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Biomedical subjects

S M Pond

Publications and source records attributed to S M Pond.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pretreatment with drug-specific antibody reduces desipramine cardiotoxicity in rats.

The effect of a drug-specific antibody on desipramine (DMI) cardiotoxicity was studied in rats. Animals were pretreated i.v. with 4.2 g/kg of a monoclonal antibody (anti-TCA) followed by DMI HCl 30 mg/kg i.p. (molar ratio of anti-TCA binding sites to DMI = 0.56). Peak QRS complex prolongation was substantially lower after pretreatment with anti-TCA than after control antibody (70 +/- 14 v. 21 +/- 4%, p less than 0.001). Time to peak toxicity was the same in both groups. Binding of DMI by anti-TCA was demonstrated by a higher serum total DMI concentration and increased DMI binding in serum after anti-TCA compared to controls. The DMI concentration in anti-TCA treated animals was lower in some organs (brain, lung, liver, spleen), but not in others (heart, muscle, kidney, fat). The calculated fraction of the DMI dose bound by anti-TCA was 19.9%. The steepness of the DMI dose-response curve was examined by administering DMI alone (without antibody) at various doses to rats. Compared to 30 mg/kg DMI, a dose reduction of 30-50% was needed to reduce QRS duration to the same extent as anti-TCA pretreatment. We conclude that DMI cardiotoxicity was markedly reduced by the binding of a relative small fraction of the DMI body burden to anti-TCA. This disproportionate effect of DMI binding was not due to the steepness of the DMI dose-response curve, nor to slowing of the rate of DMI distribution to tissues.

Animals↗
PubMed1991

Adaptation of the Müller method to allow quantitative characterization of the affinity and cross-reactivity of antibodies by competitive radioimmunoassay.

A quantitative expression is derived for the evaluation of antigen-antibody affinity constants from radioimmunoassays for the completely general situation in which antigen and antibody are both multivalent. The theoretical analysis is then extended to encompass quantitative characterization of the competitive inhibition observed in screening tests for cross-reactivity of antibody with structural analogs of the eliciting antigen. These procedures are illustrated with a radioimmunological study of the cross-reactivity of a desipramine-elicited monoclonal antibody with other tricyclic antidepressants. An unexpected finding to emerge from this immunochemical study is the demonstration that a single affinity constant suffices to describe the interaction of desipramine with a polyclonal antibody elicited by this univalent antigen.

Antibody Affinity↗
PubMed1991

Drug-specific F(ab')2 fragment reduces desipramine cardiotoxicity in rats.

Current therapy for cardiotoxicity due to tricyclic antidepressant (TCA) overdose is often ineffective in seriously poisoned patients. We studied the effect of a drug-specific antibody fragment on TCA cardiotoxicity in rats. Animals received anti-TCA F(ab')2 2.0 g/kg i.v. over 10 min starting 15 min after administration of a toxic dose of desipramine (DMI). This anti-TCA F(ab')2 dose was 36.9% of the molar DMI dose in terms of binding sites. Anti-TCA F(ab')2 infusion had no adverse effects and rapidly reduced DMI induced QRS prolongation compared with control F(ab')2 (23 +/- 14 vs 71 +/- 11% QRS prolongation at the end of infusion, P less than 0.001). This beneficial effect lasted for the 45 min duration of the study. Markedly enhanced DMI binding in serum after anti-TCA F(ab')2 was demonstrated by a 48-fold increase in the total DMI concentration over controls and a reduction in the fraction of unbound DMI (44.5 +/- 19.4 vs 0.7 +/- 0.2%). Anti-TCA F(ab')2 reduced the DMI concentration in brain but not in other organs. We conclude that anti-TCA F(ab')2 substantially reduces DMI cardiotoxicity in rats, and does so rapidly enough to be of potential clinical benefit for patients with DMI overdose. Because only a small fraction of the DMI dose was bound by antibody, these data suggest that antibody fragment doses considerably less than equimolar to the DMI dose may be effective in treating DMI cardiotoxicity.

Animals↗
PubMed1991

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4-hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM for both reactions. 6. Anti-rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7. These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.

Binding, Competitive↗
PubMed1991

Diflunisal and its conjugates in patients with renal failure.

Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated diflunisal clearance (by overestimation of plasma diflunisal concentrations through unrecognized acidic hydrolysis of diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.

Adult↗
PubMed1991

Effects of nifedipine on psychosis and tardive dyskinesia in schizophrenic patients.

In an open label study, two fixed doses of nifedipine (30 mg and 60 mg daily) were added to the usual antipsychotic drug treatments of 10 patients suffering from chronic schizophrenia. While no patient experienced significant improvements, statistically significant falls in Brief Psychiatric Rating Scales scores were observed. A significant reduction in Abnormal Involuntary Movement Scale scores was observed in those patients with tardive dyskinesia. After the addition of nifedipine, four of the 10 patients showed large increases in plasma neuroleptic activity (radioreceptor assay) that decreased to baseline levels within two weeks. The possibility that this represents competitive inhibition and subsequent induction of the liver metabolism of the antipsychotic drugs is discussed. Adverse effects encountered are also discussed.

Adult↗
PubMed1990

The importance of electrostatic interactions in the binding of paraquat to its elicited monoclonal antibody.

In this study the pH-dependent interactions interactions between a paraquat-specific murine monoclonal antibody and two antigens: paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride), and a p-nitrophenol analogue (1-(N-methyl-4,4'-bipyridinium)-1-(2-hydroxy-5-nitrophenyl)methane dichloride; PQNP) were determined by ELISA. In each case the KAS-pH profile reflected the titration of a single amino acid residue. pK'a values derived from these plots were 8.90 (paraquat) and 8.13 (PQNP). Increasing pH led to a significant increase in the association constant for each antibody complex. A spectrophotometric titration of PQNP in the presence and absence of excess antibody indicated the presence of another charged amino acid residue at the binding site, which could be assigned as a carboxylic acid. From these studies, a model for paraquat-antibody binding has been proposed.

Animals↗
PubMed1990

Efficacy of single or repeated hemoperfusion in a canine model of paraquat poisoning.

Although hemoperfusion has been used to treat paraquat poisoning, its efficacy has been widely debated. This study examines the kinetic and pathologic correlates of paraquat toxicity and hemoperfusion and the efficacy of hemoperfusion in four groups of four dogs. This species was chosen because the kinetics and toxicity of paraquat are similar to those in the human. All dogs given a lethal dose of paraquat dichloride producing 100% mortality as a 2-hr infusion (7.48 mg of paraquat ion per kg) developed the typical clinical, laboratory and pathologic features of paraquat toxicity and died within 5 to 7 days. All dogs given paraquat and hemoperfused for 8 hr daily, beginning at 12 hr, died within 3 to 6 days. Two of four dogs which were hemoperfused once, beginning at 2 hr, survived. One dog in the repeated hemoperfusion only group died from blood loss. Negligible amounts of paraquat (0.4-2.0% of the total dose) were adsorbed during repeated hemoperfusion because of extensive excretion of paraquat in urine and sequestration in peripheral tissues from which redistribution was slow. The efficacy in the single early hemoperfusion group can be attributed to removal of 25% of the dose by the procedure in the two survivors. We conclude that single hemoperfusion may have some clinical application in patients who present within a few hours of the ingestion and have not ingested a dose of paraquat that is multiples of the lethal dose producing 100% mortality. It is doubtful if there is any role for repeated hemoperfusion.

Absorption↗
PubMed1989

Concurrent determination of hepatic bioavailability of salicylamide by three techniques in the dog.

Three methods of measuring hepatic first-pass metabolism of salicylamide in dogs that had undergone portacaval transposition were compared. The drug in both its radiolabeled (0.74 MBq) and unlabeled (20 mg/kg) forms was infused concurrently into forelimb and hindlimb veins, respectively. Because of the transposition, drug from the hindlimb is subject to first-pass metabolism in the liver. Bioavailability is a complementary measure of the extent of this metabolism. The three methods of determining bioavailability were continuous withdrawal of blood to determine the ratio of the areas under the plasma concentration versus time curves, ratio of specific activities in plasma after all the drug had been administered, and the conventional method, measurement of the ratio of areas determined from sequential plasma concentrations. The three techniques were found to give virtually identical values for bioavailability. Each method has its own advantages, limitations, and possible applications. The continuous withdrawal technique is potentially most applicable for drugs with short half-lives. The ratio of specific activities may be the preferred method for drugs with long half-lives. The conventional method is limited by the number of samples needed, but is potentially useful under those conditions in which data following test and intravenous routes of administration are available.

Animals↗
PubMed1989

Purification and characterization of two human liver carboxylesterases.

1. Two carboxylesterases (EC 3.1.1.1) purified from human livers were distinguished by pI (isoelectric point), nondenaturing polyacrylamide gel electrophoresis, molecular weight, catalytic activity, N-terminus and immunological cross-reactivity. 2. The low pI carboxylesterase has not been reported previously. 3. Numerous bands seen when each enzyme was focused on analytical IEF gels could not be separated. 4. When sections of the band pattern was refocused, the original complete band pattern was generated. 5. Both the mid and low pI carboxylesterases had catalytic activity for xenobiotics as well as medium and long chain fatty acid esters.

Amino Acid Sequence↗
PubMed1989

Effects of paraquat on canine bronchoalveolar lavage fluid.

Bronchoalveolar lavage (BAL) recovers the epithelial lung fluid of the lower respiratory tract. In this study, we have used BAL to detect early pulmonary injury in beagle dogs following an intravenous infusion of 10 mg paraquat dichloride/kg bodyweight. Bronchoalveolar lavage was performed twice in 11 dogs, 60 hr before and 34 hr after an intravenous infusion of paraquat dichloride (n = 8) or saline (n = 3). The dogs were studied in three groups: (1) paraquat only (n = 4); (2) paraquat plus hemoperfusion (n = 4); and (3) hemoperfusion only (n = 3). Because hemoperfusion, a treatment used for paraquat poisoning, could have effects on BAL independent of paraquat, we evaluated the effects on BAL fluid of this procedure performed separately from and together with administration of paraquat. We examined cytology, proteins, enzymes, and glutathione in the BAL fluid and expressed all results per milliliter of aspirated lavage fluid. Hemoperfusion did not alter the BAL fluid. In contrast, in dogs studied 34 hr after administration of paraquat, total cell counts, alveolar macrophage and neutrophil counts, and concentrations of total protein, albumin, ACE, LDH, and ALP were increased. Bronchoalveolar lavage in the dog provides an excellent tool with which to detect early paraquat-induced pulmonary injury. The same technique could be useful for sequential monitoring of other types of pulmonary disease and injury.

Acetylcholinesterase↗
PubMed1989

Activation of the food-derived mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by rabbit and human liver microsomes and purified forms of cytochrome P-450.

The specificity of rabbit cytochrome P-450 involved in the mutagenic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was assessed using control and induced rabbit liver and lung microsomes, and six purified forms of cytochrome P-450. The number of revertants produced/2.5 micrograms PhIP by control rabbit liver was 260 +/- 196/10 micrograms of microsomal protein (mean +/- SD; n = 3), and this increased to 1265 +/- 248 when 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced liver microsomes were used as the activation source in the Ames test. Microsomes form phenobarbital-, rifampicin- and acetone-pretreated rabbits showed no increase in activity over controls. Control lung microsomes did not activate PhIP to a mutagen, whereas TCDD-induced lung microsomes produced 1443 +/- 136 (mean +/- SD; n = 4) Ames/Salmonella revertants/100 micrograms protein. In reconstitution experiments cytochrome P450 forms 4 and 6 were found to be efficient activators of PhIP to a mutagen Form 6 was 3.1-fold more active than form 4 and produced 4577 revertants/10 pmol with a 20-min preincubation step in the Ames test. Cytochrome form 5 produced 17 revertants/10 pmol and forms 2, 3b and 3c were not active in metabolizing PhIP to a mutagen. A highly significant statistical correlation existed between the capacity of control and induced liver microsomes to activate PhIP to a mutagen and their cytochrome P-450 form 4 (r = 0.97, r2 = 0.94) and form 6 (r = 0.95, r2 = 0.90) content. These data strongly support the involvement of polycyclic hydrocarbon-inducible forms of cytochrome P450 in the activation of PhIP in the rabbit. Anti-rabbit forms 4 and 6 IgGs recognized proteins in seven human liver microsomes of comparable mol. wt to rabbit cytochrome P-450 forms 4 and 6. However, no correlation existed between the content of these proteins and the capacity of human liver microsomes to activate PhIP.

Animals↗
PubMed1989

Albumin enhances unidirectional fluxes of fatty acid across a lipid-water interface: theory and experiments.

The effect of albumin concentration on the unidirectional fluxes of [3H]oleate across a lipid-water interface was measured by using a new model system consisting of a lipid phase (n-decane) separated from a stirred buffer phase by a planar interface. Albumin (0.15 mM) enhanced the flux of oleate from the lipid phase more than 30-fold. A similar increase in the oleate flux into the lipid was seen when the aqueous oleate and albumin concentrations were increased while keeping the unbound oleate concentration fixed. The ratio of the unidirectional fluxes was constant over the range of albumin concentrations investigated (1-100 microM). Analysis using rigorous rate theory indicated that the permeability of the interfacial surface was flux-limiting at high albumin, whereas diffusion across the unstirred water layer was flux-limiting at low albumin. The observed kinetic patterns are similar to results previously reported in cellular transport systems and attributed to specialized mechanisms for cellular uptake from the albumin-bound pool.

Carrier Proteins↗
PubMed1988

Biliary excretion of diflunisal conjugates in patients with T-tube drainage.

The urinary and biliary excretion of diflunisal and its glucuronide and sulphate conjugates were studied in 10 patients following cholecystectomy. Total urinary excretion (0-24 h) was 36.6 +/- 16.4% of the 250 mg dose. Biliary excretion (0-24 h) was restricted to the phenolic and acyl glucuronides and accounted for 3.7 +/- 2.3% of the dose. An inverse relationship existed between urinary and biliary excretion of diflunisal and its conjugates. The data indicate that the reduced plasma clearance of diflunisal in patients with renal failure may, at least in part, be due to increased biliary excretion of diflunisal glucuronides followed by hydrolysis in the gut and reabsorption of diflunisal i.e. enterohepatic cycling.

Adult↗
PubMed1988

Clinical applicability of current pharmacokinetic models: splanchnic elimination of 5-fluorouracil in cancer patients.

What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of Vmax/Q = 48.0 +/- 11.6 (SD) microM for the pooled data set, where Vmax is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave Km = 9.4 microM, while the undistributed sinusoidal perfusion model gave Km* = 26.5 microM. With these values of Km, both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were Vmax/Q = 41.0 +/- 5.1 (sem) microM, Km = 8.4 +/- 1.3 microM and Km* = 23.2 +/- 3.2 microM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant Km+ (Km+ less than or equal to Km*). A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields Km+ values for individual patients which have a mean of 20.3 +/- 2.8 microM.

Fluorouracil↗
PubMed1988

Time-dependent, plasma-sulfate-independent kinetics of salicylamide in dogs.

The mechanisms of the dose-dependent elimination kinetics of salicylamide in dogs were examined. Salicylamide was infused continuously over three consecutive 90-min periods. The rates of infusion during Periods I and III were the same. During Period II the infusion rate was 2.5-fold higher. Plasma concentrations of inorganic sulfate were kept constant by the administration of exogenous sulfate. The plasma concentrations of salicylamide, which reached steady state during Period I but not during II or III, were twice as high at the end of Period III than those at the end of Period I. Typical Michaelis-Menten kinetics do not explain these results. When salicylamide was given as 40 mg/kg single oral dose, clearance of an intravenous tracer dose of radiolabeled salicylamide was greatly reduced within 10 min but returned to baseline values by 240 min after the oral dose, despite persistently low plasma concentrations of inorganic sulfate. Therefore, dose- and time-dependent factors other than Michaelis-Menten kinetics, depletion of inorganic sulfate concentrations, and rate limitation of supply of "active sulfate" from plasma inorganic sulfate stores produce the dose- and time-dependent kinetics of salicylamide in the dog. Product inhibition of salicylamide sulfoconjugation remains a possible explanation.

Administration, Oral↗
PubMed1988

Non-linear hepatic first-pass metabolism of salicylamide in dogs after portacaval transposition.

The effect of the rate of input of salicylamide into the portal vein of dogs on the clearance and bioavailability of the drug was examined. The four dogs had undergone portacaval transposition so that a hindlimb infusion delivered the drug directly and only into the liver. On separate occasions, salicylamide, 20 mg/kg, was infused into a hindlimb vein at three different rates, the duration of each infusion was 3, 10, and 30 min. Simultaneously, to measure the bioavailability, 14C-salicylamide was infused at the same rate into a forelimb vein. As the duration of the infusion was increased from 3 to 30 min, the clearance of salicylamide increased significantly from 1.05 +/- 0.21 (mean +/- SD) to 1.57 +/- 0.38 L/min and the half-life decreased significantly from 14.66 +/- 3.60 to 9.09 +/- 2.42 min. Bioavailability decreased from 0.84 +/- 0.11 to 0.61 +/- 0.61, but the differences were not statistically significant. As predicted for a drug that has nonlinear clearance and bioavailability, the rate of infusion of salicylamide affects the values of these parameters.

Animals↗