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C J Malanga

Publications and source records attributed to C J Malanga.

At least 19 recordsLinked to original sources
PubMed2003

Does drug abuse beget drug abuse? Behavioral analysis of addiction liability in animal models of prenatal drug exposure.

Prenatal exposure to drugs of abuse is the single largest preventable cause of developmental compromise of American children today. In the clinical population, it is difficult to determine the independent effects of gestational exposure to a single drug on brain development, in part due to the confounding effects of additional risk factors that are encountered in the substance-abusing population. The enormous clinical and societal problem of gestational toxicity of drugs of abuse, both legal and illegal, has driven the need to develop and investigate animal models of gestational drug exposure in which these variables can be controlled. More specifically, as clinical data are gathered suggesting an increased liability to substance abuse among children of drug-abusing mothers, a mechanistic understanding of the lasting effects of early drug exposure on the developing brain and the behavioral repertoire of the developing animal is crucial. In this review we summarize experimental animal research that investigates the role of drug exposure in utero on the functional development of specific brain circuits that are involved in the reinforcing effects of drugs of abuse, and on the behaviors that are mediated by these brain reward systems.

Adult↗
PubMed2002

Cocaine and SKF-82958 potentiate brain stimulation reward in Swiss-Webster mice.

RATIONALE: The dopamine D(1)-like receptor agonist SKF-82958 reportedly blocks reinstatement of cocaine-seeking behavior in rats and non-human primates. It is not known if SKF-82958 reduces drug-seeking behaviors in animals exposed previously to cocaine by causing reward-like effects or withdrawal-like aversive effects. OBJECTIVES: Intracranial self-stimulation (ICSS) studies were conducted to determine if SKF-82958 has reward-like or withdrawal-like effects in mice exposed previously to cocaine, or under the influence of cocaine at the time of testing. METHODS: Swiss-Webster mice with lateral hypothalamic stimulating electrodes were trained to self-administer rewarding brain stimulation. The mice were tested in a "curve-shift" variant of the ICSS procedure after intraperitoneal administration of cocaine alone (2.5-20 mg/kg), SKF-82958 alone (0.03-0.3 mg/kg), or a mixture of both drugs (SKF 0.03 mg/kg + 2.5 or 5.0 mg/kg cocaine). Each treatment was given twice. RESULTS: Cocaine and SKF-82958 each caused dose-dependent decreases in brain stimulation reward thresholds that were largest immediately after administration. A dose of SKF-82958 with no reward-related effects of its own potentiated the reward-related effects of low doses of cocaine. Repeated administration did not cause progressive changes in the ability of any treatment to decrease thresholds. CONCLUSIONS: Cocaine and SKF-82958 each potentiate the rewarding effects of lateral hypothalamic brain stimulation in Swiss-Webster mice, implying that these drugs have rewarding effects of their own. The reward-facilitating effects of low doses of cocaine and SKF-82958 are additive (or synergistic). These data suggest that SKF-82958 may decrease cocaine-seeking behavior by mechanisms related to reward rather than aversion.

Animals↗
PubMed2000

Characterization of proteolytic activities of pulmonary alveolar epithelium.

Pulmonary alveolar type I epithelial cell and its progenitor, type II cell, present major transport and enzyme barriers for systemic delivery of pulmonary administered peptide drugs. The present study investigates the effect of cellular differentiation of type II to type I cells on their proteolytic activities, and evaluates the suitability of a continuous lung cell line, A549, for drug transport and degradation studies. High performance liquid chromatography was used to assess the degradation kinetics of two model peptide substrates, luteinizing hormone releasing hormone (LHRH) and [D-Ala(6)10-fold decrease in proteolytic activities for LHRH, as compared to type II cells. The continuous lung cell line A549 formed leaky monolayers and exhibited similar enzyme activities to the primary type II cells. The responsible enzymes for degradation of LHRH in type II and A549 cells were angiotensin converting enzyme (ACE), EP24.11, and EP24.15. In contrast, no EP24.15 or ACE activity was observed in type I-like pneumocytes and only a weak EP24.11 activity was detected. In all cell types, the degradation rate of [D-Ala(6)]-LHRH was about 3-8 times lower than that of LHRH. This peptide analog was resistant to degradation by EP24.15 and EP24.11, but was susceptible to ACE-mediated cleavage.

Animals↗
PubMed2000

Inhibition of endotoxin-induced lung inflammation by interleukin-10 gene transfer in mice.

Interleukin (IL)-10 is an anti-inflammatory cytokine that has great potential for use in the treatment of inflammatory and immune illnesses. In this study, gene transfer was used to induce IL-10 transgene expression in murine lungs for treatment of endotoxin-induced lung inflammation. Gene transfer was performed with a cytomegalovirus (CMV)-IL-10 plasmid with the aid of the liposomal agents LipofectAMINE and N-[1-(2,3-dioleoyl)propyl]-N,N, N-trimethylammonium methylsulfate (DOTAP). Administration of the endotoxin caused a marked increase in lung inflammation as indicated by increased tumor necrosis factor (TNF)-alpha release and neutrophil count. Pretreatment of the mice with IL-10 plasmid with and without LipofectAMINE had no inhibitory effect on lung inflammation and IL-10 transgene expression. LipofectAMINE by itself induced lung inflammation, an effect that was not observed with DOTAP. IL-10 plasmid when codelivered with DOTAP expressed biologically active IL-10 protein and caused a reduction in endotoxin-induced inflammation. Transgene expression was observed as early as 3 h after administration, peaked at 12 h, and declined thereafter. We conclude that IL-10 gene transfer is a feasible approach for the treatment of lung inflammation.

Animals↗
PubMed1999

Mechanisms of action of drugs of abuse on the developing fetal brain.

The consequences of public health of the acquisition and use of drugs of abuse have been well demonstrated. Despite intense effort, however, progress has been slow in recent years in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. The use of animal models allows the investigator to determine the specific biological contributions of prenatal exposure to drugs of abuse on neurodevelopmental outcome while controlling for covariates that have confounded clinical studies, such as altered nutrition in pregnancy, suboptimal rearing environment of the young, and availability of drug and nondrug stimulation to the offspring. This article selectively reviews the preclinical literature on the gestational effects of drugs of abuse with particular emphasis on cocaine, ethanol, and the opiate narcotics. Mechanisms of drug action on the mature and developing brain are summarized. A model of developmental impact on the brain regions underlying drug-induced reward and reinforcement and its potential postnatal importance is presented.

Alcoholism↗
PubMed1998

Case series: spectrum of neuroleptic-induced movement disorders and extrapyramidal side effects in childhood-onset schizophrenia.

OBJECTIVE: Neuroleptic-treated pediatric patients with childhood-onset schizophrenia (COS) are at risk for developing extrapyramidal side effects and involuntary movement disorders. A preliminary examination of the incidence of withdrawal dyskinesias (WD), tardive dyskinesia (TD), and extrapyramidal side effects in these patients is presented. METHOD: Thirty-four COS patients (mean age +/- SD, 14.2 +/- 2.1 years) were examined for TD using the Abnormal Involuntary Movements Scale and for extrapyramidal side effects using the Simpson-Angus Neurologic Rating Scale, after a 14- to 28-day drug-free period (n = 33), at week 6 of treatment and 2 to 4 years after completion of the study (n = 14). The mean (+/-SD) number of months of prior neuroleptic exposure for the group was 22.4 (15.0) months. RESULTS: Seventeen (50%) of 34 patients were noted to have either WD or TD at some point during their participation in the studies. The majority of patients experienced WD that were mainly in the orofacial region, transient in nature, and diminished with haloperidol and clozapine. Patients with TD/WD had greater levels of premorbid impairment (p = .02), increased severity of positive symptoms of schizophrenia (p < .01), and a trend toward more months of neuroleptic exposure (p = .10, one-tailed). CONCLUSIONS: A high proportion of COS patients were found to have TD/WD. The majority of these abnormal movements were not severe and generally improved over time. TD/WD in COS appears to be associated with greater premorbid impairment, severity of illness, and duration of neuroleptic exposure. J. Am. Acad.

Adolescent↗
PubMed1998

Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents.

OBJECTIVE: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting. METHOD: Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective (n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement. RESULTS: For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to "ideal" admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03). CONCLUSION: These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics.

Adolescent↗
PubMed1997

Chronic morphine treatment of guinea pigs induces nonspecific sensitivity changes in the nucleus tractus solitarius in vitro.

Chronic morphine treatment results in the development of an opioid tolerance in guinea pig myenteric S-neurons that is nonspecific among pharmacologically unrelated inhibitory agonists and the concurrent development of a nonspecific super-sensitivity to unrelated excitatory agonists. The purpose of these studies was to extend this model of opioid tolerance in the guinea pig to central neurons, specifically to the medial nucleus tractus solitarius (mnTS), the primary brainstem relay for visceroceptive information. Pharmacological responses of the guinea pig mnTS neurons were examined in an in vitro brainstem slice preparation and compared between chronically morphine-treated animals and untreated controls. The spontaneous activity of guinea pig mnTS neurons was inhibited by gamma-aminobutyric acid (GABA), the GABAA-selective agonist muscimol, 2-chloroadenosine and clonidine and was excited by glutamate and elevations in extracellular potassium. Applied alone, morphine or the GABAA-selective antagonist bicuculline inhibited and excited approximately equal proportions of nucleus tractus solitarius (nTS) neurons. However, when applied in the presence of bicuculline, morphine inhibited most neurons tested. Reduced inhibitory responses to four agonists, i.e., morphine, muscimol, 2-chloroadenosine and clonidine, were observed in mnTS neurons in slices obtained from chronically morphine-treated animals. Increased excitation of these neurons by elevated extracellular potassium was observed. It is concluded that 1) guinea pig nTS neurons respond similarly to nTS neurons from other species in vitro, 2) opioids disinhibit some proportion of guinea pig nTS neurons in vitro through a GABAergic mechanism and 3) the development of opioid tolerance in guinea pig nTS neurons is qualitatively similar to that of guinea pig myenteric S-neurons.

Action Potentials↗
PubMed1997

Hyperpolarizing effects of morphine, clonidine and 2-chloroadenosine in myenteric neurons associated with tolerance to morphine.

Chronic treatment of guinea pigs with morphine produces non-specific subsensitivity (tolerance) of the longitudinal smooth muscle myenteric plexus (LM/MP) preparation of the guinea pig ileum to morphine, clonidine and 2-chloroadenosine correlated with a partial depolarization of myenteric S neurons. The purpose of our investigation was to gain further evidence regarding the cellular mechanism of tolerance. Either morphine or placebo pellets were implanted s.c. in guinea pigs 7 days before the experiment. Subsensitivity was confirmed by a marked decrease of the inhibitory effect of 0.1 microM morphine and 0.3 microM clonidine on neurogenically induced twitches in longitudinal smooth muscle myenteric plexus preparations from the morphine-pretreated guinea pigs. Intracellular microelectrode recording established that only myenteric S neurons that were hyperpolarized by morphine exhibited the depolarized state (difference of 7.2 mV), which occurred without a change in the threshold for initiation of action potentials. S neurons that were hyperpolarized by superfusion with solution containing morphine, 0.1 microM, were acutely hyperpolarized an equivalent amount (6-8 mV) by clonidine, 0.3 microM, or 2-chloroadenosine, 0.1 microM. Morphine and clonidine, but not 2-chloroadenosine, reduced input resistance. The hyperpolarizations and changes in conductance were not different between tolerant and control preparations for any agonist. It is concluded that 1) the receptors for the three agonists are colocalized on selected S neurons, 2) the transduction process for the hyperpolarizing effect of 2-chloroadenosine is different than that for morphine and clonidine, 3) cross-tolerance among the agonists is not a function of altered receptors or signal transduction processes and 4) the depolarized state is associated with tolerance of myenteric S neurons.

2-Chloroadenosine↗
PubMed1996

Oligonucleotide targeting to alveolar macrophages by mannose receptor-mediated endocytosis.

Antisense oligonucleotides (ONs) have proven useful for selective inhibition of gene expression. However, their effective use is limited by inefficient cellular uptake and lack of cellular targeting. In this paper, we report a drug targeting system which utilizes mannose receptor-mediated endocytosis to enhance cellular uptake of ONs in alveolar macrophages (AMs). The system employs a molecular complex consisting of partially substituted mannosylated poly(L-lysine) (MPL), electrostatically linked to a 5' fluorescently labeled ON. Upon recognition by the macrophage mannose receptors, the MPL was internalized by the receptor-mediated pathway, co-transporting the ON. Our results indicate that the AMs treated with the MPL:ON complex exhibited a significant increase in ON uptake (up to 17-fold) over free ON-treated controls. Effective ON uptake was shown to require the recognition of the mannose moiety since unmodified polylysine was much less effective in promoting ON uptake. Specific internalization of the ON:MPL complex by the mannose receptor pathway was verified by competitive inhibition using mannosylated albumin. Under this condition, the ON complex uptake was inhibited. The requirement of mannose receptors for complex uptake was further demonstrated using a macrophage cell line, J774.1, which expresses a low level of mannose receptors. When treated with the complex, these cells showed no susceptibility to ON uptake, thus suggesting the targeting ability of the carrier system to the AMs. Following cellular internalization, the ON complex appeared largely accumulated in endocytic vesicles. Enhanced endosomal exit of the ON was achieved using a fusogenic peptide derived from the amino terminal sequence of influenza virus hemagglutinin HA2. Cytotoxicity studies showed that at the concentrations effectively enhancing ON uptake, both MPL and the fusogenic peptide caused no toxic effects to the cells, thereby suggesting their potential safety and utilization in vivo.

Animals↗
PubMed1994

Alveolar permeability enhancement by oleic acid and related fatty acids: evidence for a calcium-dependent mechanism.

Pulmonary exposure to oleic acid (OA) is associated with permeability alterations and cellular damage; however, the exact relationship between these two effects has not been clearly established. Using cultured alveolar epithelial monolayers, we demonstrated that OA and some other fatty acids (< or = 50 microM) can induce permeability changes without detectable cellular damage. At higher concentrations, however, OA caused severe membrane damage and leakage to solute flux. The permeability enhancing effect of OA was observed with both the paracellular marker 3H-mannitol and the lipophilic transcellular indicator 14C-progesterone. While the effect of OA on transcellular permeability may be attributed to its known effect on membrane fluidity, the paracellular promoting effect of OA and its mechanism are not well established. We postulated that OA may increase paracellular permeability through a Ca(2+)-dependent tight junction mechanism. Using dual-excitation fluorescence microscopy, we demonstrated that OA can increase intracellular calcium, [Ca2+]i, in a dose-dependent manner. This effect was transient at low OA concentrations (< or = 50 microM) but became more pronounced and sustained at higher concentrations. Free hydroxyl and unsaturated groups were required for this activation since esterified OA (oleic methyl ester) and stearic acid (a saturated fatty acid with equal chain length) had much reduced effects on both the [Ca2+]i and the permeability alterations. Degree of unsaturation was unimportant since linolenic acid (18:3), linoleic acid (18:2), and OA (18:1) had similar and comparable effects on the two parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Targeted gene delivery to alveolar macrophages via Fc receptor-mediated endocytosis.

Alveolar macrophage (AM) plays important roles in lung homeostasis and pathogenesis of diseases. The study of macrophage gene function and regulation as well as its potential therapeutic intervention will require the development of vectors capable of safe and efficient transfer of DNA to the AM. In the present study, we report a new transfection system that utilizes Fc receptor-mediated endocytosis as a means to target DNA to the AM. This system employs molecular conjugates consisting of a cognate moiety, in this case IgG which recognizes the AM Fc receptor, covalently-linked to a DNA-binding moiety, such as a cationic polyamine. A Complex was formed between immunoglobulin G-polylysine conjugate (IgG-pL) and plasmid DNA carrying the LacZ reporter gene (pSV beta). The conjugate-DNA complex was added directly to the AMs in culture and incubated for 24 h, after which LacZ gene expression was analyzed for beta-galactosidase activity by microfluorometry using a fluorogenic beta-galactosidase substrate, 5-dodecanoylaminofluorescein di-beta-D-galactopyranoside (C12FDG). The AMs treated with the IgG-pL/DNA complex exhibited galactosidase activity significantly augmented over background levels. Effective gene transfer was shown to require both the DNA-binding moiety and cognate moiety for the cell surface receptor. Specific internalization of the complex by the Fc receptor pathway was verified by competitive inhibition using excess IgG. Under this condition, LacZ gene expression was inhibited, suggesting complex internalization through the Fc mediated endocytosis pathway. The requirement of Fc receptors for complex internalization was further demonstrated using cells that lack Fc receptors, e.g., alveolar epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Receptor-mediated peptide delivery in pulmonary epithelial monolayers.

The present study investigated the feasibility of utilizing receptor-mediated endocytosis as a means to enhance peptide delivery to the pulmonary epithelium. The strategy employs a molecular conjugate consisting of a cognate moiety, transferrin (TF), covalently-linked to a model polypeptide, horseradish peroxidase (HRP), via a reversible disulfide linkage. A cultured alveolar epithelial monolayer system was used to simulate the conditions of the pulmonary epithelium and to allow accurate quantitation of intra- and transcellular peroxidase transport. The alveolar cells were isolated from rat lungs by enzymatic digestion and grown on microporous tissue culture-treated polycarbonate filters. A significant increase in the uptake of HRP by the cell monolayer was observed upon its conjugation with TF. The effect was found to be concentration-dependent, being more pronounced at low concentrations, i.e., 3.9- and 1.2-fold increase over unconjugated HRP controls at the concentration levels of 0.05 and 1.50 U/ml respectively. Effective peroxidase uptake was shown to require the TF cognate moiety for the cell surface receptor. Specific internalization of the conjugate by the TF endocytic pathway was verified by competition for the TF receptor. Conjugate internalization was not followed by a proportional increase in transcytosis, i.e., at 0.05 U/ml conjugate level, a 1.7-fold increase in transcytosis was observed as compared to 3.9-fold for endocytosis. Effective enhancement of transcytosis was achieved by treating the monolayers with brefeldin A (BFA), a compound known to affect intracellular transport of TF receptor complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Altered calcium homeostasis and cell injury in silica-exposed alveolar macrophages.

There is evidence to suggest that cell injury induced in alveolar macrophages (AM) following phagocytic activation by silica particles may be mediated through changes in intracellular free calcium [Ca2+]i. However, the mechanism of silica-induced cytotoxicity relative to [Ca2+]i overloading is not yet clear. To provide a better insight into this mechanism, isolated rat AMs were exposed to varying concentrations of crystalline silica (particle size < 5 microns in diameter) and the fluctuation in their [Ca2+]i and cell integrity were quantitatively monitored with the fluorescent calcium probe, Fura-2 AM, and the membrane integrity indicator, propidium iodide (PI). Results from this study indicate that silica can rapidly increase [Ca2+]i in a dose-dependent manner with a characteristic transient calcium rise at low doses (< 0.1 mg/ml) and an elevated and sustained rise at high doses (> 0.1 mg/ml). Depletion of extracellular calcium [Ca2+]o markedly inhibited the [Ca2+]i rise (approximately 90%), suggesting that Ca2+ influx from extracellular source is a major mechanism for silica-induced [Ca2+]i rise. When used at low doses but sufficient to cause a transient [Ca2+]i rise, silica did not cause significant increase in cellular PI uptake during the time of study, suggesting the preservation of membrane integrity of AMs under these conditions. At high doses of silica, however, a marked increase in PI nuclear fluorescence was observed. Depletion of [Ca2+]o greatly inhibited cellular PI uptake, induced by 0.1 mg/ml or higher doses of silica. This suggests that Ca2+ influx, as a result of silica activation, is associated with cell injury. Indeed, our results further demonstrated that the low dose effect of silica on Ca2+ influx is inhibited by the Ca2+ channel blocker nifedipine. At high doses of silica (> 0.1 mg/ml), cell injury was not prevented by nifedipine or extracellular Ca2+ depletion, suggesting that other cytotoxic mechanisms, i.e., nonspecific membrane damage due to lipid peroxidation, are also responsible for the silica-induced cell injury. Silica had no significant effect on cellular ATP content during the time course of the study, indicating that the observed silica-induced [Ca2+]i rise was not due to the impairment of Ca(2+)-ATPase pumps, which restricts Ca2+ efflux. Pretreatment of the cells with cytochalasin B to block phagocytosis failed to prevent the effect of silica on [Ca2+]i rise. Taken together, these results suggest that the elevation of [Ca2+]i caused by silica is due mainly to Ca2+ influx through plasma membrane Ca2+ channels and nonspecific membrane damage (at high doses).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Regulation of tight junction permeability by calcium mediators and cell cytoskeleton in rabbit tracheal epithelium.

The present study investigates the mechanisms controlling tight junction permeability of the tracheal epithelium, with an emphasis on the regulatory role of intra- and extracellular calcium as well as the cell cytoskeleton. The tracheas were isolated from rabbits and their junctional permeability barrier was investigated in vitro by means of transepithelial electrical resistance measurements and flux measurements of the radiolabeled paracellular tracer, 14C-mannitol. The effects of intra- and extracellular calcium were studied using the calcium ionophore A 23187 and EGTA, and that of the cytoskeleton was investigated using cytochalasin B. Intracellular calcium of the tracheal epithelium was monitored microfluorometrically using the specific calcium indicator, Fura-2 AM (acetoxymethyl ester). The results indicate that the tight junction permeability of the trachea was significantly increased upon treatment with all three of the test compounds, as evidenced by a substantial decrease in transepithelial electrical resistance and an increase in transepithelial flux of 14C-mannitol. The effects of EGTA and cytochalasin B on the tight junction permeability are fully reversible upon removal of the compounds from the bathing media. On the other hand, tissues treated with the calcium ionophore demonstrate a partial or no recovery in membrane permeability, depending on the intracellular calcium levels. Moderate and transient increases in intracellular calcium caused a partial reversibility of the membrane resistance, while high and sustained intracellular calcium levels induce a complete irreversibility of the membrane resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The transport barrier of epithelia: a comparative study on membrane permeability and charge selectivity in the rabbit.

The transport barrier of the epithelial presents one of the major problems limiting the effective use of these tissues as alternate delivery routes for macromolecules such as peptides and proteins. In the present study, two membrane transport properties, namely, the permeability and permselectivity of the shunt pathway, were investigated and compared in various tissues including the nasal, tracheal, bronchial, buccal, rectal, vaginal, corneal, epidermal, duodenal, jejunal, ileal, and colonic epithelia. Membrane permeability was evaluated using a combined method based on electrical conductance and flux measurements of a hydrophilic fluorescent probe, 6-carboxy fluorescein (CF). Membrane permselectivity or the charge discriminating ability of the membrane was evaluated by KCl diffusion potential measurements. The results indicate that all epithelia under investigation possess a relatively high degree of permeation barrier and are highly selective for the absorption of positively charged solutes. Shunt path permeability was found to vary greatly among tissues from different epithelia, whereas membrane charge selectivity was relatively constant in these tissues. A good correlation was observed between membrane electrical conductance and steady-state flux of CF, indicating a paracellular transport of the compound. The rank order of the intrinsic membrane permeability was as follows: intestinal approximately nasal greater than or equal to bronchial greater than or equal to tracheal greater than vaginal greater than or equal to rectal greater than corneal greater than buccal greater than skin. Membrane permselectivity, expressed as the ratio of transport number (positive over negative), ranges from 1.78 for the buccal to 1.33 for the rectal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of bisbenzylisoquinoline alkaloids on alveolar macrophages: correlation between binding affinity, inhibitory potency, and antifibrotic potential.

The Chinese have conducted extensive studies concerning the medicinal properties of plant products. In this investigation the ability of three bisbenzylisoquinoline alkaloids to inhibit particle-induced activation of alveolar macrophages was evaluated and this inhibitory potential was correlated with the ability of those drugs to bind to membrane components. Tetrandrine, i.e., an herbal medicine used as an antifibrotic agent in China, was a potent inhibitor of particle-stimulated oxygen consumption, superoxide release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine also exhibited substantial binding affinity for membrane lipids and alveolar macrophages. In contrast, tubocurine, an analogue with little antifibrotic potential, exhibited low binding affinity and had little effect on macrophage activation. Methoxyadiantifoline, an alkaloid of unknown antifibrotic potential, exhibited inhibitory and binding properties similar to those of tetrandrine. The data indicate that a strong relationship exists between the antifibrotic potential of these alkaloids and their ability to bind to alveolar macrophages and inhibit particle-induced activation of these phagocytes. These drugs should serve as useful probes to evaluate the role of alveolar macrophages in pulmonary fibrosis.

Administration, Oral↗