Linearized solar elastosis of the legs: A novel presentation and review of the literature.

There exists a spectrum of solar elastotic variants based on the clinical and histopathologic findings. We present here a peculiar case of solar elastosis that is unusual in its anatomic location, relative lack of background actinic damage, and pattern of linearization. Its presentation suggests that other factors in addition to ultraviolet radiation may play a role in the pathogenesis of solar elastosis.

Quantitative assessment of neuropilin-2 as a simple and sensitive diagnostic assay for spitzoid melanocytic lesions.

There is a significant need for the development of diagnostic tools that can precisely distinguish Spitz nevi and spitzoid melanomas. Here, we report the development of a PCR-based quantitative diagnostic assay for spitzoid melanocytic lesions utilizing the expression ratio of neuropilin-2 and melan-A genes in primary tumor specimens. We find that the expression ratio of neuropilin-2/melan-A is significantly increased in spitzoid melanomas compared with Spitz nevi. The diagnostic potential of this quantitative assay was validated in two independent sets of patient samples as demonstrated in a receiver operating characteristic curve analysis showing an area under the curve value of 91.8%. Furthermore, the assay was found to quantitatively distinguish the clinical nature of atypical spitzoid melanocytic lesions that were diagnostically undetermined using histopathologic criteria alone. Our data indicate that this quantitative assay may be used as a tool in determining the diagnostic classification of histologically challenging spitzoid tumors.

Rupioid psoriasis and other skin diseases with rupioid manifestations.

The term rupioid has been used to describe well-demarcated, cone-shaped plaques with thick, dark, lamellate, and adherent crusts on the skin that somewhat resemble oyster or limpet shells. We present a case of rupioid psoriasis that was treated with methotrexate, topical steroids, and intralesional steroid injections. Rupioid manifestations have been clinically observed in a variety of disease settings, including rupioid psoriasis, reactive arthritis, disseminated histoplasmosis, keratotic scabies, secondary syphilis, and photosensitive skin lesions in association with aminoaciduria. To diagnose the underlying infectious or inflammatory diseases beneath the thick crusts, skin biopsy and a blood test for syphilis may be necessary. Our aim is to familiarize clinicians with the differential diagnoses for skin diseases with rupioid manifestations.

Pharmacokinetic interaction between liquiritigenin (LQ) and DDB: increased glucuronidation of LQ in the liver possibly due to increased hepatic blood flow rate by DDB.

It has been reported that both liquiritigenin (LQ) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) have a hepatoprotective effect, and administration of both drugs together shows additive protective effect against acute liver injuries. Therefore, the pharmacokinetic interaction between LQ and DDB in rats was studied. LQ (20 and 50mg/kg for the i.v. and p.o. administration, respectively), DDB (10mg/kg for both i.v. and p.o. administration), and both drugs together were once administered intravenously or orally to rats. After the i.v. administration of both drugs together, the Cl(nr) and AUC of LQ were significantly faster (by 30.5%) and smaller (by 22.5%), respectively, than those of without DDB due to the faster hepatic blood flow rate by DDB. After the p.o. administration of both drugs together, the AUC of LQ was comparable to that of without DDB due to negligible effect of DDB on intestinal metabolism of LQ. The pharmacokinetic parameters of DDB after both i.v. and p.o. administration were not altered by LQ, indicating that LQ did not considerably affect the pharmacokinetics of DDB in rats.

Pharmacokinetics of ipriflavone and its two metabolites, M1 and M5, after the intravenous and oral administration of ipriflavone to rat model of diabetes mellitus induced by streptozotocin.

Ipriflavone was reported to be primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2 and 2C11 in male Sprague-Dawley rats. The protein expression and/or mRNA levels of hepatic CYP1A subfamily and 2C11 was reported to be increased and decreased, respectively, in diabetic rats induced by streptozotocin (DMIS rats). Thus, the pharmacokinetic parameters of ipriflavone and its two metabolites, M1 and M5, were compared after the i.v. (20mg/kg) and p.o. (200mg/kg) administration of ipriflavone to control and DMIS rats. After both i.v. and p.o. administration of ipriflavone to DMIS rats, the AUCs of ipriflavone were significantly smaller (by 31.7% and 34.2% for i.v. and p.o. administration, respectively) than controls. The faster Cl(nr) (smaller AUC) of i.v. ipriflavone could have been due to the faster hepatic Cl(int) (because of an increase in the protein expression and/or mRNA level of hepatic CYP1A subfamily) and the faster hepatic blood flow rate than controls. The smaller AUC of p.o. ipriflavone in DMIS rats could have mainly been due to the faster intestinal Cl(int) (because of an increase in the intestinal CYP1A subfamily) than controls.

Ipriflavone pharmacokinetics in mutant Nagase analbuminemic rats.

Ipriflavone, a derivative of naturally occurring isoflavones, was primarily metabolized in rats via hepatic CYP1A1/2 and 2C11. Protein and mRNA expression of CYP1A2 in the liver, reported to be increased in mutant Nagase analbuminemic rats (NARs), should influence the pharmacokinetic parameters of ipriflavone. In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20 mg/kg) and oral (200 mg/kg) administration to male Sprague-Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Cl(nr) and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the control rats (53.0% decrease), possibly due to the increased intestinal CYP1A that resulted in increased intestinal metabolism and decreased gastrointestinal absorption of ipriflavone in NARs.

Effects of E. Coli lipopolysaccharide on the pharmacokinetics of ipriflavone and its metabolites, M1 and M5, after intravenous and oral administration of ipriflavone to rats: decreased metabolism of ipriflavone due to decreased expression of hepatic CYP1A2 and 2C11.

It was reported that ipriflavone was primarily metabolized via hepatic CYP1A1/2 and 2C11 in rats. In the present study, the expression of CYP1A2 and 2C11 decreased in the liver, but increased in the intestine in rats pretreated with E. coli lipopolysaccharide (ECLPS; an animal model of inflammation). Thus, pharmacokinetic parameters of ipriflavone and its metabolites, M1 and M5, were evaluated in ECLPS rats. After intravenous administration (20 mg/kg) to ECLPS rats, the AUC of ipriflavone was significantly greater (26.7% increase) and CL(NR) of ipriflavone was significantly slower (19.9% decrease) than in the controls. This could have been due to decreased expression of hepatic CYP1A2 and 2C11 compared to the controls. After oral administration (200 mg/kg) to ECLPS rats, the AUC of ipriflavone was also significantly greater (130% increase) than in the controls. Although the expression of intestinal CYP1A2 and 2C11 increased in ECLPS rats, contribution of this increase to the significantly greater AUC of ipriflavone after oral administration of ipriflavone to ECLPS rats was not considerable. This could have also been due to a significantly decreased expression of hepatic CYP1A2 and 2C11 in ECLPS rats. The formation of M1 and M5 could be mediated via CYP1A2 and/or 2C11 in rats.

Effects of water deprivation on the pharmacokinetics of theophylline and one of its metabolites, 1,3-dimethyluric acid, after intravenous and oral administration of aminophylline to rats.

It has been reported that the expressions of hepatic microsomal cytochrome P450 (CYP) 1A1/2, 2B1/2 and 3A1/2 were not changed in rats with water deprivation for 72 h (rat model of dehydration) compared with the controls. It has been also reported that 1,3-dimethyluric acid (1,3-DMU) was formed from theophylline via CYP1A1/2 in rats. Hence, it could be expected that the formation of 1,3-DMU could be comparable between the two groups of rats. As expected, after both intravenous and oral administration of theophylline at a dose of 5 mg/kg to the rat model of dehydration, the AUC of 1,3-DMU was comparable to the controls. After both intravenous and oral administration of theophylline to the rat model of dehydration, the Cl(r) of both theophylline and 1,3-DMU was significantly slower than the controls. This could be due to significantly smaller urinary excretions of both theophylline and 1,3-DMU since the AUC of both theophylline and 1,3-DMU were comparable between the two groups of rats. The smaller urinary excretion of both theophylline and 1,3-DMU could be due to urine flow rate-dependent timed-interval renal clearance of both theophylline and 1,3-DMU in rats.

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability.

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.

Pharmacokinetic changes of ipriflavone in rats with acute renal failure induced by uranyl nitrate.

Pharmacokinetic parameters of ipriflavone were compared after intravenous (20 mg/kg) and oral (200 mg/kg) administration in control rats and in rats with acute renal failure induced by uranyl nitrate (U-ARF rats). It was expected that the time-averaged nonrenal clearance (Cl(nr)) of ipriflavone in U-ARF rats could be significantly slower than in the control rats, since it was reported that ipriflavone was metabolized via the hepatic microsomal cytochrome P450 (CYP) 1A1/2 and 2C11 and the expression and mRNA level of CYP1A2 were not changed, but those of CYP2C11 were decreased in U-ARF rats compared with control rats. Unexpectedly, after intravenous administration in U-ARF rats, the Cl(nr) of ipriflavone was significantly faster than in the controls (40.8 compared with 29.0 ml/min/kg). This may be due to an increase in the glucuronide conjugate formation of ipriflavone metabolites in U-ARF rats. After oral administration of ipriflavone in U-ARF rats, the AUC(0-24 h) was significantly smaller (194 compared with 295 microg min/ml) than in the controls.

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous ipriflavone in rats.

In order to find out what types of the hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of ipriflavone, ipriflavone at a dose of 20 mg kg(-1) (or 15 mg kg(-1)) was infused in male Sprague-Dawley rats. In rats pretreated with SKF 525-A (a non-specific CYP isozyme inhibitor in rats), the total body clearance (CL) of ipriflavone was significantly slower (29.9% decrease) than that in control rats. This indicates that ipriflavone is metabolized via CYP isozymes in rats, hence various enzyme inducers and inhibitors were used in in-vitro or in-vivo studies in rats. In rats pretreated with 3-methylcholanthrene and phenobarbital (main inducers of CYP1A1/2 and 2B1/2 in rats, respectively), the CL values were significantly higher (153 and 67.2% increases, respectively). In rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats), the CL was significantly slower (22.5% decrease) than that in control rats. On addition of furafylline (a main inhibitor of CYP1A2 in rats), the in-vitro intrinsic clearance for the disappearance of ipriflavone was significantly slower (50.8% decrease) than that without furafylline. However, the CL values were not significantly different in rats pretreated with orphenadrine and isoniazid (a main inducer of CYP2E1 in rats), and quinine and troleandomycin (main inhibitors of CYP2D1 and 3A23/2 in rats, respectively) compared to controls. These data suggest that ipriflavone could be metabolized mainly via CYP1A1/2, 2B1/2 and 2C11 in rats.

Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.

Pharmacokinetics of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034), a derivative of flavonoid, in mouse and rat models of chemically-induced inflammatory bowel disease.

The pharmacokinetics (including distribution in the gastrointestinal tract) of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034) has been investigated in several mouse and rat models of chemically-induced inflammatory bowel disease (IBD). In the female ICR mouse model, IBD was induced by dextran sulfate and the mice administered 30 mg kg(-1) DA-6034 intravenously or orally. In the male SJL mouse model of IBD induced by oxazolone, 30 mg kg(-1) DA-6034 was administered orally. In the male Sprague-Dawley rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS), 10 mg kg(-1) DA-6034 was administered intravenously and orally. After intravenous administration, the total area under the plasma concentration-time curve from time zero to the last measured time, t, in plasma (AUC(0-t)) values were comparable between control and dextran sulfate-induced IBD mice, and between control and TNBS-induced rats. This suggested that the disposition of DA-6034 was not affected considerably by dextran sulfate in mice and TNBS in rats. However, after oral administration in mice and rats with IBD, the AUC(0-t) values were greater compared with the respective controls. This could have been due to an increase (slow) in the gastrointestinal transit time (in IBD mice and rats, the percentages of the oral dose recovered from the rinsing fluid of the small intestine and large intestine as unchanged drug were greater and smaller, respectively), and an increase in intestinal permeability.

Dose-dependent pharmacokinetics of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage in dogs.

Dose-dependent pharmacokinetic parameters of KR-31378, a new neuroprotective agent for ischaemia-reperfusion damage, were evaluated after intravenous and oral administration of the drug at doses of 5, 10 and 25 mg/kg to male beagle dogs. After intravenous administration, the dose-normalized (based on 5 mg/kg) areas under the plasma concentration-time curve from time zero to time infinity (AUC values, 725, 1450 and 2300 micro g min/ml for 5, 10 and 25 mg/kg, respectively) were significantly different among the three dose ranges studied; the value increased more proportionally as the dose increased. This could be due to slower total body clearance (Cl) with increasing doses (6.90, 3.46 and 2.17 ml/min/kg). The slower Cl value with increasing doses may be due to saturable metabolism of KR-31378 in dogs. After oral administration, the dose-normalized (based on 5 mg/kg) AUC values (833, 1450 and 1920 micro g min/ml) at 5 mg/kg were significantly smaller than those at 10 and 25 mg/kg. Note that the AUC values were comparable (not significantly different) between intravenous and oral administration at all doses studied, indicating that the absorption of KR-31378 from the gastrointestinal tract was essentially complete and the first-pass (gastric, intestinal and/or hepatic first-pass) effects were almost negligible in dogs.