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Biomedical subjects

T J Maher

Publications and source records attributed to T J Maher.

At least 37 records · Page 2Linked to original sources
PubMed1999

Synergistic interactions between fenfluramine and phentermine.

'Fen-phen' refers to the off-label combination of the appetite suppressants fenfluramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fenfluramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may reflect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fenfluramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.

Animals↗
PubMed1998

Extracellular glutamate increases in rostral ventrolateral medulla during static muscle contraction.

The ventrolateral medulla is an important site involved in increases in arterial pressure and heart rate during static muscle contraction. Glutamate, an excitatory amino acid neurotransmitter, appears to play a role in mediating these responses. We measured glutamate concentration in the extracellular fluid of the rostral ventrolateral medulla during static muscle contraction in anesthetized rats. A 2-min tibial nerve stimulation-evoked muscle contraction increased blood pressure by 30 +/- 4 mmHg and heart rate by 32 +/- 4 bpm. Extracellular glutamate in the rostral ventrolateral medulla also increased from 9 +/- 1 pmol/4 microl to 14 +/- 1 pmol/4 microl. Results were repeatable over two subsequent contractions. Tibial nerve stimulation following neuromuscular blockade did not elicit changes in blood pressure, heart rate or extracellular fluid glutamate. Data demonstrate that muscle contraction increases extracellular fluid concentration of glutamate in the rostral ventrolateral medulla, suggesting that rostral ventrolateral medullary glutamate release is a neurochemical change associated with cardiovascular responses during static muscle contraction.

Animals↗
PubMed1998

Use of a hemoglobin-trapping approach in the determination of nitric oxide in in vitro and in vivo systems.

We describe methods for measuring the release of nitric oxide (NO) derived from organic nitrates in vitro, using triple wavelength and difference spectrophotometry in the presence and absence of concentric microdialysis probes. These methods are based on the ability of NO to oxidize oxyhemoglobin (OxyHb) to methemoglobin (MetHb) quantitatively in aqueous solution. Isosorbide dinitrate (ISDN), a thiol-dependent organic nitrate, increased MetHb concentration in 45 min from 2.47 +/- 0.47 to 4.15 +/- 0.12 microM (p < 0.05) and decreased OxyHb concentration from 2.13 +/- 0.35 to 0.33 +/- 0.26 microM (p < 0.05) at 37 degrees C. At 27 degrees C, the OxyHb concentration was not significantly altered (2.04 +/- 0.23 to 1.60 +/- 0.04 microM) by ISDN, nor was the MetHb concentration (from 2.68 +/- 0.50 to 2.59 +/- 0.25 microM). Sodium nitroprusside (SNP), a thiol-independent organic nitrate, increased MetHb concentrations in 30 min from 4.21 +/- 0.26 to 6.00 +/- 0.56 microM (p < 0.05) at 37 degrees C, and from 4.23 +/- 0.39 to 5.90 +/- 0.43 microM (p < 0.01) at 27 degrees C. SNP also decreased OxyHb concentrations in 30 min from 1.99 +/- 0.32 to 0.13 +/- 0.12 microM (p < 0.01) at 37 degrees C, and from 2.25 +/- 0.31 to 0.13 +/- 0.09 microM (p < 0.01) at 27 degrees C. Difference spectrophometry indicated that 0.25-5 mM SNP significantly increased NO production in a dose-dependent fashion. This hemoglobin-trapping technique was also useful in quantifying the concentrations of NO released from SNP in aqueous solution in vitro, using concentric microdialysis probes. The NO concentration following exposure to SNP was 530 +/- 50 nM, as determined using the difference spectrophotometric technique. To demonstrate the applicability of this technique to in vivo microdialysis, we implanted concentric microdialysis probes into hippocampus and cerebellum of conscious and anesthetized rats. Baseline NO concentrations in hippocampus of conscious and anesthetized rats were 11 +/- 2 nM and 23 +/- 9 nM, respectively, while in the cerebellum NO concentrations were 28 +/- 9 nM and 41 +/- 20 nM, respectively. These results demonstrate that microdialysis using a novel hemoglobin-trapping technique possesses adequate sensitivity to measure the NO levels produced from organic nitrates in aqueous solutions, and further document the applicability of this approach to in vivo systems.

Anesthesia, General↗
PubMed1998

Involvement of nitric oxide in the mediation of NANC inhibitory neurotransmission of guinea-pig trachea.

1. The involvement of nitric oxide (NO) in the non-adrenergic non-cholinergic inhibitory (NANC-i) neurotransmission was evaluated in guinea-pigs anaesthetized with chloralose-urethane, using a tracheal pouch preparation. 2. The tracheal pouch, a surgically isolated segment of trachea with intact nerve and blood supply, is an in situ method to demonstrate NANC-i response after complete cholinergic and adrenergic blockade using atropine (5 mg kg(-1)) and propranolol (1 mg kg(-1)), respectively. Cervical vagi and sympathetic trunks were isolated and cut cranially. The distal ends of the vagi were positioned on bipolar electrodes for subsequent stimulation with 5 V pulses for 2 ms duration at 15 Hz for a total of 90 s. The relaxation response was measured as a pressure drop (cm of H2O) in the pouch. Each experimental group was composed of six animals. 3. NANC-i responses to two consecutive nerve stimulations at 25 min apart were reproducible. 4. Pouch relaxation responses to electrical nerve stimulations were determined before and after incubation of the pouch with N(omega)-nitro-L-arginine methyl ester (L-NAME; 10(-5) M), a NO synthase (NOS) inhibitor, for 30 min. L-NAME significantly, but not completely, inhibited the NANC-i response of the pouch, suggesting involvement of NO in the NANC-i neurotransmission. 5. The pouch relaxations to vagal stimulations were inhibited significantly after incubation with oxyHb indicating that NO was released. 6. The amount of methaemoglobin (metHb) formed from oxyhaemoglobin (oxyHb) during vagal stimulation was measured by spectrophotometry. Comparison of the values between the control and after nerve stimulation indicated a trend (P = 0.07) toward greater metHb formation in the pouch perfusate after nerve stimulation. 7. NANC-i responses were not significantly inhibited by incubation of the pouch with either of the guanylate cyclase inhibitors, methylene blue or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). However, a trend toward significance (P < or = 0.07) was observed. 8. This study demonstrated that NO is involved in NANC-i neurotransmission. However, the findings did not conclusively support the contention that NO is the sole neurotransmitter of NANC inhibition. It is possible that NO produced relaxation of guinea-pig trachea through a cGMP-independent mechanism.

Animals↗
PubMed1997

Improved method for the estimation of hydroxyl free radical levels in vivo based on liquid chromatography with electrochemical detection.

Free radical damage to proteins, lipids, DNA and RNA has been thought to play an important role in many diseases as well as the aging process. One free radical, the hydroxyl free radical (HFR), is extremely reactive and is difficult to measure directly. HFRs were quantified by measuring the hydroxylation products 2,3- and 2,5-dihydroxybenzoic acids (DHBAs) formed as a result of the reaction between HFR and systemically administered salicylate (SAL). DHBAs and SAL concentrations were determined using RP-HPLC with dual coulometric electrode detection. The method has limits of detection of 1 pg for the DHBAs and 100 pg for SAL (signal-to-noise ratio 3:1). A detailed interference study as well as analyte stability and linearity studies were performed. This method was used to determine basal ratios of DHBA/SAL in a variety of tissues and to study the effects of glutamatergic and dopaminergic drugs on DHBA/SAL ratios in brain region homogenates.

Animals↗
PubMed1997

Enhancement of lithium elimination by multiple-dose sodium polystyrene sulfonate.

OBJECTIVE: To determine whether multiple doses of sodium polystyrene sulfonate (SPS) enhance the elimination of IV-administered lithium (Li). METHODS: The study was a placebo-controlled, investigator-unblinded, murine trial of multiple doses of SPS on serum Li concentrations. Seventy-five male CD-1 mice were given IV pretreatment with LiCl (125 mg/ kg) followed by gavage treatments with SPS (5 g/kg/dose) 20, 40, 90, 150, and 210 minutes after LiCl (experimental group) or deionized water at equivalent times (control group). Subgroups of each treatment group were sacrificed at 1, 2, 4, and 6 hours after LiCl administration and blood was collected for Li analysis. RESULTS: Statistical analyses indicated that the SPS group had lower serum Li concentrations overall than did the control animals. This difference was apparent at the 2-, 4-, and 6-hour time points. CONCLUSION: In this murine model, repetitive doses of orogastric SPS enhanced the elimination of parenterally administered Li.

Administration, Oral↗
PubMed1996

Sodium polystyrene sulfonate treatment for lithium toxicity: effects on serum potassium concentrations.

OBJECTIVE: To examine the effects of sodium polystyrene sulfonate (SPS) on serum potassium (K) concentrations in mice pretreated with parenteral lithium (Li). METHODS: A placebo-controlled murine model trial of SPS therapy following IV Li was performed. Sixty male CD-1 mice weighing 18-22 g were administered either IV LiCl (125 mg/kg) or a control solution (normal saline). Half of the mice in each of these groups were then given orogastric water 20, 40, 90, 150, and 210 minutes after LiCl or normal saline; the other half received SPS (5 g/kg/dose) at equivalent times. Subgroups of each of these four groups were sacrificed at one, two, and six hours after pretreatment and the serum was analyzed for K concentration. Serum K concentrations for the various groups were compared with analysis of variance and Newman-Keuls tests for the comparison of multiple means. RESULTS: A statistically significant reduction of serum K concentrations occurred in the animals that received SPS treatment following either IV saline or LiCl solutions. The degree of K reduction that resulted from the combination of LiCl and SPS treatment (35% reduction at six hours, compared with the placebo-treated controls) was larger than that which resulted from either IV Li with oral water (15% reduction) or IV saline with oral SPS (20% reduction). CONCLUSIONS: These findings suggest that development of hypokalemia may represent a potential limitation in the use of SPS in the treatment for Li toxicity.

Analysis of Variance↗
PubMed1995

Effect of delayed treatment with sodium polystyrene sulfonate on serum lithium concentrations in mice.

OBJECTIVES: To determine the efficacy of sodium polystyrene sulfonate (SPS) in lowering serum lithium (Li) concentrations. Specifically, to determine the effects of both different doses of SPS and different times to treatment with SPS on serum Li levels. METHODS: The study was a controlled, single-dose murine trial of SPS on serum Li levels. Male CD-1 mice (n = 525) were given orogastric LiCl and then divided into three main treatment groups: group SPS received a single orogastric administration of SPS in a dose of 5 gm/kg body weight at either 0, 15, 30, 45, or 90 minutes after LiCl; group half-SPS received a single orogastric administration of SPS in a dose of 2.5 gm/kg body weight at times equivalent to those of group SPS; and the control group received orogastric deionized water in a volume equivalent to that of group SPS at 0, 15, 30, 45, or 90 minutes after LiCl. Subgroups of seven to ten mice in each of the four treatment groups were sacrificed at one, two, four, and eight hours after administration of LiCl, and their blood was analyzed for Li concentration. RESULTS: 1) Single doses of SPS significantly lowered serum Li concentrations; 2) this effect was dose-related; 3) the delays in administration of SPS used in this study did not significantly reduce its ability to lower serum Li concentrations; and 4) even when administered after peak serum Li concentrations had been achieved, a single dose of SPS was effective in lowering serum Li levels. CONCLUSIONS: SPS may be efficacious in the treatment for Li toxicity under certain circumstances, even when there is delay to treatment. Additional study is warranted to further characterize the ability of SPS to alter Li kinetics.

Administration, Oral↗
PubMed1994

L-tyrosine potentiation of opioid-induced analgesia utilizing the hot-plate test.

The effects of L-tyrosine (L-TYR) on the analgesic activity of several opioids were determined utilizing a hot-plate test. L-TYR (200 mg/kg) significantly potentiated (P < .05) the analgesic activity of morphine sulfate (10 mg/kg) and codeine sulfate (30 mg/kg). The opioid-induced analgesia and its potentiation by L-TYR was abolished by naloxone pretreatment. Increasing the dose of L-TYR (25-200 mg/kg) resulted in a dose-dependent potentiation of morphine-induced analgesia. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine attenuated this potentiation. With the exception of L-tryptophan, all other L-amino acids, as well as D-TYR, failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment, the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. These results demonstrate that L-TYR dose dependently potentiates the analgesic activity of opioids and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response.

Analgesia↗
PubMed1993

Comparison between phenylpropanolamine and structurally related compounds on gastric transit in the rat.

Our laboratory previously reported several pharmacological differences between phenylpropanolamine [PPA; (+/-)-norephedrine] and its structurally related compounds in regard to their activity on cardiovascular and appetite-suppressant parameters. The present study investigates the pharmacological differences between PPA, [1R,2R]-(-)-norephedrine [(-)-NOR], [1S,2S]-(+)-norephedrine [(+)-NOR], [1R,2S]-(-)-ephedrine [(-)-EPH], [1S,2R]-(+)-ephedrine [(+)-EPH], [1R,2S]-(-)-norpseudoephedrine [(-)-NORP], [1S,2R]-(+)-norpseudoephedrine [(+)-NORP], [1R,2R]-(-)-pseudoephedrine [(-)-PSE], and [1S,2S]-(+)-pseudoephedrine [(+)-PSE], as determined by their ability to inhibit gastric transit in the rat. (-)-Norephedrine was approximately three times more potent in inhibiting gastric transit than (+)-NOR (p < 0.01). As anticipated, the racemic mixture, PPA, demonstrated an ED50 (25.1 mg/kg) of approximately the mean of the ED50s from the component enantiomers (14.7 and 47.0 mg/kg, respectively). Similarly, administration of 20 mg/kg of either (-)-EPH, (+)-EPH, (-)-PSE, or (+)-PSE significantly decreased gastric transit by 26% (p < 0.001), 12% (p < 0.01), 10% (p < 0.01), and 11% (p < 0.01), respectively. Administration of (-)-NORP and (+)-NORP were without effect. These data confirm and extend previous findings demonstrating pharmacological differences between PPA and its structurally related compounds.

Animals↗
PubMed1993

Cholestyramine as an adsorbent in acute lindane poisoning: a murine model.

STUDY OBJECTIVES: To compare the effectiveness of single-dose cholestyramine versus single-dose activated charcoal in preventing clinical toxicity after acute lindane ingestion. DESIGN: CD-1 mice received lindane by enteral (gavage) and parenteral (intraperitoneal) routes, followed by enteral administration of either cholestyramine (2.25 g/kg) or activated charcoal (2.25 g/kg), with subsequent observation for convulsions and death. MEASUREMENTS: The doses of lindane at which 50% of mice developed convulsions (CD50) and at which 50% of mice died (LD50) were established and compared among control, charcoal-, and cholestyramine-treated groups. RESULTS: For lindane administered by gavage, the differences in the CD50 and LD50 between the control and the activated charcoal groups were not statistically significant. However, a significant difference did exist in both the CD50 and the LD50 between the group receiving cholestyramine and the control group and between the cholestyramine and activated charcoal groups. After IP administration of lindane, the difference in CD50 or LD50 among control, activated charcoal, or cholestyramine groups was not significantly different. CONCLUSION: In the murine model, cholestyramine is more effective than activated charcoal in preventing absorption of lindane, thus preventing convulsions and death. These data support the need for clinical studies to determine whether cholestyramine may be a more effective treatment than activated charcoal for acute lindane ingestions in human beings.

Acute Disease↗
PubMed1993

Determination of kainic acid-induced release of nitric oxide using a novel hemoglobin trapping technique with microdialysis.

We have demonstrated the usefulness of a novel hemoglobin-trapping technique to quantify nitric oxide (NO) concentrations in vivo. Concentric microdialysis probes were implanted into the hippocampus of rats under urethane anesthesia and perfused with 1 microM oxyhemoglobin in artificial CSF to sequester NO in extracellular fluid. The concentration of methemoglobin was then determined spectrophotometrically. The basal level of NO in hippocampus was 2.2 +/- 0.5 nM (in vitro sensitivity of the probe was 0.2 nM). Administration of 13 mg/kg, i.p., of kainic acid (KA) produced a maximal 5.3-fold increase at 100 min in NO levels (11.8 +/- 0.2 nM). This response was significantly attenuated by pretreatment with the NO synthase inhibitor N-monomethyl-L-arginine (50 mg/kg, 30 min before KA). These results demonstrate that a microdialysis probe using a novel hemoglobin-trapping technique possesses adequate sensitivity to determine the basal levels of NO and document the ability of KA to increase these levels via a NO synthase-mediated mechanism.

Animals↗
PubMed1993

Extra-nodal monocytoid B-cell lymphoma of the urinary bladder.

Monocytoid B-cell lymphoma (MBCL) is a low-grade neoplasm considered to be the neoplastic counterpart to monocytoid B-lymphocytes, derived from marginal zone lymphocytes. Recently, a 72-yr-old woman presented with urinary symptoms of burning, urgency, and hematuria. Examination of the urinary bladder revealed the presence of an exophytic mass at the bladder base. This lesion was grossly suspected of being a transitional cell carcinoma, but on initial histologic examination it was found to be lymphoma composed of cells with moderately abundant cytoplasm and an overall size reminiscent of a large cell type. Detailed histologic examination led to a diagnosis of MBCL in this submucosal site. Clinical staging showed no evidence of lymphoma in other organs and the patient responded to therapy for non-Hodgkin lymphoma (NHL). This case represents an unusual presentation of low-grade NHL and may be consistent with previous suggestions of a relationship between MBCL and lymphomas of mucosa-associated lymphoid tissue.

Aged↗
PubMed1993

Effect of phenylpropanolamine and related compounds on beta-adrenoceptor-induced activation of adenylyl cyclase.

While oral administration of therapeutic doses of phenylpropanolamine (PPA) does little to cardiovascular function in humans, intravenous doses administered to experimental animals are known to alter heart rate and blood pressure. Previous in vivo and in vitro studies have documented a beta-adrenoceptor agonist action for PPA and thus it was of interest to investigate whether these effects could be partially mediated by a direct interaction with beta-adrenoceptors. Phenylpropanolamine, [1R, 2R]-(-)-norephedrine, [1S, 2S]-(+)-norephedrine, [1S, 2R]-(+)-norpseudoephedrine, [S]-(+)-amphetamine, and [1R, 2S]-(-)-ephedrine, were compared with the known beta-adrenoceptor agonists [R]-(-)-epinephrine (EPI), [R]-(-)-norepinephrine (NE), and [R*, S*]-(+/-)-isoproterenol (ISO) for their ability to increase the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cAMP) in minces of rat heart. Of the compounds investigated only NE, EPI, and ISO, as well as, forskolin, which directly stimulates adenylyl cyclase, significantly (p < 0.05) increased intracellular levels of cAMP. The other phenethylamines were without effect. The results of this study demonstrate that PPA and its diastereomers do not act directly at beta-adrenoceptors to alter cardiac function and supports the hypothesis that significant agonist activity of beta-phenethylamines at the beta-adrenoceptor requires phenolic/aryl ether substitution on the phenyl-ring (typically positions 3, 4 and/or 5).

Adenylyl Cyclases↗
PubMed1992

Effects of L-tyrosine on mixed-acting sympathomimetic-induced pressor actions.

We previously reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including [R*S*]-(+/-)-norephedrine [phenylpropanolamine (PPA)], [1R,2S]-(-)-ephedrine (EPH), and [S]-(+)-amphetamine (AMPH) in hyperphagic rats. Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid that competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. Additional studies demonstrated the inability of L-TYR to alter the peripherally mediated PPA-, EPH-, and AMPH-induced increases in gastrointestinal transit time and retention and intrascapular brown adipose tissue thermogenesis. Because the mixed-acting sympathomimetics are known to increase blood pressure, these studies examined the ability of L-TYR to influence the pressor responses to PPA, EPH, and AMPH (0.03-1 mg/kg) in urethane-anesthetized rats. Each of the mixed-acting sympathomimetics significantly increased mean arterial, systolic, and diastolic blood pressures when administered alone, but no potentiation by L-TYR was observed. These results demonstrate the inability of L-TYR to potentiate the peripheral vasopressor effects of PPA, EPH, and AMPH. These data, in conjunction with our previous findings, suggest that the potentiation by L-TYR of the mixed-acting sympathomimetics is largely restricted to centrally mediated responses.

Amphetamine↗
PubMed1992

Multiple-dose sodium polystyrene sulfonate in lithium intoxication: an animal model.

Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N = 144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full-Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half-Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post-treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose-related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.

Animals↗
PubMed1991

Decreases in repetitive extrasystole threshold in the conscious pig with myocardial infarct were reversed by tyrosine.

Reports indicate that the administration of tyrosine, the precursor amino acid for catecholaminergic neurotransmitters, may be beneficial under conditions of physiologic stress. We studied the effects of tyrosine on vulnerability to ventricular arrhythmia in conscious pigs with healing myocardial infarcts, and sham operated (intact) pigs. Mean arterial pressure and heart rate were measured via chronically implanted aortic catheters. The repetitive extrasystole threshold (defined as the energy in milliamperes (ma) needed to cause a spontaneous ventricular beat following a premature beat induced by an electrical impulse), was measured via a bipolar pacing catheter placed during instrumentation surgery in the apex of the right ventricle. One week after infarct, the myocardial infarct group was studied before and ninety minutes after the administration of tyrosine (8 mg/kg iv). Before tyrosine, the myocardial infarct group had a significantly lower repetitive extrasystole threshold (12 +/- 1 ma) compared to the intact group (19 +/- 2 ma). Ninety minutes after tyrosine, the repetitive extrasystole threshold in the myocardial infarct group was 17 +/- 1 ma. The availability of tyrosine did not alter the repetitive extrasystole threshold in the intact group. Thus, vulnerability to ventricular arrhythmia was enhanced in pigs with recent myocardial infarction. Tyrosine, which can be nutritionally manipulated, may reduce myocardial vulnerability to arrhythmia after infarct.

Animals↗