[Fertility after hysteroscopic resection of submucosal myoma in infertile women]. / Fertilité après résection hystéroscopique de myomes sous-muqueux chez des patientes infertiles.

OBJECTIVES: Myoma is the most frequent benign uterine tumor and might have a negative impact on fertility. In 5 to 10% of cases, infertility is associated with myoma and in 1 to 3% myoma is the only infertility factor. Even if effect of myomectomy on fertility is controversial, benefit of hysteroscopic myomectomy for submucosal myoma on fertility has already been shown. The aim of this study is to evaluate fertility of infertile women less than 46years old after hysteroscopic resection of submucosal myoma. MATERIAL AND METHODS: This retrospective unicentric study took place in the gynecologic unit of a teaching hospital. All infertile women with a hysteroscopic myomectomy for submucosal myoma between March 2009 and May 2013 were included. A phone questionnaire was conducted to evaluate pregnancy rate, eventual medical assistance, time between submucisal resection and pregnancy and issue of pregnancies. RESULTS: Seventy-one infertile women with a hysteroscopic resection of submucosal myoma were included. Pregnancy rate was 33.8% with 50% of live births, 41.6% of miscarriages and 8.4% of late fetal losses with a mean follow-up of 28.7months. Mean time between hysteroscopic resection and pregnancy was 9.9months. A medical assistance was necessary for 6 women (25% of pregnancy). CONCLUSION: This study reports hysteroscopic resection of submucosal myoma for infertile women. The rate of pregnancy after treatment is 33.8%.

Effective and safe treatment with cyclosporine in nephrotic children: a prospective, randomized multicenter trial.

We conducted a prospective, open-label multicenter trial to evaluate the efficacy and safety of treating children with frequently relapsing nephrotic syndrome with cyclosporine. Patients were randomly divided into two groups with both initially receiving cyclosporine for 6 months to maintain a whole-blood trough level between 80 and 100 ng/ml. Over the next 18 months, the dose was adjusted to maintain a slightly lower (60-80 ng/ml) trough level in Group A, while Group B received a fixed dose of 2.5 mg/kg/day. The primary end point was the rate of sustained remission with analysis based on the intention-to-treat principle. After 2 years, the rate of sustained remission was significantly higher while the hazard ratio for relapse was significantly lower in Group A as compared with Group B. Mild arteriolar hyalinosis of the kidney was more frequently seen in Group A than in Group B, but no patient was diagnosed with striped interstitial fibrosis or tubular atrophy. We conclude that cyclosporine given to maintain targeted trough levels is an effective and relatively safe treatment for children with frequently relapsing nephrotic syndrome.

Enhancing effect of 5 alpha-cyprinol sulfate on mucosal membrane permeability to sodium ampicillin in rats.

Effect of 5 alpha-cyprinol sulfate, a bile alcohol sulfate specific to carp bile, on rectal membrane permeability to sodium ampicillin (AMP Na) was examined in rats. AMP Na is not easily absorbed through rat rectal membrane without aid. 5 alpha-Cyprinol sulfate significantly enhanced the rectal membrane permeability to AMP Na even at a low concentration (6.25 mM), though sodium taurocholate needed a higher concentration (25 mM). Co-administration of phosphatidylcholine significantly suppressed the enhancing action of both sodium taurocholate and 5 alpha-cyprinol sulfate. On the other hand, calcium ion did not suppress the action of 5 alpha-cyprinol sulfate, although it did clearly suppress the action of sodium taurocholate. In conclusion, 5 alpha-cyprinol sulfate was found to have a potent enhancing effect on mucosal membrane permeability to water-soluble compounds. The enhancing mechanism of 5 alpha-cyprinol sulfate appeared to be different from that of sodium taurocholate.

Iontophoretic transdermal delivery of salicylic acid dissolved in ethanol-water mixture in rats.

The usefulness of iontophoresis is restricted to highly water-soluble compounds, since drugs are generally applied as an aqueous solution in a drug electrode. In the present study, salicylic acid (SA) dissolved in ethanol-water mixture was loaded in a drug electrode, and the effect of ethanol on the iontophoretic transdermal delivery of SA was evaluated. Ethanol at a concentration of 10 or 30% showed no significant effect on the iontophoretic transdermal delivery of SA compared to that in the absence of ethanol, but 40 or 70% ethanol increased it significantly. The current density passing through in vivo during iontophoretic treatment decreased with increase in ethanol concentrations. These results suggested that the enhanced transdermal absorption of SA iontophoretically by the presence of ethanol in a drug solution is not due to the increased current density in vivo, but probably due to the direct action of ethanol on the stratum corneum. In conclusion, addition of ethanol to a drug solution at an appropriate concentration was proved to enhance the iontophoretic transdermal delivery of SA. A mixture of ethanol and water can dissolve many poorly water-soluble drugs, and therefore it would be able to expand the application of iontophoresis to include many drugs that are poorly soluble in water.

Enhancement of topical delivery of a lipophilic drug from charged multilamellar liposomes.

To enhance the topical delivery of rhodamine B base (Rho), a model lipophilic compound, the electrostatic interaction between the positive and negative components incorporated in the liposomal bilayer was utilized. The higher in vitro permeability to Rho in rat skin was observed with positive and neutral multilamellar liposomal preparations, the former was prepared with phosphatidylcholine (PC) and stearylamine (SA) and the latter with PC alone, than that given as a solution. Negative liposome composed of PC and dicetyl phosphate (DCP) showed lower skin permeability to Rho. To enhance the Rho retention in the skin, the electrostatic interaction between SA and DCP, which was confirmed by in vitro partition study, was utilized. By pretreating the skin surface with SA solution or empty SA liposome, the skin distribution of Rho given as DCP liposome was substantially enhanced, with increase in the PC distribution into the skin. The pretreatment effect of empty SA liposome was also observed in rats in vivo. In conclusion, it was found that negative DCP liposome provides better drug retention in the skin with lower skin permeability, and the topical drug delivery from DCP liposome was further enhanced by the pretreatment of the skin surface with empty SA liposome.

Transnasal delivery of 5-fluorouracil to the brain in the rat.

The purpose of this research is to clarify the feasibility and to determine the extent of transnasal drug delivery to the brain through the cerebrospinal fluid (CSF) in the rat, using 3H-5-fluorouracil (5FU) as a model drug. It was confirmed first that the concentration of 5FU in the CSF was significantly higher following nasal administration compared with intravenous injection, indicating direct transport of 5FU from the nasal cavity to the CSF. Concentration-time profiles of 5FU in the plasma and in the cerebral cortex were determined following intravenous infusion, nasal instillation and nasal perfusion. In order to evaluate the extent of drug transport from the nasal cavity to the cerebral cortex by way of the CSF, the apparent brain uptake clearances were calculated. The uptake clearance following nasal perfusion (8.65 microl/min/g tissue) was significantly large (p < 0.001) in comparison with that following intravenous infusion (6.20 microl/min/g tissue), while that following nasal instillation (6.94 microl/min/g tissue) was not. Consequently, significant amount of 5FU is transported from the nasal cavity to the brain through the CSF and thus, the delivery of the hydrophilic drug to the brain is augmented by nasal drug application.

In-vivo calibration of microdialysis probe by use of endogenous glucose as an internal recovery marker: measurement of skin distribution of tranilast in rats.

To estimate the absolute concentration of substrates surrounding a microdialysis probe in-vivo, we developed a simple calibration method using endogenous glucose as an internal recovery marker and determined the skin distribution of tranilast (N-(3,4-dimethoxy-cinnamoyl)anthranic acid), an anti-allergic agent, in rats. This calibration method was based on the assumption that the concentration of glucose in the extracellular fluid of skin tissues is the same as that in plasma and that the in-vivo recovery ratio of glucose to tranilast by microdialysis is the same as that estimated in-vitro. Based on these assumptions, the dialysate concentrations of tranilast and glucose recovered from cutaneous microdialysis, glucose concentration in plasma, and in-vitro recovery ratio of tranilast to glucose by microdialysis were determined for the estimation of absolute unbound concentration of tranilast in the extracellular fluid of skin tissues. In an in-vitro study employing plasma containing tranilast, the unbound concentration of tranilast in plasma estimated from the dialysate concentration was just comparable with that determined by ultrafiltration methods. Also in an in-vivo study under steady-state plasma concentration of tranilast in rats, the estimated concentration of tranilast in the skin extracellular fluid was the same level as the unbound concentration of tranilast in plasma. Using the present calibration method, the skin distribution of tranilast administered into the intestinal loop or transdermally was continuously monitored in a quantitative manner.

N-acetyl-L-gamma-glutamyl derivatives of p-nitroaniline, sulphamethoxazole and sulphamethizole for kidney-specific drug delivery in rats.

Kidney-specific delivery of p-nitroaniline, sulphamethoxazole and sulphamethizole after either intravenous administration of the L-gamma-glutamyl or N-acetyl-L-gamma-glutamyl derivatives or the parent drugs has been examined in a rat model. All L-gamma-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-gamma-glutamyl derivatives were fairly stable in the systemic circulation after parenteral administration. Concentrations of p-nitroaniline and sulphamethoxazole 20 min after administration of the parent drugs were somewhat higher in the kidney than in the liver and lung. The concentration of sulphamethizole in the kidney was dramatically higher than those in the hepatic and pulmonary tissue. Kidney-specific delivery of the drugs of interest was evaluated by determining the tissue concentrations of the released parent drug and the total drug levels (i.e. drug levels after hydrolysis of all conjugate to the parent drug). For L-gamma-glutamyl-p-nitroaniline released renal levels of p-nitroaniline and total p-nitroaniline concentrations were both higher than those obtained after p-nitroaniline dosing. Use of L-gamma-glutamylsulphamethoxazole resulted in higher total sulphamethoxazole concentrations in the kidney, but did not lead to an increase in released (unconjugated) sulphamethoxazole levels. In contrast, no kidney-selective distribution was observed for L-gamma-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-gamma-glutamyl-p-nitroaniline and N-acetyl-L-gamma-glutamylsulphamethoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-gamma-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-gamma-glutamyl-p-nitroaniline. In conclusion, N-acetyl-L-gamma-glutamyl derivatization of certain compounds seems to be useful for kidney-specific drug delivery and preliminary data suggests that lipophilic drugs are better substrates than hydrophilic compounds. Results related to the selectivity of tissue distribution of the derivatives and species differences are discussed.

Hepatic clearance of ONO-5046, a novel neutrophil elastase inhibitor, in rats and in the rat perfused liver.

The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenylsulphonylamino]benz oyl]aminoacetic acid), a low-molecular-weight neutrophil elastase inhibitor, has been investigated in rats and in the rat perfused liver. This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[(4-hydroxyphenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogenate and in erythrocytes suspension in-vitro. On the other hand, it was stable in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum albumin (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 x 10(4) (M(-1)) and 4.33, respectively. Thus, ONO-5046 (100 microM) would bind to plasma proteins to an extent >99% at physiological plasma-protein concentrations. The total plasma clearance of ONO-5046 in rats was constant (approximately 9 mL min(-1) kg(-1)) under different steady-state plasma concentrations (5-50 microM) a value equivalent to the hepatic clearance. In the rat perfused liver, the hepatic extraction ratio of ONO-5046 was significantly reduced by adding BSA to the dosing solution. Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolysis, was found to be because of the extremely high protein-binding of the compound.

[Enhancement of drug absorption by iontophoresis and phonophoresis and clinical application].

Concepts of iontophoresis and phonophoresis are described. Main factors regarding iontophoretic transdermal drug delivery of ionized drugs or non-ionized drugs and clinical applications are outlined. Iontophoretic and sonophoretic transdermal drug delivery has some advantages and disadvantages. However, its clinical use for controlled drug delivery corresponding to chronopharmacology will bring more benefit to patients in near future.

Topical delivery of keloid therapeutic drug, tranilast, by combined use of oleic acid and propylene glycol as a penetration enhancer: evaluation by skin microdialysis in rats.

Topical delivery of tranilast (N-(3,4-dimethoxycinnamoyl)anthranic acid), an inhibitor of collagen synthesis and a therapeutic drug for keloid and hypertrophic scar, was examined, in rats, with oleic acid alone or a combination of oleic acid and propylene glycol as penetration enhancer. Evaluation was by measurement of the concentration of tranilast in plasma and in the dialysate from skin microdialysis. When tranilast at a dose of 1.5 mg was applied topically as an ethanol solution containing 5% polyvinylpyrrolidone on a dorsal skin surface (2.25 cm2), the maximum concentration of tranilast in skin dialysate was approximately 2 microM. When 10 or 20% oleic acid was added to the same ethanol solution the maximum concentration of tranilast in the dialysate increased to 10-20 microM, and this value was further increased to 60 microM by the addition of a combination of oleic acid (10 or 20%) and propylene glycol (10%) to the solution. With the combination of oleic acid and propylene glycol the area under the plot of the concentration of tranilast in skin dialysate against time between 0 and 4 h (AUC0-4) was more than 400-fold that after intravenous administration. The transdermal bioavailability of tranilast as assessed by the AUC0-4 of tranilast in plasma, was 0.2% of the dose applied in the ethanol solution, 3-5% of that applied in the ethanol solution containing oleic acid, and 14-16% of that applied in the ethanol solution containing both oleic acid and propylene glycol. These results suggest that the topical delivery of tranilast with an absorption enhancer such as a mixture of oleic acid and propylene glycol might be a more effective medication than oral administration of tranilast for the treatment of keloid and hypertrophic scar.

Effect of ointment bases on topical and transdermal delivery of salicylic acid in rats: evaluation by skin microdialysis.

Microdialysis has been used to determine the concentration of salicylic acid in skin tissue and plasma periodically for 4 h to evaluate the effect of ointment bases on topical and transdermal delivery of salicylic acid. The ointment bases examined were solbase (water-soluble), poloid and white petrolatum (oleaginous), hydrophilic poloid (water in oil (w/o) type emulsion lacking water) and absorptive ointment (w/o-type emulsion containing water). The ointments (0.1 g) containing 25 micromol salicylic acid were applied for 2 h to the surface of rat skin (1 cm2) with (intact) or without the stratum corneum. For intact skin, the extent of topical delivery from different ointments, evaluated by the area under the concentration-time curve (AUC) of salicylic acid in the skin tissue (AUCskin), increased in the order solbase << white petrolatum, poloid, hydrophilic poloid << absorptive ointment. The ratio of AUCskin (topical delivery) to the AUC of salicylic acid in plasma (AUCplasma, transdermal delivery) varied remarkably among the different bases, the greatest ratio being observed for absorptive ointment. When the ointments were applied to skin surface without stratum corneum, AUCskin for solbase was much higher (about 45 times that for intact skin), whereas only a small (two-fold) increase was observed for poloid and hydrophilic poloid and the increase was negligible for white petrolatum and absorptive ointment. For skin without the stratum corneum, the ratio AUCskin/AUCplasma for the different ointments was comparable, although the magnitudes of AUCskin and AUCplasma still varied substantially. The variance of AUC values arises as a result of the different rates of release of salicylic acid from the bases. These results indicate that: the topical and transdermal delivery of salicylic acid in intact skin varies substantially among different ointment bases, and the greatest topical delivery is observed for absorptive ointment; use of absorptive ointment increases the retention of salicylic acid in the stratum corneum; and the stratum corneum functions strongly as a penetration barrier for solbase, moderately for poloid and hydrophilic poloid, and less for absorptive ointment and white petrolatum.

Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast.

The feasibility of iontophoretic transdermal delivery of tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) for the treatment of keloid and hypertrophic scars was evaluated in hairless rats and humans. A drug electrode containing tranilast 1.5 ml (8 mg/ml in ethanol/water (8/2, v/v) mixture) was placed on the dorsal skin surface of anaesthetised rats or the affected parts of patients, and connected to the negative pole; an electric current (0.5-4 mA for rats, 2 mA for people) was pulsed through at one minute intervals. Tranilast was effectively delivered transdermally iontophoretically into the restricted skin tissues of hairless rats and the affected parts of four patients with hypertrophic scars with no skin damage. In four other patients tranilast given iontophoretically for a period of 30 minutes a week reduced the patients' complaints of pain and itching after only one or two treatments although there were some variations among patients. These results indicate that the transdermal iontophoretic delivery of tranilast is a useful treatment for keloid and hypertrophic scars, particularly for relieving pain and itching, and is more beneficial than tranilast given orally.

Effects of low-dose phenytoin administered to newborn mice on developing cerebellum.

To examine correlations between dose levels of phenytoin (PHT) and neurotoxic effects on cerebellar development, we administered 10, 17.5, 25, and 35 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-4 and determined plasma PHT concentrations during the administration period. Mortality rates were 12.5% and 35.2% in males and 15.3% and 33.3% in females for the 25 and 35 mg/kg PHT-treated groups during the PHT treatment, respectively. In the 25 and 35 mg/kg PHT-treated groups, total brain weight, the size of the cerebellum, and cerebellar weight were significantly reduced on postnatal day 21. However, in the 10 and 17.5 mg/kg PHT-treated groups, total brain weight and the size and weight of the cerebellum did not differ from those of the control group. Histologically, the number of pyknotic cells in the external granular layer (EGL) in the 25 and 35 mg/kg PHT-treated groups was increased on postnatal day 5, and the EGL was thicker than in the control group on postnatal day 14. Some of the Purkinje cells in the 35 mg/kg PHT-treated group showed degeneration. Plasma PHT levels were 10.7 +/- 2.2 and 24.6 +/- 2.6 micrograms/ml in the 25 and 35 mg/kg PHT groups on the third day of PHT treatment, respectively. In the 25 mg/kg PHT group, plasma PHT level was found to be in the therapeutic range for humans, 10-20 micrograms/ml. Accordingly, during pregnancy, epileptic women should be carefully given PHT at the lowest effective dose while plasma PHT levels are monitored properly. These findings emphasize the importance of pharmacokinetics in evaluating of phenytoin-induced developmental neurotoxicity.

First-pass metabolism of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino]benzoyl]aminoacetic acid), a novel elastase inhibitor, in rats.

The first-pass metabolism in the intestine and liver of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)-phenylsulfonylamino]benz oyl]aminoacetic acid), a newly synthesized elastase inhibitor, was separately estimated in rats. When ONO-5046 solution was administered into the whole intestine via the bile duct at a dose of 5 mumol/rat, the extent of bioavailability was only 1.5%. A small but significant increase in the bioavailability with an increase in the dose suggested marked first-pass metabolism with a saturable process. Hepatic first-pass metabolism was estimated by determining the hepatic extraction ratio of ONO-5046 after administration into the portal vein at two different infusion rates (5 mumol/kg/9 min or 5 mumol/kg/20s). The extraction ratio was relatively small and constant (about 20%) under 2 different infusion rates of the drug. Intestinal first-pass metabolism was estimated by determining the drug recovery in the mesenteric plasma after administering the drug into the intestinal loop in situ (mesenteric blood collecting method in situ). The recovery percentage of ONO-5046 in the mesenteric plasma was small (2.58 +/- 0.04% at a dose of 1 mumol/rat), and the remaining ONO-5046 recovered in the mesenteric plasma and in the intestinal loop was a metabolite of ONO-5046 (El-601, N-[2-[(4-hydroxyphenyl)sulfonylamino]benzoyl]amino-acetic acid). Recovery percentage of ONO-5046 in the mesenteric plasma increased significantly with an increase in the dose, although the recovery percentage was still low, even at a higher dose (9.55 +/- 1.17% of dose at a dose of 5 mumol/rat). These results indicate that the low oral bioavailability of ONO-5046 in vivo is mainly due to the marked intestinal first-pass metabolism, including the metabolism in the intestinal fluid, and the dose-dependent oral bioavailability was derived from the saturable intestinal first-pass metabolism.

Transdermal iontophoretic delivery of triamcinolone acetonide: a preliminary study in hairless rats.

Transdermal iontophoretic delivery of triamcinolone acetonide was examined using a commercially available iontophoretic system (Phoresor, Iomed) in hairless rats. A drug electrode containing triamcinolone acetonide 10 mg dissolved in 1 ml of N,N-dimethylacetamide and water (7/3 v/v) was connected to the positive pole of a Phoresor (set at 4 mA) and direct current was applied for 10, 30, or 90 minutes. The amount delivered to the skin tissues increased with time at a constant rate. Even after the drug electrode had been removed, triamcinolone acetonide was retained in the local skin tissues beneath where it had been for about 24 hours after 30 minutes iontophoresis. These results suggest that the iontophoresis with an organic solvent used as a drug vehicle is useful to increase transdermal absorption of compounds that do not dissolve completely in water.

Acetaminophen plasma level after oral administration in liver cirrhotic patients suffering from schistosomal infection.

Hepatosplenic schistosomal infection is a common parasitic liver disease in Egypt, resulting in the formation of granuloma followed by fibrosis which leads to the chronic liver disease. Plasma level of acetaminophen (AAP) and its glucuronide and sulfate metabolites after oral administration at a dose of 1 g was determined in liver-cirrhotic younger (9 - 25 years old) and elderly patients (45 - 65 years old) suffering from schistosomal infection. These levels of AAP and its metabolites in patient groups were compared with those in corresponding healthy subject groups. Examinations for participants in the present study by physicians indicated the more severe cirrhosis in elderly patients compared to younger patients and the formation of collateral circulation and the renal insufficiency in elderly patients. The elimination of AAP from plasma was significantly prolonged in both younger and elderly patient groups. In elderly patients plasma concentration of AAP in early stage (before the time to reach Cmax) was significantly higher, indicating the partial avoidance of first-pass metabolism due to the formation of hepatic shunt pathway. Plasma concentration of AAP-glucuronide was greatly decreased in both patient groups, whereas no significant difference in the plasma concentration of AAP-sulfate compared to those in corresponding healthy subject groups. These results will suggest that with repeated dosing of AAP special care must be taken in schistosomal patients since the elimination of AAP from plasma is remarkably reduced.

Characteristics of shed snake skin permeability to indomethacin and fatty alcohols.

To investigate the utilities of a shed snake skin as a model membrane for preclinical studies of transdermal drug delivery, the flux of indomethacin was determined under various conditions by using a diffusion cell. The flux of fatty alcohols was determined and compared with that in human skin reported in references. The esterase activity of shed snake skin was also determined. It was found that the flux of indomethacin decreased with an increase of pH and the amount of ethanol in a vehicle. The flux of indomethacin increased by the addition of Azone, N-methyl-2-pyrrolidone and N,N-dimethyl-m-toluamide in the cream. The flux of fatty alcohols in shed snake skin was greater than that reported in human skin, and shed snake skin had similar esterase activity to human skin.

Effect of polyol fatty acid esters on diclofenac permeation through rat skin.

The effects of a series of polyol fatty acid esters (sefsols) on diclofenac permeation through rat skin were investigated using in vitro and in vivo methods. Four monoesters and one diester of sefsol were selected as a vehicle components. The effects of each sefsol on in vitro diclofenac permeation were compared at a concentration of 5% sefsol in water. Monoesters of sefsol, except the glyceryl monoester, enhanced the percutaneous permeation of diclofenac. The highest enhancement was observed in propylene glycol monocaprylate. The plasma concentration of diclofenac was increased dramatically by the addition of 10% propylene glycol monocaprylate when applying the diclofenac sodium suspension to abdominal rat skin in vivo. These results suggest that the monoesters of polyol fatty acid are potential candidates to enhance the transdermal absorption of diclofenac sodium.

Effect of some amino acids on the rectal irritation caused by sodium caprate in conscious rats.

The effects of some amino acids such as L-glutamine (Gln), L-arginine (Arg) and L-methionine (Met) on rectal irritation caused by sodium caprate were studied in rats. Rectal irritation was assessed by the balloon method in fasting conscious rats. This method is based on measuring rectal contractions due to possible irritation caused by the presence of drugs and/or adjuvants in the rectum. Strong contractions were observed after rectal administration of an aqueous solution of 100 mM sodium caprate. However, the presence of Gln, Arg or Met (100 mM) in sodium caprate (100 mM) solution resulted in a significant decrease in the intensity of the rectal contraction caused by sodium caprate. The rectal absorption-promoting effect of sodium caprate on 6-carboxyfluorescein (6-CF) was examined following administration with amino acids in rats. The absorption of 6-CF was not influenced by the concurrent administration of amino acids. In addition, the rectal tissue interaction of sodium caprate, with or without Gln, was examined. The concentration of sodium caprate in rectal tissue was reduced by the presence of Gln.