). In seven rats with 66 HCC lesions, enhancements of different abdominal organs and tumors were compared on T1-weighted images after intravenous administration of Gd-DTPA (0.3 mmol/kg) and MS-264 (0.05 mmol/kg). MR images were correlated with postmortem microangiographic and histological findings. An overall enhancement of different organs, which normalized within 24 h, was observed after Gd-DTPA and MS-264 injection. MS-264 caused a higher relative enhancement (RE) in liver (60%), compared with that of Gd-DTPA (40%), which resulted in a prompt negative contrast enhancement in 59 of 66 HCCs. All were moderately to poorly differentiated (Grades II-IV) tumors. Six of these 59 negative contrast-enhancing lesions showed a positively enhanced peritumoral rim, which corresponded histologically to malignant infiltration (n = 2) or compression (n = 4). On the other hand, six well differentiated HCCs showed prolonged positive enhancement. However, one well differentiated HCC was not positively enhanced by MS-264, probably due to poor access of the agent to the lesion. In comparison to that of the precontrast images, enhancement with Gd-DTPA and MS-264 increased the number of detected lesions by 22 and 42%, respectively. In this animal study, MS-264 proved to be useful in detection and characterization of primary liver cancers.

Animals↗

PubMed1984

Immunologic enhancement of experimental metastasis in the rat.

Using a series of immunologically cross-reactive metastatic tumor variants, we demonstrate that serum from animals bearing pulmonary tumor colonies possesses enhancing properties in the experimental metastasis (lung colony) assay. Enhancement is produced by chronic serum administration and promotes the growth of tumor cells arrested in the lungs which would not otherwise proliferate to form grossly detectable lung nodules. Tumor-bearer serum from animals with lung colonies derived from the most highly metastatic variant examined is shown to possess enhancing properties in both BD-IX(H-1d) and BD-IV(H-1d) rat strains, while tumor-bearer serum from animals with lung colonies derived from the less metastatic parent tumor cell line possesses enhancing properties in the BD-IX rat strain only. Removal of immunoglobulin from enhancing serum by affinity column chromatography simultaneously removes the enhancing factor(s), and enhancing activity correlates with the presence of increased levels of Clq-binding immune complexes in the serum. Serum levels of immune complexes are shown to be more elevated in serum from animals bearing lung colonies derived from the most highly metastatic variant. The enhancing moieties are shown to bind to concanavalin A, but not to staphylococcal protein A, and the active fraction elutes from concanavalin A-Sepharose with alpha-methyl-mannoside. Consideration of immunoprecipitation studies on whole and fractionated enhancing sera, along with studies on affinity purified isotype fractions reveals that the activity resides with antibodies of IgG2b subclass.

Animals↗

PubMed1991

Enhancing effect of mouse peritoneal exudate cells and their products on antibody productivity of hybridoma cells: application of in vivo factors to in vitro culture.

Mouse peritoneal exudate cells induced by casein enhanced in vitro antibody production rate per cell of a hybridoma in co-culture. Culture supernatant of the exudate cells also enhanced three-fold the antibody productivity when added to cultures of a hybridoma at 10% (v/v). Hence the enhancement of antibody productivity by the exudate cells seemed to be caused by soluble enhancing factors secreted by the exudate cells. The exudate cells maximally secreted the enhancing factors when harvested from mice on day 4 of the induction period following the injection of casein. A semi-continuous culture of the hybridoma demonstrated the applicability of the culture supernatant to enhance antibody production by producing a two-fold increase over the control for seven days when supplemented with the supernatant at 5%. Significant amounts of interleukin-6 were detected in culture supernatant of the exudate cells. Interleukin-6 obtained from other sources enhanced the antibody productivity two-fold when added to the hybridoma culture at the concentration of 5 unit/ml. Interleukin-6, therefore, is expected to be one of the principal antibody enhancing factors secreted by the exudate cells. Other interleukins examined, that is, interleukin-1 to -5 did not enhance the antibody productivity.

Animals↗

PubMed1987

Fluoxetine enhances memory processing in mice.

Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory processing ("consolidation") and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 micrograms per mouse). FLU enhanced retention when administered prior to training (1-5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance over the dose range 0.5-35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min, as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU (15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this task as well as in the active avoidance task.

Animals↗

PubMed1999

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958.

RATIONALE: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D1 and D2 receptors. OBJECTIVES: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D1 receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D1 and D2 receptor using a varied range of startle-eliciting intensities. METHODS: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D1 receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D1 or D2 receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). RESULTS: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. CONCLUSIONS: These data suggest that dopamine D1 receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D1/D2 receptor interaction whereby D2 receptor activation is necessary for the full expression of the D1 receptor-mediated enhancement of startle.

Animals↗

PubMed1998

High-dose gadolinium-enhanced MRI for diagnosis of meningeal metastases.

We compared high-dose (0.3 mmol/kg) and standard-dose (0.1 mmol/kg) gadolinium-enhanced MRI for diagnosis of meningeal metastases in 12 patients with suspected meningeal metastases. They were imaged with both standard-dose and high-dose gadolinium. All patients with abnormal meningeal enhancement underwent at least one lumber puncture for cerebrospinal fluid (CSF) cytology, while patients with normal meningeal enhancement were followed clinically. All patients with negative CSF cytology also were followed clinically. A single observer reviewed all the images, with specific attention to the enhancement pattern of the meninges. Abnormal leptomeningeal enhancement was present in three cases, and abnormal pachymeningeal enhancement in three other patients. All of these patients had abnormal CSF analyses. In two of the three cases of abnormal leptomeningeal enhancement the disease was more evident on high-dose than on standard-dose imaging; in one case the abnormal enhancement was visible only on high-dose imaging. In one of the three cases with abnormal pachymeningeal enhancement, the disease was evident prospectively only with high-dose imaging.

Adult↗

PubMedDate not supplied

Adrenal tumors with late enhancement on CT and MRI.

OBJECTIVES: To identify adrenal masses showing gradual persistent enhancement on delayed contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Computed tomography or magnetic resonance images of pathologically proven 400 adrenal tumors were retrospectively reviewed over a 10-year period. We included only adrenal tumors showing gradual persistent enhancement on CT and MRI performed at 15 and 5 min, respectively, after contrast material injection. RESULTS: Four tumors in four patients (three men and one woman; mean age, 51 years) met the inclusion criteria. These lesions were as follows: two ganglioneuromas, one myelolipoma with infarction, and one angiomyolipoma with minimal fat. All of these tumors showed gradual persistent enhancement, and highest attenuation during delayed contrast-enhanced CT or strongest enhancement during delayed contrast-enhanced MRI. CONCLUSION: The differential diagnosis of adrenal tumors showing gradual persistent enhancement on delayed contrast-enhanced CT and MRI should include ganglioneuroma, myelolipoma with infarction, and angiomyolipoma with minimal fat.

Adrenal Gland Neoplasms↗

PubMed2005

Detection of pericardial inflammation with late-enhancement cardiac magnetic resonance imaging: initial results.

OBJECTIVE: To examine the value of late-enhancement cardiac magnetic resonance imaging (MRI) for detection of pericardial inflammation. MATERIALS AND METHODS: Late-enhancement cardiac MRI was performed in 16 patients with clinical suspicion of pericardial disease. Pericardial effusion, pericardial thickening and pericardial enhancement were assessed. MRI findings were compared with those of definitive pericardial histology (n=14) or microbiology (n=2). A control group of 12 patients with no clinical evidence of pericardial disease were also imaged with the same MRI protocol. RESULTS: Sensitivity and specificity for late-enhancement MRI detection of pericardial inflammation was of 100%. There was MRI late enhancement of the pericardial layers in all five patients with histological/microbiological evidence of inflammatory pericarditis. MRI demonstrated no pericardial thickening and no MRI late enhancement with or without a pericardial effusion in any of the five patients with histological evidence of a normal pericardium. MRI detected pericardial thickening in the absence of both pericardial effusion and late enhancement in all six patients with histological evidence of chronic fibrosing pericarditis. The 12 control subjects showed no evidence of pericardial MRI late enhancement. CONCLUSIONS: These findings demonstrate that MRI late enhancement can be used to visualize pericardial inflammation in patients with clinical suspicion of pericardial disease.

Adult↗

PubMed2005

Detection of hepatocellular carcinoma: comparison of Gd-DTPA- and ferumoxides-enhanced MR imaging.

The aim was to compare the diagnostic performance of dynamic Gd-DTPA- and ferumoxides-enhanced MRI for hepatocellular carcinoma (HCC). Twenty-five patients with chronic hepatitis or liver cirrhosis underwent both dynamic gadopentetate- and ferumoxides-enhanced MRI studies of the liver for HCC detection on the same day. MR data of both studies were retrospectively and independently analyzed. Two observers determined in consensus the grade of diffuse fibrotic liver changes (mild, moderate or severe) and the number of focal lesions. HCCs were confirmed by histology (n=22) and/or follow-up studies for at least six months (n=64). Differences in results obtained from both MR data sets were tested for significance with the McNemar's test (p<0.05). Ferumoxides-enhanced MR images detected 84 of 99 hepatic lesions, including 82 of 86 HCCs and 2 false positive, nonmalignant lesions, while Gd-DTPA-enhanced MR images detected 92 of 99 hepatic lesions, including 81 of 86 HCCs and 11 false positive, nonmalignant lesions. Sensitivity of MRI for detection of HCCs was not significantly different between ferumoxides-enhanced (95.3%; p>0.05) and Gd-DTPA-enhanced scans (94.2%). Gd-DTPA- and ferumoxides-enhanced MRI perform equally well for HCC detection. The majority of small hypervascular hepatic lesions, detected on dynamic Gd-DTPA-enhanced MRI but not on ferumoxides-enhanced MRI, represent no HCCs.

Adult↗

PubMed2001

Magnitude and decay of stretch-induced enhancement of power output.

There is ample evidence that the pre-stretching of a muscle enhances performance of the subsequent shortening or concentric contraction. The purpose of this study was to investigate this stretch-induced enhancement in terms of the effect of load on the magnitude and decay of the muscle's power output. Instantaneous, mean and peak power outputs were compared between concentric-only and rebound bench press throws at different loads. The maximal strength [1 RM = 84.0 (10.5) kg] of 18 male subjects [21.1 (3.0) years, 87.2 (11.9) kg] was determined using an isoinertial Smith press machine. The results of this study indicate enhancement of concentric motion by prior eccentric muscle action (200-780% enhancement in the first 100 ms). However, the magnitude and temporal characteristics of this enhancement differed across loads. Using a lighter load produced greater initial enhancement (P < 0.05) but the decay of this enhancement was more rapid. The heavier 80% 1 RM loading showed a later time to peak enhancement (80 ms versus 20 ms) and slower decay of the stretch induced augmentation (460 ms versus 260 ms). It is concluded that the degree of stretch-shorten cycle enhancement differs according to the load and the time-dependent characteristics of the motion.

Adult↗

PubMed2005

Superparamagnetic iron oxide-enhanced MR imaging for focal hepatic lesions: a comparison with CT during arterioportography plus CT during hepatic arteriography.

BACKGROUND: We aimed to evaluate the efficacy of a breath-hold superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging protocol for the detection of focal hepatic lesions, in comparison with a non-breath-hold SPIO-enhanced imaging protocol and computed tomography during arterioportography (CTAP) plus CT during hepatic arteriography (CTHA). METHODS: Findings of SPIO-enhanced MR imaging and CTAP/CTHA for 24 hepatic metastases in 17 patients and 29 HCCs in 21 patients were analyzed. All patients underwent breath-hold SPIO-enhanced MR imaging (1.5 tesla), breath-hold plus non-breath-hold SPIO-enhanced MR imaging, and CTAP plus CTHA prior to partial hepatectomy or laparoscopic ablation therapy. Histopathology for lesion characterization and intraoperative ultrasound for lesion detection were available for all patient. Breath-hold SPIO-enhanced MR imaging consisted of T2-weighted single-short fast spin echo (FSE), T2-weighted (T2W) FSE, T2*-weighted gradient echo (GRE), and T1-weighted GRE. For the non-breath-hold imaging protocol, respiratory-triggered, fat-suppressed T2W-FSE was added to the breath-hold MR imaging protocol. Double phase CTAP plus CTHA was performed on an angio-CT system. To compare the three imaging protocols, three radiologists performed blind film reading, and all data, on a hepatic segment-to-segment basis, were entered for alternative free-response receiver-operating characteristic (AFROC) analysis. RESULTS: ROC analysis showed that there was no significant difference in the area under the AFROC curve (A1) value for metastases and HCCs among the three protocols; the breath-hold SPIO-enhanced MR imaging protocol, non-breath-hold MR imaging protocol, and CTAP plus CTHA. The breath-hold SPIO-enhanced MR imaging protocol showed a sensitivity, specificity, and accuracy equivalent to the non-breath-hold MR imaging protocol and CTAP plus CTHA. CONCLUSIONS: As a preoperative test, SPIO-enhanced MR imaging could have the potential to replace CTAP plus CTHA in a certain clinical setting.

Adult↗

PubMed2003

Anal fistula: Levovist-enhanced endoanal ultrasound: a pilot study.

PURPOSE: The aim of the study was to investigate the usefulness of the contrast agent Levovist in ultrasound assessment of anal fistula. METHODS: Fifteen patients (11 females, mean age 46) with a diagnosis of anal fistula were assessed by physical examination, conventional ultrasound, Levovist-enhanced ultrasound, and surgery. Levovist was injected a cannula into the fistula. The results of physical examination, conventional ultrasound and Levovist-enhanced ultrasound were compared with surgical findings as criterion standard. RESULTS: At physical examination, three intersphincteric fistulas and two sinuses were diagnosed. Using conventional ultrasound, five intersphincteric and five transsphincteric fistulas were found; four fistulas and one sinus were not detected. Levovist-enhanced ultrasound revealed one sinus, five intersphincteric, seven transsphincteric, and one extrasphincteric fistulas; only one fistula was not detected. At surgery, three intersphincteric, seven transsphincteric, and two sinuses were found; however, the extrasphincteric fistula detected by Levovist was missed. Compared with physical examination, Levovist-enhanced ultrasound and surgery were significantly favorable in the diagnosis of anal fistula (P < 0.05 in chi-squared test and Fisher's exact probability test). The concordance rate of surgery with conventional ultrasound was 69 percent (9/13) and with Levovist-enhanced ultrasound was 77 percent (10/13). However, because the extrasphincteric fistula was missed at surgery, the accuracy of Levovist-enhanced ultrasound was in fact 85 percent (11/13) if surgical finding was not used as the standard. The internal opening was detected at physical examination in 2 patients (13 percent), with conventional ultrasound in 4 patients (27 percent), with Levovist-enhanced ultrasound in 9 patients (60 percent) and during surgery in 11 patients (85 percent). Consistently, Levovist-enhanced ultrasound and surgery were significantly better than physical examination in the diagnosis of internal opening (P < 0.05). One secondary extension and two sphincter defects were detected by both types of ultrasound. The extension was not confirmed during surgery. No patients developed recurrence or nonhealing of wound. One patient developed incontinence to flatus and one developed a perianal hematoma. CONCLUSION: Levovist-enhanced ultrasound is better at assessing anal fistula than physical examination and conventional ultrasound. However, a future trial comparing Levovist, hydrogen peroxide, and magnetic resonance imaging is needed to establish which is the most cost-effective preoperative imaging technique to use.

Adult↗

PubMed1976

Effects of local anaesthetics on intracellular fusion processes. Enhancement of concanavalin A-induced macrophage vacuolation.

The extensive vacuolation elecited in mouse peritoneal macrophages in response to interaction with concanavalin A is markedly enhanced by a simultaneous exposure to anaesthetics. The potency of enchancing vacuolation increases within the series of normal alcohols with chain length C10 greater than C8 greater than C7 greater than C6. From the four tertiary amine local anaesthetics tested lidocaine and procaine are by far more effective than tetracaine and dibucaine. The latter two induce extensive cell shrinkage at concentrations at which the first two exhibit optimum enhancing capacity. Of the tested compounds chlorpromazine has the highest membrane/buffer partition coefficient and it exhibits its optimum enhancing effect on concanavalin A-induced macrophage vacuolation at the lowest drug concentration. The binding of [3H] concanavalin A as well as its internalization by macrophages incubated with the lectin for 15, 45 and 90 min are not affected significantly in the presence of decanol, procaine or chlorpromazine at concentrations of maximum enhancing effect on vacuolation. Thus enhancement of vacuolation does not stem from an increase in the rate or extent of concanavalin A interiorization. The rate at which vacuoles are generated is however markedly increased in the presence of chlorpromazine and the resulting vacuoles are of a larger diameter. At 2-5 fold the concentration required for inhibition of maximum enhancing effect, the drugs lead to extensive macrophage shrinkage and to depletion of intracellular ATP. Phagocytosis of heat-killed yeast cells is reduced by tertiary amine anaesthetics at concentrations optimal for enhancement of concanavalin A-induced vacuolation. Enhanced intracellular fusion of concanavalin A-bearing pinosomes to form vacuoles is discussed in terms of current ideas on factors vacuoles is discussed in terms of current ideas on factors vacuoles is discussed in terms of current ideas on factors affecting membrane fusion and the effects of anaesthetics on membrane organization of lipids, intramembraneous particles, glycoprotein receptors and the possible control by cytoskeletal elements. The results best fit the hypothesis that enhanced fusion correlates with membrane aggregation of both intramembraneous particles and concanavalin A receptor and the formation of areas relatively deplete of these structures and enriched in phospholipids.

Adenosine Triphosphate↗

PubMed1993

Enhancement of murine gustatory neural responses to D-amino acids by saccharin.

Taste enhancing effects of sodium saccharin (Sac) on responses to particular sweet-tasting D-amino acids were found during the recording of mouse chorda tympani nerve responses to various taste stimuli in C57BL and BALB strains. In both strains, responses to D-tryptophan and D-histidine significantly increased (167.7-216.7% of control) after the stimulation with Sac as compared with those applied before Sac. In C57BL mice, the enhancement of Sac was also observed in response to D-phenylalanine (262.5% of control), but this was not the case for BALB mice, suggesting a prominent strain difference in response to D-phenylalanine, as shown previously. Responses to other sweet-tasting D- and L-amino acids and sugars were not enhanced by Sac. Enhancement of responses to these D-amino acids by Sac was also evident when responses to a mixture of D-amino acids and Sac were compared with the sum of responses to each component, although in this response analysis, the calculated magnitude of enhancement generally become smaller (135.7-180.5% of the sum) and enhancement of D-histidine responses disappeared. Except for Sac, various sweet-tasting amino acids and sugars and NaCl also tested showed no enhancing effect on D-phenylalanine responses in C57BL mice. Sac and D-amino acids, to which responses were enhanced by Sac, possess some common molecular features, namely ring structures. This structural similarity probably relates to the occurrence of the enhancement at the receptor sites.

Amino Acids↗

PubMed1982

Enhancement of benzodiazepine and GABA binding by the novel anxiolytic, tracazolate.

Tracazolate (ICI 136,753) 4-butylamine-1-ethyl-6-methyl-1H-pyrazolo[3,4]pyridine-5-carboxylic acid ethyl ester is a non-benzodiazepine with anxiolytic-like activity in animal models. In contrast to the benzodiazepines, it enhances [3H]flunitrazepam binding in rat synaptic membrane fragments. The enhancement is potential by chloride ion and is due to an increase in affinity of the receptor. The enhancement of benzodiazepine binding by gamma-aminobutyric acid (GABA) is additive with that of tracazolate; however, the GABA antagonist bicuculline blocks the enhancement by both compounds. Tracazolate enhances [3H]GABA binding to frozen and thawed Triton X-100-treated membrane fragments. The enhancement is due to an increase in the number of sites and potentiated by chloride. Benzodiazepines also enhanced GABA binding but the effect was due to an apparent change in affinity and not potentiated by chloride. The rank order to chlorodiazepoxide, diazepam and flunitrazepam for enhancement of GABA binding and displacement of [3H]flunitrazepam binding were the same. The enhancement of [3H]GABA binding by flunitrazepam and tracazolate were additive. Possible interactions between these various receptors are discussed.

Animals↗