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Unintended intravascular injection from inferior alveolar nerve blocks can result in frustrating distant complications affecting such structures as the middle ear and eyes. Possible complications affecting the eyes include blurring of vision, diplopia, mydriasis, palpebral ptosis and amaurosis ( temporary or permanent). In this article, we present a complication that has been reported only rarely. Two patients developed transient loss of power of accommodation of the eye resulting in blurred vision after routine inferior alveolar nerve blocks on the ipsilateral side. Clear vision returned within 10 - 15 minutes after completion of the blocks. The possible explanation for this phenomenon is accidental injection into the neurovascular bundle of local anesthetic agents, which were carried via the blood to the orbital region. This resulted in paralysis of a branch of cranial nerve III, the short ciliary nerves that innervate the ciliary muscle, which controls accommodation.

Aim: We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. Volunteers and methods: A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. Results: The differences in bioavailability parameters (i.e., AUC0–24h, AUC0-∞ and Cmax) between the Treatments were within the range of 80–125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. Conclusion: These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol. [ABSTRACT FROM AUTHOR]

Communication is an integral component of effective healthcare delivery to patients, and this includes breaking bad news (BBN). However, clinicians in dentistry are rarely exposed to diseases that can negatively and seriously affect an individual's view of their future and pose a mortality risk, except for oral cancer. The aim of this study was to assess clinician practices in BBN of oral cancer diagnosis in Malaysia. An exploratory sequential mixed-methods study design was used. A qualitative study was conducted among 12 clinicians to gather relevant information regarding their practices in BBN of oral cancer diagnosis using a descriptive-interpretive approach. The themes that emerged were preparation for BBN, BBN setting, communication, emotional aspects, and summarizing the session. These themes were used to develop a questionnaire with 34 items. In the quantitative study, this questionnaire was sent to 87 clinicians who had experienced BBN of oral cancer diagnosis in the past 5 years; the response rate was 100%. An arbitrary cut-off score between the third and fourth quartiles was set to distinguish 'good' and 'poor' practice in BBN among the clinicians. The data analysis was performed using IBM SPSS Statistics version 23.0. Overall, at least two-thirds of the clinicians had good practices in BBN of oral cancer diagnosis. The clinicians' designation (oral and maxillofacial surgery consultant/specialist vs dental officer) and BBN experiences were factors associated with their practices in BBN of oral cancer diagnosis., (Copyright © 2024 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Pharmacokinetics of nicotine was studied in rats following intravenous (i.v.) administration of nicotine base (NB) and nicotine hydrogen tartarate salt (NS) at a nicotine dose of 1 mg/kg. The area under the plasma concentration-time curve (AUC), mean residence time (MRT), systemic clearance (CL), distribution volume at steady state (V(ss)) and terminal plasma half-life (T(1/2,beta)) of nicotine were compared between NB and NS. Compared to NS, NB exhibited higher and sustained plasma nicotine levels, thereby yielding significantly (P<0.05) larger AUC (66.3 vs. 27.7 microg ml/min), MRT (165.7 vs. 58.3 min), T(1/2,beta) (144.2 vs. 51.4 min) and a lower CL (18.3 vs. 46.3 ml/min per kg). The V(ss) was comparable between the two compounds. The metabolic conversion to cotinine from NS was threefold larger than that from NB. The plasma protein binding and distribution to blood cells were comparable between the compounds. The apparent partition coefficient (APC) of NS decreased as a function of its concentration, while that of NB remained nearly constant. Particles of different mean sizes were observed for the 1% (w/v) aqueous solutions of NS (388.6 nm) and NB (123.8 nm). Different metabolism and/or elimination between NB and NS appear to be mainly responsible for their different pharmacokinetics.

Isopropryl 2-(1-3-dithiethane-2-ylidene)-2[N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439) is currently under phase II clinical trials by the Yuhan Research Center for use as a hepatoprotective agent. Unfortunately, the oral bioavailbility of YH439, which is sparingly soluble in water (i.e., 0.3 microg/ml or 0.91 microM at room temperature), reportedly, is negligible regardless of the dose administered to rats in the 10-300 mg/kg range. The bioavailability of the compound increased up to 24%, when administered in the form of a micellar solution (700 microg/ml or 2.1 mM for YH439) at a dose of 10 mg/kg, suggesting that its limited solubility is associated with its negligible bioavailability. In order to obtain additional information concerning the bioavailability of YH439, the mechanism(s) involved in gastrointestinal (GI) absorption were investigated in the present study. For this purpose, the transport of YH430 across a Caco-2 cell monolayer was measured in a Transwell. A permeability of 4.07 x 10(-5) cm/s was obtained for the absorptive (i.e., apical to basolateral direction) transport of 0.42 pM YH439, implicating that the in vivo GI absorption is nearly complete. The absorptive transport exhibited a slight concentration-dependency with an intrinsic clearance (CLi) of 0.38 microLL/cm2/sec, which accounted for 28.1% of the total intrinsic clearance (i.e., CLi plus the intrinsic clearance for the linear component) of the transport. Thus, saturation of the absorption process appears to be a minor factor in limiting the bioavailability of the compound. The apparent permeability of YH439 from the basolateral to the apical direction (i.e., efflux, 6.67 x 10(-5) cm/s) was comparable to that for absorptive transport, but, interestingly, a more distinct concentration-dependency was observed for this transport. However, the efflux does not appear to influence the bioavailability of the compound, as evidenced by the sufficiently high permeability in the absorption direction. Rather, a reportedly extensive first-pass hepatic metabolism appears to be a principal factor in limiting the bioavailability. In this respect, reducing the first-pass metabolism by some means would lead to a higher bioavailability of the compound. Thus, elevation of the absorption rate of YH439 becomes a necessity. From a practical point of view, increasing the concentration of YH439 in the GI fluid appears to be a feasible way to increase the absorption rate, because the compound is primarily absorbed via a linear mechanism. In summary, the solubilization of YH439, as previously demonstrated for a micellar solution of the compound, appears to be a practical way to increase the oral bioavailability of YH439.

The objective of this study was to examine whether ion pair complexation with endogenous bile salts in hepatocytes contributes to the preferential biliary excretion of organic cations (OCs). Tributylmethylammonium (TBuMA; mol wt 200) and triethylmethylammonium (TEMA; mol wt 116) were selected as model OCs that exhibit significant and negligible biliary excretion, respectively, in rats. The apparent lipophilicity of TBuMA, but not that of TEMA, was increased by the presence of either rat bile or specific bile salts, suggesting the formation of lipophilic ion pair complexes for TBuMA with bile salts in the liver. The uptake of TBuMA into canalicular liver plasma membrane (cLPM) vesicles, but not that of TEMA, was increased in the presence of bile salts, with a significant increase for both ATP-dependent transport and passive diffusion. The uptake of TBuMA in the presence of the bile salts was inhibited by representative P-glycoprotein (P-gp) substrates and vice versa, suggesting the involvement of P-gp in the canalicular excretion of TBuMA-bile salt complexes in vivo. Increased affinity toward P-gp is suggested as the mechanism responsible for the increased ATP-dependent transport for the ion pair complexes. We propose that ion pair formation with bile slats in hepatocytes may be responsible for the preferential biliary excretion of high-molecular-weight OCs including TBuMA.

DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this study is to test the feasibility of the topical administration of this compound. Specifically, our goal was to identify vehicle system that permit a reasonable transdermal permeation of the compound in mice. Among the vehicles examined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 +/- 5.42 microl/cm2/h). However, due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 +/- 2.87 microg/cm2/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethoxydiglycol (EG) and oleic acid (OA) were selected as examples of good solvents. The addition of EG or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (i.e., to 61.1 and 50.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1:1 volume ratio, for example, increased the flux 6.3 fold (i.e., 279 microg/cm2/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., 9.26 microg/cm2/hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corneum-removed skin of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG (0.41 microl/cm2/hr) and OA (0.086 microl/cm2/hr), suggesting that a higher permeability across the viable skin layer is needed for the second solvents. The maximum flux across the intact skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the bes approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving 14C-procyclidine in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., 60 microl/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to dogs at a dose of 0.3 mg/kg (i.e., 6 microl/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1,440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of procyclidine in rats and dogs, based on the radioactivity, was calculated to be 81.1 and 98.6%, respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.

5,6-Dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3, 4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride (YH1885) is under development as a novel acid pump antagonist by Yuhan Research Center. Previous studies have suggested that the AUC and C(max) of orally dosed YH1885 are dose-dependent in the range of 2 to 500 mg/kg. The objective of the present study was to investigate the absorption mechanism of YH1885 using a human colon carcinoma cell line, Caco-2. The cells were grown to confluency on a permeable polycarbonate membrane insert to permit loading of YH1885 on either the apical or basolateral side of the cell monolayer. The flux across the monolayer from the apical to basolateral side was 3 to 5 times greater than that from the basolateral to apical side. The uptake of YH1885 into the Caco-2 cell monolayer was saturable and appeared to be mediated by a high-affinity transporter, with an apparent K(m) of 1.47+/-0.21 microM and a V(max) of 25.14+/-1.16 pmol/cm(2)/40 s. The apical to basolateral transport across the monolayer was Na(+)-independent, H(+)-sensitive, and energy-dependent. The transport was inhibited significantly by the presence of structural analogs of YH1885 (e.g., YH957, YH1070, and YH1041), some pyrimidine nucleobases (uracil and 5-methyluracil), and nucleobase transport inhibitors (e.g., papaverine, dipyridamole, and phloridzin). These results demonstrate that the apical to basolateral transport of YH1885 across the Caco-2 cell monolayer is partially mediated by a nucleobase transport system, which exhibits high-affinity and energy-dependent properties for YH1885. Saturation of this transport system, in addition to the limited solubility of YH1885 (i.e., approximately 5.3 microM), appears to contribute to the dose-dependent bioavailability of the drug.

To investigate the effect of two prokinetic drugs, cisapride and metoclopramide, on the bioavailability of drugs, a marker drug, ranitidine, was administered to healthy volunteers following pre-treatments with or without the prokinetic agents. Cisapride or metoclopramide HCl (a respective dose of 10 mg) was administered orally 30 min prior to an oral administration of ranitidine (300 mg). Serum samples were collected for a 12 h period after the administration of ranitidine and the concentration of ranitidine was determined by an HPLC method. The bioavailability parameters of the groups with the prokinetic agent pretreatment were compared with those of the control group. In addition, the effects of these prokinetic drugs on the in vitro apparent permeability of ranitidine across the rat jejunum in the Ussing chamber, and on the in vivo intestinal transit of charcoal meals in rats were also examined. The Tmax of ranitidine in human subjects was shortened significantly by the either of the pretreatments (i.e., with cisapride and metoclopramide). The AUC(inf) of ranitidine in human subjects was also decreased significantly in the case of cisapride pretreatment. However, no changes were observed for the values of Cmax and T(1/2) by the pretreatments. Rat studies revealed that cisapride and metoclopramide had no influence on the in vitro permeability of ranitidine or the in vivo intestinal transit of charcoal meals. Therefore, these data indicated that the changes in the bioavailability parameters (i.e., Tmax and AUC(inf)) in humans are not related with the intestinal permeability or intestinal transit of ranitidine. The shortened Tmax of ranitidine appears to be due to accelerated gastric emptying of the drug. However, underlying mechanisms for the decreased AUC(inf) of ranitidine in the case of cisapride pretreatment are currently unclear.

Aim: A bioequivalence study of the closerin capsules to the dura seromycin capsules was conducted., Patients and Methods: Twenty-four healthy male Korean volunteers received each medicine at the cycloserine dose of 250 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of cycloserine were monitored by a high-performance liquid chromatography for over a period of 72 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and untransformed Tmax., Results: There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were, in point estimate (90% confidence interval), 0.992 (0.950 approximately 1.037) and 1.051 (0.965 approximatly 1.144), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of Tmax was 0.000 (-0.250 approximatly 0.125). Moreover, the modified Pitman-Morgan's adjusted F test and equal variance test (one-sided) indicated that the 2 medications were comparable in intra- and inter-individual variability in cycloserine bioavailability., Conclusion: Therefore, these results indicate that the 2 medications of cycloserine are bioequivalent and, thus, may be prescribed interchangeably.

Purpose: The effect of CCl4-induced experimental hepatic failure (EHF) on the sequential hepatobiliary transport of model organic cations (OCs), triethylmethylammonium (TEMA), and tributylmethylammonium (TBuMA), was investigated in rats., Methods: EHF was induced by an i.p. injection of CCl4 at a dose of 1 ml/kg 24 hr prior to the transport study. The cumulative in vivo biliary excretion, in vitro hepatic uptake by isolated hepatocytes, in vitro efflux (i.e., release) from hepatocytes, and in vivo hepatobiliary excretion clearance were measured for normal and CCl4-EHF rats., Results: The CCl4-EHF decreased the apparent in vivo biliary clearance (CL(b)) and the in vitro maximum uptake rate (Vmax, uptake) of TBuMA by 66 and 48%, respectively. The CCl4-EHF had no effect on the CL(b) of TEMA. but decreased both the Vmax, uptake (59%) and the in vitro maximum hepatic efflux rate (Vmax, efflux) of TEMA (80%). On the contrary, the CCl4-EHF had no influence on the in vivo hepatobiliary excretion clearance (CL(exc)) of both OCs., Conclusions: Transport systems for the OCs on the sinusoidal membrane (uptake and/or efflux), rather than those on the bile canalicular membrane (excretion) appear to be prone to damage by the CC14-EHF.

Two structurally similar quaternary ammonium compounds, triethylmethylammonium (TEMA, M(r) 116) and tributylmethylammonium (TBuMA, M(r) 200) were used as model compounds to identify the unit process of hepatobiliary excretion that is responsible for markedly different biliary excretion of organic cations (OCs). Cumulative biliary excretion (in percentage of dose; i.v., 12 micromol/kg) was 0.17 for TEMA and 34.5 for TBuMA. In vivo uptake clearance into the liver was 0.686 +/- 0.020 ml/min for TEMA and 0.421 +/- 0.028 ml/min for TBuMA. When the uptake clearance was examined in an isolated hepatocyte system, comparable clearance between TEMA and TBuMA was obtained, consistent with the in vivo result. These observations suggest that uptake into the liver is not the major determinant for the difference in biliary excretion of the OCs. Coadministration of colchicine, an inhibitor of microtubule formation, had no effect on biliary excretion of the model compounds, and the primary site of subcellular distribution of the OCs appears to be the cytosol, suggesting that intracellular movement does not play a major role in the markedly different biliary excretion of the OCs. In contrast, in vivo excretion clearance across the canalicular membrane for TBuMA was 180-fold greater than that for TEMA, and in vitro efflux clearance of TBuMA was smaller than that of TEMA (p <.01), indicative of involvement of these processes in the markedly different biliary excretion of the OCs. Therefore, these data indicate that canalicular transport is primarily responsible for the markedly different biliary excretion of TEMA and TBuMA.

Purpose: The mechanism(s) responsible for the significantly higher biliary excretion of tributyl methyl ammonium (TBuMA) than of triethyl methyl ammonium (TEMA) was investigated in canalicular liver plasma membrane vesicles (cLPM)., Methods: The uptake of [3H]TBuMA and [3H]TEMA into cLPM in the presence of a pH gradient or ATP was measured by a rapid filtration technique., Results: The uptake of substrates into the vesicle was significantly increased by an outwardly directed pH gradient. The pH dependent uptake was saturable and cross-inhibited by the other organic cation, indicating that TEMA and TBuMA share a common transport mechanism. Kinetic analysis revealed the two compounds show similar characteristics for the pH-gradient dependent uptake. Thus, the organic cation/H+ exchange mechanism does not appear to explain the significant difference in biliary excretion of the organic cations. In the presence of ATP, however, uptake into cLPM was readily observed for TBuMA while TEMA uptake was negligible. Inhibition studies with typical P-glycoprotein substrates indicated the uptake may be mediated by the P-glycoprotein., Conclusions: Differences between TBuMA and TEMA in reactivity for an ATP dependent transport process, rather than for an organic cation/H+ exchanger, may be responsible for the markedly different biliary excretion of TBuMA and TEMA.

A bioequivalence study of the Neoplanta capsule to the Sandimmune Neoral capsule, microemulsion formulations of cyclosporin A (CyA), was conducted. Twenty-four healthy Korean male subjects received each formulation at the CyA dose of 175 mg in a 2 x 2 crossover study. There was a 2-week washout period between the doses. Blood concentrations of CyA were monitored by a radioimmunoassay for over a period of 48 h after the administration. AUCinf (area under the blood concentration/time curve from time zero to infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum blood drug concentration) and Tmax (time to reach Cmax) were compiled from the blood concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax and untransformed Tmax. There were no significant differences between the formulations in these parameters. The point estimates and 90% confidence intervals for AUCinf (parametric), Cmax (parametric) and Tmax (nonparametric) were, in point estimate (90% confidence interval), 0.978 (0.937 approximately 1.02), 0.954 (0.900 approximately 1.01) and 0.000 (-0.125 approximately 0.000), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the U.S. Food and Drug Administration guidelines. Moreover, the modified Pitman-Morgan's adjusted F test and equal variance test (1-sided) indicated that the 2 formulations were comparable in intra- and interindividual variability in CyA bioavailability. Therefore, these results indicate that the 2 formulations of CyA are bioequivalent and, thus, may be prescribed interchangeably.

Pharmacokinetic parameters of YH439 and its metabolites, M4, M5, and M7, were compared after iv administration of YH439 to rats (1-10 mg/kg), rabbits (1-10 mg/kg), and dogs (1-20 mg/kg) and oral administration of YH439 to rats (50-500 mg/kg) and dogs (0.5-2 g per whole body weight). After oral administration of YH439 to rats, the F values were 3.67, 1.33, and 0.859% for YH439 oral doses of 100, 300, and 500 mg/kg, respectively. However, the F value increased significantly, 21.2%, after oral administration of YH439-contained mixed micelles (10 mg as free YH439) to rats due to increased water solubility of YH439. Species differences in the pharmacokinetics of YH439 and its metabolites were found. First, M7 was detected in both plasma and urine after both iv and oral administration of YH439 to dogs, whereas it was detected neither in rats nor in rabbits, indicating that considerable amount of M7 was formed from YH439 only in dogs. Second, the AUC (or AUC0-->t) ratios of M4 to YH439 after iv administration of YH439 were 24.6-31.3, 42.2-49.2, and 2200-7640% for rats, rabbits, and dogs, respectively, indicating that formation of M4 after iv administration of YH439 was maximal in dogs. Third, the AUC (or AUC0-->t) ratios of M5 to YH439 after iv administration of YH439 were 103-127, 2.93-3.31, and 92.4-158% for rats, rabbits, and dogs, respectively, indicating that formation of M5 after iv administration of YH439 was minimal in rabbits.

The in-vivo cutaneous absorption of hydrocortisone was examined following topical application of hydrocortisone-containing liposomes. The formulation was applied onto the skin (1.0 cm2) of the hairless mouse (at a dose of 0.1 mg hydrocortisone) in the presence and absence of occlusion, and temporal profiles of the drug in the skin (stratum corneum and viable skin) were monitored. Under the non-occluded condition, the drug amount in the stratum corneum and viable skin reached its maximum within 1 h, and then decreased rapidly. Gelation of the liposomes by complete dehydration of the formulation under non-occlusion, which may prevent partition of the drug into the skin, appears to be a cause of the rapid decrease. Under the occluded condition, the drug amount in the skin was sustained although it then decreased dramatically compared with that under the non-occlusion (i.e. approximately 1/22 for stratum corneum and 1/8 for viable skin at 1 h, for example). A prevention of gelation of the liposomes by occlusion appears to be a potential mechanism of the maintenance of the drug concentration in the skin. The dramatic decrease in drug content in the skin may be attributed to the reduced partition of hydrocortisone, a hydrophobic drug, from the liposomes into the hydration-maintained stratum corneum under occlusion. In both application conditions, the concentration of hydrocortisone in the hydrophilic viable skin layer was markedly lower than that in the stratum corneum, indicating that partitioning between these tissues is a primary determinant of hydrocortisone reaching viable skin tissue. The estimated penetration depth of the drug into the stratum corneum was not affected significantly by the application conditions. These results demonstrate that excessive dehydration (non-occlusion) is not desirable for the prolonged delivery of hydrocortisone from liposomes into the skin. They also indicate that either hydration of the dosed skin (occlusion) is not preferable for the efficient delivery of hydrocortisone from the liposomes to the skin, especially to the viable skin. Therefore, both excessive dehydration of the liposomes and excessive hydration of the dosed skin (occlusion) should be avoided in the topical application of liposomal formulations for efficient delivery of hydrocortisone to the skin for a prolonged period of time.

A high-performance liquid chromatographic method was developed for the simultaneous determination of YH439, and its metabolites (M4, M5, and M7) in human plasma and rat urine using testosterone as an internal standard. The method involved deproteinization (plasma sample) or extraction (urine sample) followed by injection onto a C18 reversed-phase column. The mobile phase was acetonitrile-0.063 M phosphoric acidisopropyl alcohol (38:48:14, v/v/v), and the flow rate was 1.0 ml/min for the two methods. The column effluent was monitored by a UV detector set at 317 nm. The detection limits for YH439, M4, M5, and M7 in human plasma were 50, 40, 50, and 50 ng/ml, respectively, using the deproteinization method, and the corresponding values in rat urine were 50, 100, 50, and 50 ng/ml using the extraction method. No interferences from endogenous substances were found.

Aims: The objective of this study was to determine the extent of period effect on the pharmacokinetics of cyclosporin A (CsA) during consecutive dosing., Methods: Sandimmune Neoral and Neoplanta capsules were administered to twenty-four healthy Korean male subjects at a single CsA dose of 175 mg in a 2 x 2 crossover investigation with a 2-week wash-out phase. Concentrations of CsA in blood were measured by a r.i.a. method for a period of 48 h., Results: The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there is a significant (P < 0.01) period effect in AUC(0,last) (area under the blood concentration-time curve above the assay limit) and Cmax (maximum blood concentration) between the administrations. A 6 and 9% decrease in the AUC(0,last) and Cmax, respectively was seen at the second administration., Conclusions: This period effect on the pharmacokinetics of CsA may be relevant for the patients who need consecutive administration of the drug.