Biopharmaceutics: 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 μmol 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 AUC_skin (topical delivery) to the AUC of salicylic acid in plasma (AUC_plasma, 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, AUC_skin 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 AUC_skin/AUC_plasma for the different ointments was comparable, although the magnitudes of AUC_skin and AUC_plasma 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.     

Electron microscopic finding of eccrine sweat gland epithelial cells in a patient with Krabbe disease

A 13 month old boy was found to have severely reduced β-galactocerebrosidase activity suggesting infantile Krabbe disease. Clinically, the patient showed a progressive neurological deterioration with white-matter disease on radiological study. Axillary skin biopsy was performed to support the diagnosis. On electron microscopy, needle-like inclusions, which are the typical finding seen in the cytoplasm of astrocytes and Schwann cells in the classic infantile form, were present in eccrine sweat gland epithelial cells. This method is useful for diagnosis when nerve biopsy and biochemical analysis are not readily available.     

Primary undifferentiated carcinoma arising from the retroperitoneum: a case report

A 35-year-old woman, gravida 1, para 1, underwent cesarean section in her 39th week of pregnancy. At the time of operation, multiple retroperitoneal tumors were found. Postoperative computed tomography and magnetic resonance imaging showed multiple solid tumors, each approximately 3-5 cm, in the right pelvic retroperitoneal space. Total resection of the tumors was performed without any macroscopic residual. A systematic workup for the primary tumor from which the retroperitoneal tumors may have metastasized failed to demonstrate any responsible tumor. We therefore assumed it to be a primary retroperitoneal tumor. The histopathologic features of the tumors were consistent with small-cell carcinoma. Two months postoperatively, recurrent tumors in the right inguinal and common iliac regions were detected. Since chemotherapy with irinotecan hydrochloride or paclitaxel did not produce any beneficial effect, a second tumor reduction surgery was performed 8 months after the initial operation. Four months after the second operation, a third operation including total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection in the contralateral iliac region were done. Afterward, a new recurrent tumor appeared along the aorta up to the left supraclavicular node. The patient died 19 months after the first operation.     

Epidemiology of sudden infant death syndrome in Japan

An epidemiological survey was carried out to examine the present situation with respect to sudden infant death syndrome (SIDS) in Kanagawa Prefecture. Questionnaires on sudden unexpected death of infants aged < 1 year in 1990-91 were sent to the hospitals and clinics in Kanagawa Prefecture which may take care of such infants. By analysing information from 10 485 replies, 48 out of 73 reported sudden infant deaths were confirmed to be SIDS, although autopsy was not performed in 13 cases (27%). The incidence of SIDS per 1000 live births in Kanagawa Prefecture was 0.29 in 1990 and 0.31 in 1991; and if limited to autopsy cases 0.19 and 0.25, respectively. Sudden infant death syndrome cases in Japan were found to occur more frequently when infants were < 6 months old, at home and sleeping alone, but less in the winter and between midnight and early morning. There was little difference between the numbers in prone and supine sleeping positions at discovery. It was not clear whether SIDS occurred more often to babies sleeping prone than supine, because there were no controls matched with the SIDS cases. In future, continuous epidemiological surveys of SIDS in Japan should be carried out.     

MATERNAL HYPERTHYROIDISM AND CONGENITAL MALFORMATION IN THE OFFSPRING

Six hundred and forty-three neonates from mothers with Graves' disease were examined for major malformations of external organs to compare the influence of maternal hyperthyroidism vs. ingestion of methimazole (MMI) during the first trimester on the incidence of congenital malformations. The subjects were divided into four groups according to maternal therapy and thyroid status during the first trimester as follows: (1) infants whose mothers did not receive MMI and were hyperthyroid (Group 1), (2) infants whose mothers did not receive MMI and were euthyroid (Group 2), (3) infants whose mothers received MMI and were hyperthyroid (Group 3) and (4) infants whose mothers received MMI and were euthyroid (Group 4). The prevalence of malformed infants in these four groups was 6.0% (three of 50), 0.3% (one of 350), 1.7% (two of 117) and 0.0% (none of 126), respectively. The incidence in Group 1 was significantly higher than that in Group 2 (P less than 0.01). There was no discernible dose dependency of MMI on the occurrence of malformations. These findings suggest that maternal uncontrolled hyperthyroidism may cause congenital malformations and that the beneficial role of MMI treatment outweighs its teratogenic effect, if any.     

Two Autopsy Cases of Diffuse Gastrointestinal Polyposis with Ectodermal Changes

Two autopsy cases of Cronkhite-Canada syndrome were reported. The caused of hypoproteinemia, electrolyte imbalance and ectodermal changes were discussed with reference to previously reported cases. The mechanism of protein loss was probably due to outflow into the intestinal lumen of the mucous substance in the cystically dilated glands, directly and/or indirectly followed by loss of mucosal surface. Electrolyte imbalance probably developed from gastrointestinal loss as well as poor substitution. The ectodermal changes were probably not a subsequent part of the emaciation or hypoproteinemis, but an inherent part of this disease. Therapy, whether substitution or surgical procedure, should be selected in order to control the general condition of the patient.     

Clinical Evaluation of an Immunoradiometric Assay for CA15-3 Antigen Associated With Human Mammary Carcinomas: Comparison With Carcinoembryonic Antigen

Serum levels of CA15-3, a mammary tumor associated antigen recognizedby two different murine monoclonal antibodies (115D8 and DF3),were investigated in patients with mammary carcinoma and otherbenign or malignant diseases. The reference value of the serumCA15-3 level was obtained as 24 units/ml at the 99% confidencelimit among healthy individuals (n = 462). Elevation of serumCA15-3 levels was observed in 24.3% of overall patients withmammary carcinoma. Serum CA15-3 levels in breast cancer patientscorrelated with the clinical stage; higher percentages of positivitywere observed in those with advanced breast cancer (stage IV,64.7%, recurrent, 52.4% and metastatic, 70.3%). Furthermore,elevated serum CA15-3 levels in breast cancer patients respondedwell to the effect of therapy. Although the serum CA15-3 testgave percentages of positivity of breast cancer similar to thosefound by the serum CEA test, the serum CA15-3 test revealedlower percentages of posi-tivity than the serum CEA test amongpatients with benign breast lesions, liver cirrhosis or othercarcinomas. These results suggest that the serum CA15-3 antigenlevel provides a very useful marker for diagnosis and clinicalmonitoring of patients with breast cancer.     

Primary gastrointestinal stromal tumor in the retroperitoneum

Abstract  Gastrointestinal stromal tumor (GIST) is the most frequent non-epithelial neoplasm in the gastrointestinal tract. GIST has received much attention both for its clinical significance and biological nature, while the retroperitoneal condition identical to GIST has been rarely described. Presented herein is a case of GIST arising from the retroperitoneum in a 67-year-old man. The solid tumor measuring 4 cm was uncovered in the retroperitoneum, between the abdominal aorta and inferior vena cava, on computed tomography. The patient underwent surgical excision of the tumor. Histological examination showed proliferating spindle cells in the clearly demarcated tumor; immunoreactivity for Kit and CD34 in tumor cells confirmed the diagnosis of GIST. The histological origin of GIST is suggested to be gastrointestinal pacemaker cells, because they share specific immunoreactivity for CD117/Kit, which is also relevant to pathogenesis of GIST. The present case was a rare primary GIST in the retroperitoneum with typical immunopathological features.     

N-Acetyl-L-γ-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-γ-glutamyl or N-acetyl-L-γ-glutamyl derivatives or the parent drugs has been examined in a rat model. All L-γ-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-γ-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-γ-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-γ-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-γ-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-γ-glutamyl-p-nitroaniline and N-acetyl-L-γ-glutamylsulpha-methoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-γ-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-γ-glutamyl-p-nitroaniline. In conclusion, N-acetyl-L-γ-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.