Indocyanine green lymphography in the congenital chylothorax and chylous ascites.

BACKGROUND: The prognosis of congenital chylothorax and ascites ranges from spontaneous resolution to death, but no established examination exists to predict the prognosis. We aimed to develop a clinically useful method to evaluate lymphatic abnormalities using indocyanine green (ICG) lymphography in infants with congenital chylothorax and ascites. METHODS: We retrospectively evaluated infants with congenital chylothorax and chylous ascites who underwent ICG lymphography in our hospital between 2012 and 2022. The ICG lymphography findings was evaluated. We defined the dermal backflow in the trunk as the lymphatic flow from the end of the limb back through the lymphatic vessels on the surface of the trunk. The association between the dermal backflow in the trunk and clinical outcomes, as follows, are investigated: the duration of the drainage period, the duration of endotracheal intubation, and the length of hospital stay. RESULTS: Twenty infants had a dermal backflow in the trunk, and ten did not. Clinical outcomes in infants with and without dermal backflow in the trunk were as follows (median): the duration of the drainage period (20 vs. 0 days, p = 0.001), the duration of endotracheal intubation (12 vs. 2 days, p = 0.04), and the length of hospital stay (62 vs. 41 days, p = 0.04), respectively. In multivariate linear regression analysis adjusted for gestational age, the duration of the drainage period was correlated with the dermal backflow in the trunk [exp(B) = 2.62; p = 0.003]. CONCLUSIONS: The dermal backflow in the trunk in ICG lymphography was useful in predicting the clinical course of congenital chylothorax and ascites.

A new aspect of tolbutamide metabolism in the rabbit: the role of 1-butyl-3-(p-formylphenyl)sulphonylurea.

We investigated the metabolism of tolbutamide by using synthetic 1-butyl-3-(p-formylphenyl)sulphonylurea (ATB), an intermediate in the metabolic pathway of tolbutamide. ATB (40 mg kg-1) administered intravenously to rabbits was oxidized to 1-butyl-3-(p-carboxyphenyl)sulphonylurea (CTB) and also reduced to 1-butyl-3-(p-hydroxymethylphenyl)sulphonylurea (HMTB). Therefore, it is likely that in the metabolism of tolbutamide, the oxidation of HMTB to ATB involved the reverse reaction, suggesting the reduction of ATB to HMTB. The oxidation of ATB to CTB was inhibited by disulfiram pretreatment. ATB was detected in the blood following intravenous administration of HMTB in rabbits pretreated with disulfiram. These results, confirm that ATB is an intermediate in the oxidative metabolism of tolbutamide in the rabbit.

Enhancing effect of pyrrolidone derivatives on transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen.

The enhancing effects of pyrrolidone derivatives on the transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen were studied by using an in vitro technique and full-thickness rat skin. The enhancers included 1-methyl (1), 1-hexyl (2), and 1-lauryl-2-pyrrolidone (3). Penetrants with various physicochemical properties were used. Flurbiprofen penetrated through skin rapidly after application alone. 5-Fluorouracil, triamcinolone acetonide, and indomethacin showed little penetration. Pyrrolidone derivatives enhanced the penetration of penetrants, especially the lipophilic compounds 2 and 3, which showed a great enhancing effect on the penetration of 5-fluorouracil and indomethacin. Pyrrolidone derivatives also enhanced the solubility of these penetrants in isopropyl myristate. Compounds 2 and 3 showed greater enhancing effects on the solubility and penetration of hydrophilic penetrants than those of lipophilic penetrants. These results suggest that the pyrrolidone derivatives enhance the flux of penetrants in skin by increasing the solubility of penetrants in the stratum corneum. Compounds 1 and 2 were detected in the receptor phase. All enhancers accumulated to a great extent in the skin. These derivatives also enhanced the skin retention of drug. It is concluded that these pyrrolidone derivatives are useful for transdermal drug delivery, although further studies are necessary before they could be used clinically.

Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives.

Several 1-acyl-2-pyrrolidinone derivatives were synthesized as derivatives of gamma-aminobutyric acid (GABA), and their pharmacological activities and stabilities were investigated. The derivatives showed anticonvulsant effect on picrotoxin-induced seizure at a dose of 200 mg/kg. In particular, 1-decanoyl-2-pyrrolidinone (7) and 1-dodecanoyl-2-pyrrolidinone (8) had a high activity. The anticonvulsant activity showed a dose dependency. Some of 1-acyl-2-pyrrolidinone derivatives prolonged sleeping time which was induced by sodium pentobarbital and showed a recovery from disruption of the memory of passive avoidance response, which was induced by an electroconvulsive shock. As shown by the results of the stability study of 1-acetyl-2-pyrrolidinone (1), it was degraded in an acidic buffer and an alkaline buffer although 2-pyrrolidinone was stable. 1-Acyl-2-pyrrolidinone derivatives were degraded in liver and brain homogenates of mouse and rat. They showed a degradation rate in rat plasma. Conversion of 8 to GABA in mouse liver homogenate was demonstrated. These results suggested that the pharmacological activity of 1-acyl-2-pyrrolidinone is probably due to the release of GABA by hydrolysis of derivatives although further work is necessary.

Comparative studies on the anticonvulsant activity of lipophilic derivatives of gamma-aminobutyric acid and 2-pyrrolidinone in mice.

Anticonvulsant activity, degradation into gamma-aminobutyric acid (GABA), and concentration in brain of 1-dodecanoyl-2-pyrrolidinone (I), a lipophilic derivative of a lactam of GABA, were compared with those of N-dodecanoyl GABA (II) and 1-dodecyl-2-pyrrolidinone (III) to get information about their pharmacological mechanisms. Compounds I and II degraded into GABA in mouse liver homogenate, gradually into GABA in brain homogenate and more slowly in plasma. Compound III had no degradation in the biological media. The derivatives administered intraperitoneally had dose-dependent anticonvulsant activity on picrotoxin-induced seizure in mice. Their anticonvulsant activities were changed by the time intervals between pretreatment of derivatives and administration of picrotoxin. Compounds II and III showed anticonvulsant activity on pentylenetetrazole-induced seizure and a prolonged sleeping time induced by sodium pentobarbital in mice. However, these three derivatives never significantly increased the GABA level in mouse brain after intraperitoneal administration compared to the endogenous GABA level. They were detected as intact derivatives in the brain. In the previous report, we demonstrated the anticonvulsant activity of sodium dodecanoate. These results suggested that the dodecyl chain of derivatives may be important for their anticonvulsant activities and I does not act as GABA via prodrug.

Acute toxicity and skin irritation of pyrrolidone derivatives as transdermal penetration enhancer.

We investigated preliminary acute toxicity and primary skin irritation of nine pyrrolidone derivatives which had been previously developed as transdermal penetration enhancers. The acute toxicity was observed at a dose of 500 mg/kg after intraperitoneal administration in mice. Their primary skin irritations were examined with rabbit dorsal skin. 1-Lauryl-2-pyrrolidone induced the most severe irritation among the derivatives. Pyrrolidone derivatives having methyl group and methyloxycarbonyl group caused little irritation. The primary irritation indices of pyrrolidone derivatives were not relative to their accumulations in the skin but to their enhancing effects. In conclusion, 1-hexyl-4-methyloxycarbonyl- and 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone are suggested to be adequate enhancers, judging from the balance of their enhancing activity and irritation.

Effect of pyrrolidone derivatives on lipid membrane and protein conformation as transdermal penetration enhancer.

Effect of pyrrolidone derivatives on lipid membrane and protein conformation has been assessed to obtain fundamental information about a mechanism of transdermal penetration enhancer. Their effects on a release of 6-carboxyfluorescein from liposome were examined. The lipophilic derivatives enhanced a release of dye and the enhancing effect showed a concentration dependency. Especially 1-lauryl-2-pyrrolidone showed the highest effect at the lowest concentration. The pyrrolidone derivatives also increased a hemolysis of rat erythrocytes. The derivatives slightly liberated SH group of keratin but did not change the electrophoresis pattern of keratin. 1-Methyl-2-pyrrolidone increased and retained a hydration of rat skin although 1-hexyl- and 1-lauryl-2-pyrrolidone showed no increase. These results suggest that the high enhancing effect of II, III and IX, as shown in the previous study, may be predominantly due to their interaction with skin lipid and their penetration behavior into the lipid.

Effect of pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The effect of pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. Latamoxef sodium (LMOX, 25 mg/kg/d, intravenously) and cephalexin (CEX, 16.7 mg/kg/d, orally) were administered for 1 or 3 d. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. By the pretreatment with LMOX for 1 or 3 d, the blood concentration of salicylic acid following oral administration of salicyluric acid was slightly decreased. In rabbits pretreated with CEX for 3 d, the blood concentration of salicylic acid was detected at low concentration. By the pretreatment with LMOX and CEX, however, the decrease in the blood concentration of salicylic acid following rectal administration of salicyluric acid was not observed. Although the examination of population of intestinal microorganisms induced by the pretreatment with antibiotics was not performed, the metabolic activity of intestinal microorganisms may be changed.

Enhancing effect of pyrrolidone derivatives on transdermal penetration of phenolsulfonphthalein and indomethacin from aqueous vehicle.

We investigated the enhancing effect of three alkyl-2-pyrrolidones on transdermal penetration of phenolsulfonphthalein (phenol red) and indomethacin from an aqueous vehicle by using an in vitro technique with excised rat skin. The enhancers included 1-methyl- (I), 1-hexyl- (II) and 1-lauryl-2-pyrrolidone (III). These derivatives effectively enhanced the penetration and skin accumulation of phenol red and indomethacin. Lipophilic enhancers such as II and III showed particularly high enhancing effects. The penetration profiles of phenol red and indomethacin showed a lag phase followed by a linear increase. Compounds II and III showed long lag times. The enhancer penetration was also determined. Compounds I and II showed a slight penetration. Compound III showed little penetration but high skin accumulation.

Enhancing effect of pyrrolidone derivatives on the transdermal penetration of sulfaguanidine, aminopyrine and Sudan III.

The enhancing effect of pyrrolidone derivatives on the percutaneous penetration of sulfaguanidine, aminopyrine and sudan III was investigated using in vitro technique and excised rat skin. 1-Methyl (MP), 1-hexyl (HP) and 1-lauryl-2-pyrrolidone (LP) were used as penetration enhancers. Aminopyrine showed high penetration through skin although sulfaguanidine and sudan III showed little penetration. Pyrrolidone derivatives enhanced their penetrations. Especially HP and LP enhanced the penetration of sulfaguanidine to a high extent. Sudan III was not detected in the receptor phase regardless of the presence of enhancer. Pyrrolidone derivatives significantly increased the skin accumulation of sulfaguanidine, aminopyrine and sudan III. Penetration of pyrrolidone derivatives was also determined. MP and HP showed high penetrations. LP was not detectable in the receptor phase. MP, HP and LP showed high skin accumulations. These results suggested the usefulness of pyrrolidone derivatives as percutaneous penetration enhancers.

Enhancing effect of combining two pyrrolidone vehicles on transdermal drug delivery.

The enhancing effect of combining 1-methyl-2-pyrrolidone (MP) and 1-lauryl-2-pyrrolidone (LP) as the vehicles for transdermal penetration of phenolsulphonphthalein (phenol red) has been investigated by using an in-vitro technique with excised rat skin. LP had a higher enhancing effect on the penetration of phenol red than MP, but there was a long lag time before steady-state penetration was attained. A potent effect with a shorter lag time was obtained when MP and LP were used together. This potentiation was maintained when the concentration of MP was decreased by 95%. The combined vehicle also enhanced the skin accumulation of phenol red. MP promoted the rapid penetration of LP into the skin and potentiated the enhancing effect of LP on the penetration of phenol red and thereby shortened the lag time. The combined vehicle also enhanced the penetration of the hydrophilic anticancer agent, 5-fluorouracil.

Effect of straight chain fatty acids on seizures induced by picrotoxin and pentylenetetrazole in mice.

The effects of straight chain fatty acids on seizures induced by picrotoxin and pentylenetetrazole were studied in mice. After i.p. injection capric, lauric, myristic, palmitic and stearic acid delayed the onset of picrotoxin-induced clonic convulsion in a dose-dependent manner. The survival time was also prolonged by the pretreatment with lauric, myristic, palmitic and stearic acid. However, the onset of the clonic convulsion induced by pentylenetetrazole was delayed only by lauric acid. The prolongation of the survival time was also observed only in the animals pretreated with capric and lauric acid. These results suggest that the straight chain fatty acids examined in the present study possess anticonvulsant activity in mice.

Effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. In fasted rabbits (24 and 48 h), the blood concentration of salicylic acid after oral administration was changed compared to the control. However, a significant effect of fasting was not observed in the blood concentration of salicylic acid after rectal administration. Following intracecal administration, the blood concentration of salicylic acid was increased in fasted rabbits compared to the control. From these results, it seems that the slow rate of stomach emptying due to coprophagy during fasting is the principal reason for the change of blood concentration of salicylic acid following oral administration of salicyluric acid.

Sustained blood concentration of salicylic acid following rectal administration of salicyluric acid in dogs.

The blood concentrations of salicyluric acid and salicylic acid following rectal, intravenous and oral administrations of salicyluric acid (5, 10 and 60 mg/kg, respectively: salicylic acid equivalent) were determined in dogs. After rectal administration, a small amount of salicyluric acid was absorbed in intact form. The rest was hydrolyzed to salicylic acid, which was subsequently absorbed. The blood concentration of salicylic acid was maintained at 0.4-0.7 microgram/ml from 2 to 12 h. Following intravenous administration of salicyluric acid, salicyluric acid was detected in the blood but was rapidly eliminated. A trace amount of salicylic acid was detected, suggesting that systemic de-conjugation of glycine was involved. After oral administration of salicyluric acid, salicyluric acid was well absorbed. Salicylic acid was detected at low concentration for 12 h. Species difference in the metabolic fate of salicyluric acid in dogs, rabbits, rats and humans reported previously is discussed.

Disposition of phenacetin in rabbits pretreated orally and intraperitoneally with 3,4-benzpyrene.

Disposition of phenacetin (PHT) administered intravenously was investigated in rabbits pretreated orally and intraperitoneally with 3,4-benzpyrene. 3,4-Benzpyrene pretreatment intraperitoneally 24 and 48 h before the disposition experiments resulted in enhanced PHT metabolism as was shown from the decreased levels of PHT and the increased levels of acetaminophen sulfate (NAPAS) in the blood after intravenous administration of PHT. Following the oral pretreatment with 3,4-benzpyrene 24 h before the disposition experiments, no effect was found on the metabolism of PHT compared to the control. 3,4-Benzpyrene pretreatment orally 48 h before the disposition experiments resulted in enhanced PHT metabolism as was shown from the decreased levels of PHT and the increased levels of acetaminophen glucuronide and NAPAS in the blood. From these results, the response to oral and intraperitoneal pretreatment with 3,4-benzpyrene appears to be profoundly different. A technique for selective enzyme induction in the intestine by the route of administration of inducer is discussed.

Effect of oral pretreatment with indomethacin on the intestinal first-pass metabolism of salicylamide in rabbits.

The effect of oral pretreatment with indomethacin on the intestinal first-pass metabolism of salicylamide (SAM) was studied in rabbits using in situ intestinal sacs with complete mesenteric venous blood collection. The appearance of both SAM and its metabolites into the mesenteric venous blood was measured directly by cannulating the mesenteric vein of exposed rabbit intestine and collecting all venous blood draining from the absorbing region. By oral pretreatment with indomethacin, the total amounts of SAM absorbed in 20 and 120 min were significantly increased compared to the control. These results indicated the alteration of the permeability in the intestinal mucosa. In 20 min, indomethacin pretreatment resulted in increased appearance of SAM and SAM glucuronide in the mesenteric venous blood. In 120 min, increased appearance of SAM and decreased appearance of SAM sulfate were observed, compared to the control. These findings suggested that the change in the intestinal first-pass metabolism of SAM is probably due to the intestinal mucosal damage by oral pretreatment with indomethacin.

Hydrolysis of salicyluric acid in intestinal microorganisms and prolonged blood concentration of salicylic acid following rectal administration of salicyluric acid in rats.

The blood concentrations of salicyluric acid and salicylic acid following oral, intravenous, intracecal and rectal administration of salicyluric acid were determined in rats. After oral administration of salicyluric acid, salicyluric acid was rapidly absorbed. Salicylic acid was detected at low concentration. Following intravenous administration of salicyluric acid, salicyluric acid was detected in the blood and was rapidly eliminated. A trace amount of salicylic acid was detected, suggesting that systemic deconjugation of glycine was involved. Furthermore, in vitro incubation of salicyluric acid with contents of the gut showed that the major source of the hydrolysis was the hind gut. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration of salicyluric acid. The blood concentration of salicylic acid was maintained at 2.6-4.0 micrograms/ml from 4 to 12 h following rectal administration of salicyluric acid (10 mg/kg: salicylic acid equivalent). Species difference in the metabolic fate of salicyluric acid in rats and rabbits reported previously is discussed.

Comparison of salicylamide and acetaminophen and their prodrug disposition in dogs.

Comparative studies on the disposition of two pairs of drugs and their prodrugs, i.e., (1) salicylamide (SAM) and ethenzamide (ETB), (2) acetaminophen (NAPA) and phenacetin (PHT), were performed in dogs following intravenous and oral administration of the drugs. ETB and PHT were largely metabolized to SAM and NAPA, respectively, and SAM and NAPA thus formed or those directly administered were conjugated with sulfuric acid and glucuronic acid. It was found that the prodrugs, ETB and PHT, were more susceptible to first-pass metabolism than the corresponding parent drugs, SAM and NAPA, respectively at 30 mg/kg dose of each drug. Free NAPA levels in the blood of dogs receiving PHT were found to be considerably high, whereas free SAM levels in the blood of dogs receiving ETB were very low. These are consistent with results in humans which have been reported earlier, suggesting the similarity between dogs and humans. The ratio of sulfate to the sum of sulfate and glucuronide (S-ratio) as the area under blood concentration-time curve and urine were examined. The prodrugs (ETB and PHT) showed higher S-ratios than the corresponding parent drugs (SAM and NAPA). The S-ratios were greater than 0.6 in ETB and SAM and less than 0.5 in PHT and NAPA, indicating that sulfate formation was predominant in the former pair while glucuronide formation was predominant in the latter pair. No intestinal metabolism was found in the prodrugs. In the parent drugs, however, conjugation with sulfuric acid and glucuronic acid was observed.(ABSTRACT TRUNCATED AT 250 WORDS)