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Biomedical subjects

E Kokue

Publications and source records attributed to E Kokue.

At least 55 records · Page 3Linked to original sources
PubMed1990

Use of a chronic ureter cannula in the pig for the determination of renal clearance.

The surgical implantation of chronic ureter cannula to determine the renal clearance was evaluated using 24 pigs. The silicon tubing was surgically implanted into both ureters of each pigs. Two types of thick tubing (the inside diameter 1.0 or 2.5 mm and the outside diameter 4.0 mm) were used for these cannulas. The tubing was exposed out of the pig's body on the flank, on the hypogastric zone near the umbilicus, or near the groin. The following steps were effective to minimize the opportunity of a bacterial infection in the kidney and to maintain the functional integrity of the chronic ureter cannula for as longer period as possible: 1) to use the tubing of larger opening as the ureter cannula, 2) to expose the tubing from the hypogastric zone near the groin, and 3) to apply the disinfectant frequently to the incision sites, cannula outlets and pig's metabolic cage. The oral ingestion of the GGES solution increased the urinary volume, which might in turn have resulted in the effective rinsing of the kidney and the chronic ureter cannula. The cannula served satisfactorily for more than 3 weeks in 13 of the pigs, up to a maximum of 7 weeks. The PSP clearances values were low during the first week of the postoperative period, which may be attributed to surgical stress. The chronic ureter cannula, associated with the postoperative period of more than 1 week, can be recommended for the evaluation of the renal clearance of drugs in the pig.

Animals↗
PubMed1989

Effect of albumin distribution. A simulation analysis of the effect of altered albumin distribution on the apparent volume of distribution and apparent elimination rate constant of drugs.

The effects of altered albumin distribution on the apparent volume of distribution (V) and the apparent elimination rate constant (kappa) of drugs were investigated by a simulation analysis. The Equations derived by Oie et al. were modified for this purpose. Within the range observed in normal healthy subjects and patients, the change in albumin distribution significantly affected V of drugs but, in general, not kappa. For drugs with more than 90% plasma-protein binding, V changed by more than 100%. The change in plasma-protein binding caused by an altered albumin distribution produced a greater effect on V than that caused by an altered albumin amount. These results suggest that albumin distribution is an important factor in controlling the kinetics of drugs which are highly bound to plasma protein. This is illustrated using midazolam as an example.

Blood Proteins↗
PubMed1989

Nonlinear pharmacokinetics of intravenous sulphadimethoxine and its dosage regimen in pigs.

The time courses of the total (Ct) and unbound plasma (Cf) concentration after the i.v. injection of 20, 50 and 100 mg/kg of sulphadimethoxine (SDM) were examined in pigs. The area under the Ct-time curve per unit dose decreased dose-dependently. Vdarea and total body clearance of Ct increased dose-dependently. The concentration-dependent plasma protein binding of SDM was evident after 50 and 100 mg/kg. The time courses of Cf en Ct after 3 doses were analyzed by a one compartment open model with nonlinear plasma protein binding. The agreement between calculated curves of Cf and Ct and the observed values, and relative constancy of pharmacokinetic parameters were obtained over 3 doses. These results suggested that the nonlinear pharmacokinetics of SDM was caused by saturable plasma protein binding. The multiple i.v. dose of SDM was based on the dosage regimen using the nonlinear pharmacokinetic model (50 mg/kg, 24 hour interval, 4 days). The observed Cf was maintained in the intended range by the dosage regimen. Therefore, the dosage regimen based on the nonlinear pharmacokinetics may allow the unbound concentration after i.v. injection of SDM in pigs to be controlled.

Animals↗
PubMed1989

Experimental induction of splayleg in piglets by pyrimethamine.

Dietary administration of 3.6 mg/kg (BW)/day of pyrimethamine (PYR) to the 10 pregnant Goettingen minipigs for the 1st quarter (during days 11 to 16) or the 2nd quarter (during days 17 to 22) of the organogenetic period elicited the congenital splayleg (CSL) in 20 out of 27 live newborns. Only a splayleg piglet out of 18 was found in the control group. The incidence of stillbirth was higher in the PYR groups than the control group, but no major external malformation was observed in the piglets of the PYR groups. Histological and biochemical examinations of the muscles from the hindleg, foreleg and truncus were carried out. The severity of myofibrillar hypoplasia depended on neither CSL symptoms nor PYR administration. Although a significant decrease of protein content of the muscles was observed in the piglets of the PYR groups, the mechanism underlying the pathogenesis of induced splayleg was obscure.

Animals↗
PubMed1989

An appropriate ingestion volume of oral sulfa drug suspension in pigs.

The influence of ingested volume of a sulfa drug suspension, sodium sulfamonomethoxine (SMMNa), on the oral pharmacokinetics was studied in pigs, with regard to bioavailability and gastric emptying. Eighteen pigs, weighing 30-70 kg, were used. Phenol red solution was used for the evaluation of gastric emptying study. SMMNa suspension was used for pharmacokinetic study. Both of these fluids were administered by natural swallowing. Three experimental groups were constructed: G-I; 5 ml/kg of the test fluids to starved animals, G-II; 5 ml/kg of the test fluids to fed animals and G-III; 20 ml/kg of the fluids to fed animals. The glucose glycine electrolyte solution (GGES) was used as the vehicle for both the compounds. Six pigs, having duodenal cannula, were used for the study of gastric emptying. The gastric emptying rate was rapid in G-I, relatively rapid in G-III, and slow and variable in G-II. In agreement with the result of gastric emptying study, the values of Cmax and tmax were high and rapid in G-I, relatively high and rapid in G-III, and low and slow in G-II. Accordingly, the voluminous ingestion of drug suspension can facilitate the gastric emptying, in turn may make the oral absorption of the drug rapid-and-uniform. The 20 ml/kg volume of sulfa drug suspension may practically be recommended for the oral administration in pigs.

Administration, Oral↗
PubMed1988

Pharmacokinetics of oral sulfa drugs and gastric emptying in the pig.

The plasma pharmacokinetics of sulfamonomethoxine (SMM) and sulfamethazine (SMZ) in the pig were examined after the oral and intravenous (i.v.) administration of the sodium salt solutions. Eight pigs from a commercial breed and 8 Goettingen minipigs were used. Both the Cmax and tmax of SMM and SMZ ranged widely. A flipflop phenomenon was found after the SMM solution but not after the oral SMZ. Duodenal cannulae were inserted in 5 pigs. The SMM solution and the SMM suspension were directly injected into the duodenum through the duodenal cannula. Both Cmax values were in a narrow range. Both tmax values were in a narrow range and were reached within 30 min. There was no flipflop phenomenon. Gastric emptying in the pig was examined using duodenal cannulated pigs. Phenol red solution and SMM suspension were administered orally. The time courses of gastric emptying of the two markers were nearly coincident and they approximated an exponential decrease. The times required for the 50% passage of the marker from the stomach ranged widely between 0.06-7.7 h, which may cause the variation in the Cmax and tmax of the sulfadrugs after oral administration. The kappa-GE (rate constant of the terminal phase of gastric emptying) also ranged widely. Nine kappa-GE values among 22 were smaller than the minimum value of the SMM kappa el values, which may cause the flipflop phenomenon of the oral SMM. In contrast, all of the kappa el values of SMZ were smaller than the minimum value of kappa-GE. And no flipflop phenomenon was found after the oral SMZ. Accordingly, the pharmacokinetics after the oral sulfonamides solution may be intimately influenced by the gastric emptying.

Administration, Oral↗
PubMed1988

Role of deacetylation in the nonlinear pharmacokinetics of sulfamonomethoxine in pigs.

The role of deacetylation in the pharmacokinetics of sulfamonomethoxine (SMM) in pigs was studied using 6 Goettingen minipigs and a pig from a commercial breed. The rapid decrease of plasma concentration of the parent compound followed by the rapid increase of plasma concentration of the deacetylated metabolite, SMM, was observed after an i.v. injection of N4-acetylsulfamonomethoxine (AcSMM; 10 mg/kg). The concentration of the metabolite, SMM, was greater than that of AcSMM and after reaching peak, both compounds decreased in parallel on a semilogarithmic graph. On the other hand, the acetylated compound of SMM (AcSMM) appeared in the plasma and reached peak after an i.v. injection of SMM. After reaching the peak, both SMM and AcSMM decreased in parallel. The slopes of the terminal phases of SMM and AcSMM after both injections showed no significant difference. After the i.v. injection of a high dose of SMM (100 mg/kg), a nonlinear pharmacokinetics profile with capacity limited elimination type of SMM was observed. The concentration of plasma AcSMM increased rapidly and the parallel decrease of SMM and AcSMM was observed in both nonlinear and linear phases, while the renal excretion of AcSMM was saturated in the nonlinear phase. The results suggest that the deacetylation in pigs is so strong that it largely affected the pharmacokinetics of SMM in both high and low doses. In spite of the saturation in renal excretion of the main metabolite, AcSMM, after the high dose, the profile of the parallel decrease remained unchanged, which may be due to the rapid conversion of the excess AcSMM to SMM. The converted SMM was added to the existing plasma SMM. As a result, the nonlinear pharmacokinetics of SMM may have occurred after a high dose of SMM in pigs.

Acetylation↗
PubMed1987

Functional significance of histologic alterations induced by Escherichia coli pig-specific, mouse-negative, heat-stable enterotoxin (STb).

In contrast to cholera enterotoxin and other Escherichia coli enterotoxins, a pig-specific, heat-stable E. coli enterotoxin (STb) causes morphologic lesions (loss of villous epithelial cells and partial villous atrophy). These lesions reflect a loss of absorptive cells and thus suggest that STb causes impaired absorption as well as inducing net secretion. The present studies assess functional significance of morphologic changes induced by STb. Net fluid movement, mucosal surface area, sucrase activity and the electrical response induced by alanine were measured in swine jejunal loops exposed to E. coli culture filtrates with and without STb. Net fluid secretion (-11.1 +/- 1.1 ml) occurred in some STb loops (secretors) and net absorption (2.7 +/- 0.3 ml) in others (nonsecretors), but net absorption occurred in all control loops (4.9 +/- 0.2 ml). The mucosal surface area of STb loops was about 20% less than that of controls (P less than 0.01). Sucrase activity was also lower (about 15%) in STb loops than in control loops (P less than 0.01). The electrical response induced by alanine in mucosa from nonsecreting STb loops did not differ from that induced in mucosa from control loops. However, the response to alanine in mucosa from secreting STb loops was reduced about 70% from that in mucosa from nonsecreting STb loops or from control loops (P less than 0.05). It is concluded that reduced sucrase activity is a functional correlate to villous atrophy induced by STb, that STb impairs alanine absorption in some loops (secretors), and that the impaired alanine absorption is independent of the decreased surface area caused by STb. Because the impaired alanine absorption occurred independent of the decreases in surface area, it is suggested that the secretory response to STb is associated with an impairment of active absorption of alanine.

Animals↗
PubMed1986

Possible active tubular secretion of sulfamonomethoxine and its metabolites in pigs.

The effect of probenecid on the plasma kinetics of sulfamonomethoxine (SMM) was examined in conscious pigs. A linear kinetic dose of SMM (10 mg/kg) was injected with or without probenecid. Probenecid (25 mg/kg, i.v.) was injected immediately before SMM injection and against at 1, 2, 3, 4 and 6 h later. The AUCs of SMM and of the acetylated compound of SMM (AcSMM) in probenecid injected animals were significantly larger when compared with those of non-injected animals (p less than 0.05). Next, possible active secretion from the renal tubule of SMM and its metabolites was examined using probenecid and pyrazinoate. Ten commercial pigs with ureter cannulae were used under anesthesia. The plasma concentration of SMM and AcSMM was maintained at a steady state by a priming dose of SMM (5 mg/kg, i.v.) followed by sustaining infusion (4 micrograms/kg/min). Renal clearance of AcSMM was suppressed by bolus injection of probenecid (25 mg/kg), but that of SMM was not. The renal excretion of a water soluble metabolite was suppressed by probenecid. No marked changes in renal excretory kinetics were found by pyrazinoate injection (12.5 mg/kg, i.v.). Consequently, the saturation in the active tubular secretion of AcSMM may play an important role in the nonlinear pharmacokinetics of SMM in pigs.

Acetylation↗
PubMed1986

Contribution of renal active secretion in renal excretion of N4-acetylsulfamonomethoxine in conscious pigs.

The contribution of renal active tubular secretion of N4-acetylsulfamonomethoxine (AcSMM) in renal excretion was examined using 3 conscious pigs with permanent ureter cannulae. AcSMM was the main metabolite of sulfamonomethoxine (SMM) in pigs. When AcSMM (100 mg/kg) was intravenously injected, the renal clearance of AcSMM increased with the decrease of AcSMM plasma concentration. Michaelis-Menten kinetics was demonstrated in the renal excretion of AcSMM. It can be concluded that AcSMM is mostly excreted through active tubular secretion. The decrease of renal clearance of AcSMM may be thought as the causal factor of nonlinear plasma kinetics of SMM in pig.

Animals↗
PubMed1985

Use of the Goettingen miniature pig for studying pyrimethamine teratogenesis.

Although pigs are suitable animals for experimental teratology, use of miniature pigs developed as a medicobiological experimental animal is essential for this purpose. Miniature pigs are established genetically so that the background data on the naturally occurring birth defects are reliable, whereas the commercial breeds are always improved genetically to seek higher productivity. In this review the authors summarized pyrimethamine teratogenesis in Goettingen miniature pigs. Pyrimethamine administration to a pregnant sow during the early stage of the organogenetic period caused cleft palate and other birth defects, and also hind leg paralysis, a functional defect in newborns.

Abnormalities, Drug-Induced↗
PubMed1985

Laparoscopic-assisted serial biopsy of the bovine kidney.

A serial renal biopsy with endoscopy was done, using 10 calves and a cow. In 8 of the calves, biopsy materials were collected 3 to 5 times over a period of 15 to 41 days. A laparoscope was inserted into the peritoneal cavity from the center of the right paralumbar fossa through the outer cannula of the trocar. Under laparoscopic observation, the renal parenchyma was collected with the cutting prong of a biopsy needle. Of 34 biopsy attempts, 32 were successful; in 2, there was incomplete penetration of the trocar assembly into the peritoneal cavity. In one instance, the trocar was misguided to the small intestine which was closely adherent to the peritoneum. The error may have been the result of the presence of a persistent blood clot resulting from the preceding biopsy. An immediate saline rinse of the blood clot attached to kidney and the surrounding tissues was effective in preventing such adhesions. The size of the average sample obtained was 1.5 mm in diameter and 16 mm (2 to 40 mm) long. The tissues were collected in 61 times from the 72 insertions of the biopsy needle to the renal tissue. The 11 unsuccessful attempts were caused by bluntness of the cutting parts of the needle. Adverse clinical signs were no observed after the serial biopsy of kidney, except for the presence of blood in he urine persisting for 1 to 5 days. Although a dehydrated blood clot was found in the renal pelvis of one animal at necropsy, any complication such as obstruction of urinary flow was not observed.

Anesthesia, Local↗
PubMed1984

Pharmacokinetic analysis of plasma concentration and urinary excretion of sulphamonomethoxine and its metabolite in Goettingen minipigs.

The plasma concentration and renal excretion after a bolus intravenous injection of a low (10 mg/kg) or high (100 mg/kg) dose of sulphamonomethoxine (SMM) were studied in five Goettingen minipigs. The time data of plasma concentration after a low dose decreased rapidly and appeared to be linear on semilog graph paper. On the other hand, a decrease in the plasma concentration after a high dose was slow at first, gradually accelerated, then became rapid, showing that SMM disposition after a high dose (100 mg/kg) seemed to be non-linear with capacity-limited elimination. A large amount of the acetyl derivative of SMM (AcSMM), which was determined to be the main excretory product of SMM in urine, was detected in the plasma after SMM injection. As the ratios of the area under plasma concentration-time curve of AcSMM to that of SMM were not significantly different at either dose, the acetylation of SMM may be unsaturable by injection of 100 mg/kg of SMM. Immediately after the injection of a low dose, a rapid hyperbolic increase of the fraction of the cumulative amount of the excretory products in urine was observed. On the other hand, the fraction curve at the high dose rose slowly at first, then rapidly and hyperbolically. These results suggested that the non-linear drug disposition after a high dose (100 mg/kg) of SMM in pigs may be the result of a limited capacity for renal excretion of SMM and excretory products, especially the acetyl derivative.

Animals↗