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.     

Experimental myelitis caused by herpes simplex virus type 2 in C57BL/6N and BALB/cN mice

Intraperitoneal and intracranial inoculation of herpes simplex virus type 2 (HSV 2) into BALB/cN and C57BL/6N mice was carried out to induce experimental myelitis. The myelitis was clearly observed in C57BL/6N mice following intraperitoneal inoculation. Within 24 hours before death, the mice showed urinary and rectal incontinence and paraplegia of the hind legs. Randomly distributed, severe necrosis was demonstrated in the spinal cord, mainly at the lower cord. In BALB/cN mice the clinical symptoms were not clearly observed, as the mice died shortly after their onset. Although spinal cord necrosis was more prominent in C57BL/6N mice than BALB/cN mice, brain necrosis was only found in the latter, and not in the former. Both strains of mouse showed marked nuclear pyknosis of the nerve cells and slight nuclear pyknosis of the astrocytes in the brain where HSV 2 antigen was demonstrated immunohistochemically. The antigen was also detected in the necrotic spinal cord. In contrast, intracranial inoculation of the virus into both strains did not cause myelitis. Spinal cord necrosis was not demonstrated and virus DNA was not detected, by PCR, in spinal cord samples. In the brain, however, the virus was demonstrated by both PCR and immunohistochemistry.     

Prognosis and pathological characteristics of five children with non-Shiga toxin-mediated hemolytic uremic syndrome

BACKGROUND: The three major signs of hemolytic uremic syndrome (HUS) are hemolytic anemia, thrombopenia and acute renal failure. HUS is classified into Shiga toxin-mediated HUS (Stx-HUS) and non-Shiga toxin-mediated HUS (nStx-HUS). The prognosis of nStx-HUS is reported to be less favorable than that of Stx-HUS. Although the association between the prognosis and pathological characteristics of HUS have been reported such that the prognosis was considered to be poor for thrombotic microangiopathy (TMA) with predominant arterial involvement (arterial TMA), good for TMA with predominant glomerular involvement (glomerular TMA) and dependent on the extent of necrosis in cases of renal cortical necrosis, it is not yet clear whether pathological findings are also related to the renal prognosis of nStx-HUS cases. Therefore the purpose of the present paper was to analyze renal biopsy findings and prognosis for five children with nStx-HUS. METHODS: Clinical records of five cases of nStx-HUS among 74 cases of diagnosed HUS were reviewed, and information and data were summarized. RESULTS: Histological examination of the kidney led to the diagnosis of arterial TMA in three cases, and glomerular TMA and severe renal cortical necrosis in one case each. Analysis of the relationship between renal histological findings and the prognosis found that three patients with arterial TMA and one patient with severe renal cortical necrosis later developed end-stage renal failure while one patient with glomerular TMA has continued to show normal renal function. CONCLUSIONS: These findings indicate that pathological findings are closely related to the prognosis in cases of nStx-HUS.     

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.     

Cutting Balloon Angioplasty for a Restenosis Lesion at the Distal Anastomosis of a Saphenous Vein Graft

We successfully performed cutting balloon angioplasty for a restenotic lesion involving the distal saphenous vein graft (SVG) anastomosis that had developed within 1 month after conventional balloon angioplasty. We considered that cutting balloon angioplasty, which has been considered to produce less vascular injury, could be a viable choice for the treatment of a lesion at the distal anastomosis of an SVG.     

Reliability and validity of the Japanese version of the Yale-Brown Obsessive-Compulsive Scale

Abstract The reliability and validity of the Japanese version of the Yale-Brown Obsessive-Compulsive Scale (JY-BOCS) were determined by 20 raters for 12 Japanese patients with obsessive compulsive disorder at four institutions. Interrater reliability for the total JY-BOCS score was excellent, and the intraclass correlation coefficient was high (ICC = 0.960). Internal consistency was also excellent (Cronbach's α= 0.889). Concurrent and discriminant validity of the JY-BOCS was examined by comparing the scores on the JY-BOCS with those on the Maudsley Obsessional Compulsive Inventory (MOCI) and scales for depression and anxiety. A slight correlation was found between scores on the JY-BOCS and MOCI, but no significant correlations were found between scores on the JY-BOCS and those on scales for depression or anxiety.     

A history of investigation on the mood stabilizing effect of carbamazepine in Japan

Abstract A history of investigation on the antimanic and prophylactic effects of carbamazepine in Japan is described. Following the initial open trials in the early 1970s in which the antimanic and prophylactic effects of carbamazepine were indicated for the first time in the world, the mood stabilizing effect was confirmed by the double blind studies which were performed with a multi-institutional cooperation in Japan in the late 1970s. During the course of the double blind trials, the problem of different therapeutic dosages of psychotropic drugs between Japan and Western countries emerged; that is, the doses of chlorpromazine and lithium carbonate, which were used as the control drugs to carbamazepine in the two double-blind group-comparison studies in Japan, were both much lower than the dosage used in most of the Western countries. The low dosage of control drugs made the evaluation of the results of the double blind studies performed in Japan difficult, and caused a delay of publication in the Western journals of the results. Whether the difference is due to biological factors or to psychosocial and cultural factors is an important problem in psychopharmacology and should be investigated further.     

Epidemiology of poliomyelitis in Karachi,Pakistan: Prospective studies during 1990–93

Between October 1989 and September 1993, 245 cases of poliomyelitis visited the Department of Pediatrics, Civil Hospital Karachi, Pakistan. The majority of them were between 6 months and 2 years of age and the epidemic occurred during the hot season. The dominant serotype was polio type 1. All of the polioviruses isolated from the patients were wild type. Virological studies also disclosed that enteroviruses other than polioviruses were prevalent among healthy children as well as diarrheal and polio patients. Serodiagnosis by poliovirus-specific immunoglobulin M antibody tests using the capture enzyme-linked immunosorbent assay method were in good agreement with the results of virus isolation. The present study demonstrated that Pakistan is a region endemic for wild poliovirus and more aggressive preventive measures are needed to eradicate poliomyelitis from the region.     

Periodicity and prediction of mania onsets in biopolar I affective disorders

Abstract In studying the periodicity of mania onsets, cycle-oriented diagrams were made of the clinical course from 257 manic episodes analyzed retrospectively in 34 bipolar I manic-depressive patients for a period of about 5 years. Using these diagrams, the frequent period of mania onsets located in one-quarter of the follow-up period was pre-estimated, and the accordance ratio during a 25 month follow-up period was analyzed. The accordance ratio in all subjects was 39% (11/28) for the first episode and 35% (7/20) for the second episode. These ratios were not significantly different from the expected level (25%). The number of subjects was limited to 11 patients (10 rapid and 1 non-rapid cyclers) whose number of episodes used for the determination of the index cycle was eight or more. The accordance ratio was 64% (7/11) and 60% (6/10) for the first and second episodes, respectively. Their levels were significantly higher than those expected. Periodicity of mania onsets existed at least in rapid cyclers with abundant past data.     

Studies of Human Erythrocyte Catalase by Fluorescent Antibody Technic The Distribution of Catalase in Acatalasia and Hypocatalasia

In order to investigate the cellular distribution of catalase in normal,hypocatalasic and acatalasic red blood cells, the fluorescent antibody labellingtechnic was employed. Sensitive anticatalase sera were produced in rabbitsby immunization with purified catalase extracted from human erythrocytes.Specificity against human erythrocyte catalase was confirmed by Ouchterlony’sdouble diffusion method.

The distribution of catalase is fairly homogeneous in normal and hypocatalasic red cells, but in acatalasic cells fluorescence due to the presence ofcatalase was not observed.

By this method the amount of catalase in hypocatalasic red cells was judgedto be between that of normal and acatalasic red cells.

Submitted on October 1, 1968 Accepted on February 13, 1969