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Biomedical subjects

Y Koseki

Publications and source records attributed to Y Koseki.

At least 37 records · Page 2Linked to original sources
PubMed1999

Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA-amyloidosis in patients with rheumatoid arthritis.

To examine whether polymorphism at the SAA loci is associated with the development of amyloid protein A (AA)-amyloidosis, we determined the genotypes at the SAA1 and SAA2 loci in 43 AA-amyloidosis patients (amyloidosis population) and 77 patients with rheumatoid arthritis (RA) who had been ill for less than 5 years (early RA population). We also compared the frequencies of the genotypes at the SAA1 locus among 90 Korean, 95 Taiwanese, and 103 Japanese healthy subjects. The frequencies of the gamma/gamma genotype and gamma alleles at the SAA1 locus were significantly higher in the amyloidosis population than in the early RA population (34.9% versus 7.8%, and 58.1% versus 33.8%, chi2 test P=0.0001). The frequencies of the gamma allele at the SAA1 locus in Koreans, Taiwanese, and Japanese were 41.6%, 35.6%, and 37.4%, respectively. The length of the latent period of AA-amyloidosis was significantly longer in the patients with smaller numbers of the gamma allele at the SAA1 locus (Spearman's correlation coefficient: -0.42, P<0.05). On the other hand, the mean C-reactive protein (CRP) level during 2 years prior to the diagnosis of AA-amyloidosis was significantly higher in the patients with larger numbers of the gamma allele at the SAA1 locus (Spearman's correlation coefficient: 0.34, P<0.05). No significant association was found between amyloidosis and polymorphism at the SAA2 locus. We postulate that the allele SAA1gamma renders an RA patient susceptible to amyloidosis, possibly by affecting the severity of inflammation in RA.

Adult↗
PubMed1999

Urinary thromboxane A2/prostacyclin balance reflects the pathological state of a diabetic.

Levels of the stable urinary metabolites of thromboxane A2 and prostacyclin, 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 2,3-dinor-6-keto-prostaglandin F1alpha (2,3-dinor-6-keto-PGF1alpha) were measured in diabetics to elucidate the relation between the thromboxane A2/prostacyclin (TX/PGI) balance and pathological states of diabetes mellitus. 11-Dehydro-TXB2 and 2,3-dinor-6-keto-PGF1alpha were derivatized to methyl ester-propylamide-dimethylisopropylsilyl ether and methyl ester-methoxime-dimethylisopropylsilyl ether derivatives, respectively, and applied to a gas chromatography/selected ion monitoring. The TX/PGI ratios of diabetics were higher than those of healthy volunteers, suggesting the hypercoagulative states of this disease. The ratios showed positive correlations with the levels of blood glucose. The levels of hemoglobin A1c and triglyceride were correlated weakly with the ratio. Some of the patients who had relatively low levels of blood glucose also showed high TX/PGI ratios. Furthermore, the ratio increased in the order of the groups 1, 2, and 3; group 1 contained patients who did not take medicine for diabetes, group 2 contained those who took oral hypoglycemic agents, and group 3 contained those who received insulin therapy. These observations indicate that the TX/PGI ratio reflects the pathological conditions of diabetes and is a useful marker, having few different features from other markers that are presently used.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

[A case of systemic lupus erythematosus complicated by Nocardia farcinica].

We report a patient with systemic lupus erythematosus (SLE) complicated with nocardiosis. This case is very important that the complication of nocardiosis in SLE is very rare and the treatment to both SLE and nocardiosis is very difficult. A twenty-one-year old female was admitted to our hospital because of thoracic empyema and active lupus nephritis. Her medical history revealed that the diagnose of SLE was made when she was 18 with lymphocytopenia, proteinuria, positive antinuclear antibodies, and high titer of antibodies to native DNA. She was treated with prednisolne 60 mg daily and became better. Proteinuria appeared again in September 1995 and she was admitted to the former hospital. Renal biopsy proved diffuse proliferative glomeluronephritis (WHO IVb). She was treated with 1 g per day of methylprednisolone for 3 days and succeeded with 60 mg day of prednisolone. In early November she developed left chest pain and fever and chest X-ray demonstrated left pleural effusion. Antibiotics, antituberculosis, and antifungal therapy failed to subside her pleuritis and it turned to empyema. Then she was transferred to our hospital for further treatment. Nocardia farcinica was detected from the aspirated pleural fluid obtained at the former hospital. Drainage and intrathoracic impenem injection were effective. While long usage of minocycline was continued for the nocardiosis, 500 mg of cyclophosphamide pulse therapy to lupus nephritis was administrated. Two weeks later a new pulmonary lesion with left chest pain and liver abscess developed. Administration of trimethoprim-sulfamethoxazole subsided the nocardiosis. She was discharged with 1 g per day of proteinuria the prescribed 13 mg per day of prednisolone and continuous TMP-SMZ intake for nocardial infection. When immunosuppressive therapy must be given to the immunocompromised host, a more potent therapy must be added to avoid infection.

Adult↗
PubMed1998

Modulation of cAMP-mediated vasorelaxation by endothelial nitric oxide and basal cGMP in vascular smooth muscle.

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.

Adrenergic beta-Agonists↗
PubMed1998

[Pneumoperitoneum with systemic sclerosis].

We report a case of systemic sclerosis (SSc) complicated with benign pneumoperitoneum without apparent pneumatosis cystoides intestinalis (PCI). A 43-year-old woman was admitted to our hospital because of prominent abdominal distension in April 1997. Raynaud's phenomenon has been detected since 1991. She was suffering from recurrent diarrhea, constipation, and subileus. The diagnosis of SSc was made in 1996 based on the sclerosis in her face, forearms, and chest, and hypomotility of the esophagus. On admission, she presented no signs of peritoneal irritation. The laboratory data revealed that white blood cell count was 7,400/mm3 and C-reactive protein was 0.1 mg/dl. Chest and abdominal roentgenograms showed massive free air under the diaphragm, dilatation of small and large intestine, and air-fluid level. PCI was not apparent. Pneumoperitoneum was improved after four weeks with intravenous hyperalimentation. But she presented recurrent severe diarrhea and high fever whenever she tried to take food orally. Klebsiella pneumoniae was proved in her jejunal juice by bacteriologic examination. Intravenous prostaglandin F2 alpha and oral fosfomycin calcium intake made her condition better. Benign pneumoperitoneum without PCI is rarely reported in the patients with SSc. In her condition, weakness of intestinal wall, hypomotility of intestine, unusual bacterial overgrowth, and elevated intraluminal pressure made intraluminal gas go through the wall of the fragile intestine of SSc. As operation of intestine of SSc usually cause miserable outcome, pneumoperitoneum accompanied with SSc even if PCI is apparent or not must be treated with conventional manner while there is no signs of peritoneal irritation.

Adult↗
PubMed1998

[A patient with acute sarcoidosis associated with fever, polyarthritis, and erythema nodosum: a typical of Löfgren's syndrome].

A 26-year-old female was admitted to Aoyama Hospital in February 1996, for evaluation of abnormal chest shadows and polyarthritis. She visited our clinic in December 1995 with complaints of fever, fatigue, and polyarthralgia which lasted for 3 weeks. Two weeks later she developed erythema nodosum on her lower legs with the exacerbation of polyarthritis. Erythrocyte sedimentation rate was 108 mm/hr and CRP 4.9 mg/dl. A chest radiograph showed hilar lymphadenopathy and multiple nodular shadows in both lung fields. On admission, she had arthritis of the shoulders and knees, erythema nodosum on her lower extremities, and keloid-like skin lesion on her left knee. Thoracoscopic lung biopsy of nodular lesion and skin biopsy of keloid-like lesion revealed noncaseating granuloma of epithelioid cells with lymphocytes, macrophages, and giant cells, confirming the diagnosis of sarcoidosis. She was cured in three months, and was well and free of the symptoms thereafter. Löfgren's syndrome is acute sarcoidosis, characterized by arthritis, erythema nodosum, and bilateral hilar lymphadenopathy. This syndrome is common in Europe and is closely related to HLA-B8 and DR-3. The frequency of HLA-B8 and DR-3 in Japanese is almost 0%, explaining the rare onset of this syndrome in Japan. Our case is the second report of typical Löfgren's syndrome in Japan, although the patient did not have these HLA loci.

Acute Disease↗
PubMed1998

Acute sympathetic hyperfunction in overlapping syndromes of systemic lupus erythematosus and polymyositis.

A 20-year-old woman with arthralgia, serositis, thrombocytopenia, proteinuria, muscle weakness, elevated creatinine kinase, and positive anti-Sm antibody was diagnosed as having polymyositis and systemic lupus erythematosus (SLE). She had persistent high temperature, sinus tachycardia, hyperhidrosis, mydriasis, visual disturbance, hallucination, and loss of consciousness. Levels of plasma adrenaline, noradrenaline, and dopamine and cerebrospinal fluid interleukin (IL)-6 and IL-8 were all high. A diagnosis of sympathetic hyperfunction accompanied by central nervous system (CNS) involvement in SLE was made parenteral. Pulse administration of high dose corticosteroid therapy was effective. This is the first reported case of a connective tissue disease with CNS involvement manifesting as sympathetic hyperfunction with high plasma catecholamine levels.

Acute-Phase Reaction↗
PubMed1998

[Lupus cystitis and peritonitis successfully treated with intravenous cyclophosphamide pulse therapy: a case report].

The patient, a 35-year-old woman, had been diagnosed as SLE since she developed butterfly rash, arthritis and hair loss with positive antinuclear antibody, anti-DNA antibody, and LE cells in 1989, and treated with daily 20 mg prednisolone (PSL). She had been suffering from nausea, vomiting and waterly diarrhea since 1992. In June 1995, she noted pollakisuria and sense of residual urine, followed by dysuria and nocturia in October. She was admitted to our hospital in January 1996 with progressive gastrointestinal and urinary symptoms. Computerized tomography (CT) depicted thickening of the wall of intestine and bladder, diminished volume of bladder, and bilateral hydronephrosis and hydroureter. Biopsy of the bladder revealed erosion of mucosa and moderate infiltration with inflammatory cells. The diagnosis of lupus cystitis and peritonitis was made and she was initially given intravenous methylprednisolon pulse therapy (500 mg/day) for 3 days, and then switched to 100 mg of daily intravenous PSL. She responded partially to this regimen, but gradually developed gastrointestinal and urinary symptoms again when PSL was tapered down to 70 mg/day. Therefore, monthly intravenous cyclophosuphamide pulse therapy was started. With this therapy, her bladder and bowel symptoms improved, and then the thickness of her bladder and intestinal wall, and the bladder volume normalized. Five months after institution of therapy, PSL was successfully tapered down to 30 mg/day and she was discharged. Intravenous cyclophosphamidepulse therapy is a choice of treatment for steroid-resistant lupus cystitis and peritonitis.

Adult↗
PubMed1997

[Effect of nipradilol on aqueous flow in glaucoma patients treated with timolol].

The effect of nipradilol solution (KT-210) on aqueous flow was evaluated using fluorophotometry in 10 patients (6 primary open-angle glaucoma and 4 ocular hypertension) treated with timolol for more than one month. A single dose of 0.5% timolol was instilled into both eyes at 8 AM, and 0.25% KT-210 or placebo was instilled into both right and left eye at 11 AM; the treated eye was chosen randomly. Aqueous flow was measured every hour from 9 AM to 3 PM. There was no significant difference in pretreatment aqueous flow between the two eyes; 1.98 +/- 0.53 microliters/min in the KT-210 treated eyes, and 1.98 +/- 0.76 microliters/min in the placebo treated eyes. The flow measured 1 to 4 hours after KT-210 instillation was 1.66 +/- 0.69 microliters/min, 2.23 +/- 1.02 microliters/min, 2.20 +/- 0.67 microliters/min, and 1.68 +/- 0.64 microliters/min, respectively. This flow did not differ significantly from the flow in the placebo treated eyes (1.83 +/- 0.86 microliters/min, 1.79 +/- 0.69 microliters/min, 2.26 +/- 0.58 microliters/min, and 1.84 +/- 0.32 microliters/min).

Adrenergic alpha-Antagonists↗
PubMed1997

[A case of microscopic polyangitis accompanied by hearing loss as the initial sign of the disease].

Here we report a case of microscopic polyangitis (MPA) with anti-neutrophil cytoplasmic antibodies against myeloperoxidase (MPO-ANCA) accompanied by perceptive dominant hearing loss as the initial sign of the disease. A 52-year-old woman was admitted to Tokyo Metropolitan Ohtsuka Hospital in April 1996 because of bilateral progressive hearing loss. On admission, she had presented bilateral perceptive hearing loss, fever, myalgia, and weight loss. Laboratory data showed accelerated erythrocyte sedimentation rate, proteinuria, microscopic hematuria, leukocytosis, hypoproteinemia, and elevated creatinine level. Serum level of MPO-ANCA was elevated. Chest X-ray and computed tomography showed mild pleural effusion and interstitial shadow in bilateral lung fields. The biopsy findings detected that focal glomerulonephritis, and necrotizing angitis of small artery in kidney. The diagnosis of MPA was made with clinical course, laboratory findings, radiographic findings, and biopsy finding. Treatment was initiated with 45 mg of prednisolone, followed by marked improvement of hearing loss and decreased titer of serum MPO-ANCA. There are only seven reports showing hearing loss as the initial sign of the disease occurred in polyarteritis nodosa and MPA. The present case suggests the possibility that hearing loss may be the symptom of MPO-ANCA associated vasculitis.

Anti-Inflammatory Agents↗
PubMed1996

[A case of Vogt-Koyanagi-Harada disease associated with aortitis syndrome].

This in a case report of Vogt-Koyanagi-Harada disease associated with aortitis syndrome in a 44-year-old female. She was diagnosed as having aortitis syndrome twenty years ago, and has been treated with systemic corticosteroids. At the first ophthalmic examination, her visual acuity was 0.2 (n. c.) in the right eye and 0.4(0.5) in the left eye. Inflammatory cells in the anterior chamber of the left eye and bilateral serous retinal detachment were observed. Fluorescein angiography revealed subretinal pooling of fluorescein. In the systemic examination, pleocytosis of the cerebrospinal fluid and human leukocyte antigen (HLA) types DR2 and DR4 were also found. We diagnosed the condition as Harada's disease from these findings, and then applied systemic administration of corticosteroids. After the treatment, the bilateral serous retinal detachment immediately disappeared, and the visual acuity improved to (1.0). Vogt-Koyanagi-Harada disease associated with aortitis syndrome is very rare, because it has never been reported previously. It is possible that there is some unknown common mechanism in these two diseases, but it is more probable that this case was simply coincidental.

Adult↗
PubMed1995

Application of 198Au grains for carcinoma of oral cavity.

PURPOSE: The purpose of this study is to analyze the results of the treatment using gold grain implants over the past 9 years and to evaluate the usefulness of this treatment method. PATIENTS AND METHODS: From January 1985 through April 1993, a total of 45 patients with squamous cell carcinomas of the oral cavity and the oropharynx were treated with 198Au grain (gold grain) at the Department of Radiology, Osaka University Medical School. The initial activity of the grains supplied weekly by the Japan Radioisotope Association was usually 5 mCi (185 MBq), and single implants were usual. In case of combined external irradiation, telecobalt gamma-rays or 4 MV X-rays were used for treatment before implant. RESULTS: The local control rate for patients with T1 stages was 80% (20/25) and with T2 stages, 59% (10/17). The local control rate was 71% (10/14) for gold grain alone and 72% (13/18) for external irradiation combined with gold grain implants (combined therapy). In combined therapy, the median of the interval between external irradiation and gold grain implants was 21 days. The treatment interval for patients with recurrent diseases was 22 days, 22, 27, 39 and 46, respectively. The progression rate showed a tendency to increase in the patients with longer interval (more than 21 days), and with partial regression after external irradiation (p = 0.0085). CONCLUSION: Our findings show that the time interval between external irradiation and gold grain implantation is an important factor in combined therapy. Therefore, we emphasize that the time interval should be shorter than 3 weeks.

Adult↗
PubMed1994

P-glycoprotein overexpression in mouse cells does not correlate with resistance to N-benzyladriamycin-14-valerate (AD 198).

The novel anthracycline N-benzyladriamycin-14-valerate (AD 198) circumvents P-glycoprotein (P-gp)- and altered topoisomerase II-mediated drug resistance. Nevertheless, AD 198-resistant (AD 198R) murine J774.2 cells overexpressed P-gp, were cross-resistant to other drugs through reduced accumulation and were rendered sensitive by continuous exposure to verapamil. Intracellular AD 198 was, however, similar in sensitive and resistant cells. Consequently, the ability of P-gp to confer AD 198 resistance was examined. It was observed that (i) AD 198 resistance in AD 198R cells grown without drug for 15 months declined by 60% with only a 10-15% loss of vinblastine cross-resistance and P-gp expression; (ii) a cloned AD 198R P388 mouse leukemic cell line did not express P-gp; and (iii) verapamil did not attenuate resistance against high-dose, short-term exposure to AD 198. Therefore, AD 198 resistance appeared to be P-gp-independent despite P-gp overexpression. Antioxidant enzyme and topoisomerase II activities remained unchanged between sensitive and resistance cells. These results suggest that AD 198 resistance was conferred by a novel mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

N-benzyladriamycin-14-valerate (AD 198)-resistant cells exhibit highly selective cross-resistance to other anthracyclines that circumvent multidrug resistance.

N-Benzyladriamycin-14-valerate (AD 198)-resistant murine J774.2 macrophage-like cells (A300) exhibited a novel mechanism of resistance in which P-glycoprotein was overexpressed without decreased AD 198 accumulation. Cross-resistance to Adriamycin (ADR), N-benzyladriamycin, and Adriamycin-14-valerate was due, at least in part, to reduced accumulation, suggesting that circumvention of P-glycoprotein-mediated transport was associated with extreme lipophilicity conferred by both substitutions. Thus, unlike multidrug resistance mediated by either P-glycoprotein, the multidrug resistance-associated protein (MRP), or decreased topoisomerase II activity, cross-resistance in A300 cells was highly structure-specific. In order to further characterize the specificity of AD 198 resistance, the cytotoxicity, accumulation, and intracellular localization of a series of 3'-morpholinyl, 3'-deamino and halogenated ADR congeners that have been reported to circumvent MDR was determined in AD 198-resistant J774.2 and P388 AD 198-resistant cells. Cross-resistance correlating with increased AD 198 resistance was observed for 2'-bromo-4'-epi-hydroxy-daunomycin (13-fold), morpholinyl doxorubicin (24-fold), and 4'-iodo-4'-deoxydoxorubicin (2.8-fold), but was attributable to decreased accumulation. Cross-resistance to 3'-hydroxy-14-O-palmitoyl-doxorubicin (6-fold) was not due to reduced accumulation. No cross-resistance was observed for the highly cytotoxic metabolite of WP474, 3'-hydroxyldoxorubicin (hydroxyrubicin; WP159), nor for the much less cytotoxic 3'-O-benzylated congeners, including 3'-O-benzyl-doxorubicin-14-valerate. These findings indicate that AD 198 resistance confers cross-resistance to compounds that, like AD 198, localize in the cytoplasm but are metabolized to highly cytotoxic, nuclear-localizing compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[Effects of nipradilol on the patients of angina pectoris: results from the study of the exercise electrocardiography using HR-ST loop method].

This study was performed to confirm the usefulness of 12 mg nipradilol, a beta-blocker with a vasodilator action similar to that of nitrate-type drugs, in the treatment of effort angina pectoris. It also discusses the mechanism of the action of this drug when using the exercise test heart rate-ST displacement analysis. The symptom threshold multistage graded exercise test was performed using nine patients with chronic stabilized effort angina pectoris after an observation period and an 8-week administration period and HR-ST analysis was performed simultaneously. The number of anginal attacks significantly decreased from the 2nd week, and the heart rate at rest decreased significantly in the prone position although blood pressure did not change. The maximum oxygen intake increased markedly from 13.7 +/- 1.1 ml/kg/min to 19.3 +/- 2.5 ml/kg/min, and the maximum ST decrease improved significantly from 1.72 +/- 0.45 mm to 1.17 +/- 0.19mm. In HR-ST analysis, delta ST/delta HR and delta ST/delta DP tended to improve slightly. Since monotherapy with a beta-blocker causes significant increase in delta ST/delta HR and delta ST/delta DP, it was assumed that a vasodilator action in addition to a beta-blocker action is involved in the improvement of maximum ST decrease brought about by nipradilol.

Adrenergic beta-Antagonists↗
PubMed1989

DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA.

Three groups of doxorubicin and daunorubicin analogues, differing by their substituents on the chromophore and sugar moieties, were used in this study. The 3'-N-unsubstituted (Group 1), 3'-N-acyl (Group 2), and 3'-N-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and in vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and (d) interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were cytotoxic, were strongly intercalative, and, except for those with C-14 side chain substitution, induced the formation of topo-II-DNA cleavable complexes. As shown previously, esterolysis of C-14-acyl substituents was required to yield a metabolite which can interact with topo-II in the purified system. The C-14-substituted compounds of Group 2 and their C-14-unsubstituted metabolites were cytotoxic. These drugs were weak intercalators, and the C-14-unsubstituted cogeners induced cleavable complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-N-position substituent determined whether Group 3 analogues were cytotoxic and strong intercalators, or less active and nonintercalating. Although C-14-unsubstituted intercalators of Group 3 did not form cleavable complexes in the purified system, they were cytotoxic. The study shows that DNA intercalation is required but not sufficient for the activity by topo-II-targeted anthracyclines. In addition to the planar chromophore which is involved in intercalation, two other domains of the anthracycline molecule are important for the interaction with topo-II: (a) substitution of the C-14 position totally inhibits drug activity in the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-N position of the sugar ring can, depending on the nature of the substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new active analogues.

Animals↗
PubMed1989

Comparative uptake and retention of adriamycin and N-benzyladriamycin-14-valerate in human CEM leukemic lymphocyte cell cultures.

N-Benzyladriamycin-14-valerate (AD 198) is a new lipophilic adriamycin (ADR) analogue that shows marked therapeutic superiority to ADR in murine tumor model systems yet differs mechanistically from ADR in a number of ways. Among its other properties, AD 198 produces a delayed but profound effect on cell-cycle progression and a pattern of continuing DNA damage in cultured cells briefly exposed to the drug. Using radiolabeled drug forms and radioassays combined with HPLC separation and fluorimetric detection techniques, aspects of drug accumulation, biotransformation, and retention in cultured human CEM leukemic lymphocytes were studied, in part to determine a possible pharmacologic basis for the latent effects seen with this drug. In addition, the cellular pharmacology of AD 198 and ADR were comparatively examined under identical experimental conditions. When CEM cells were incubated with drug at equi-growth inhibitory/minimally cytotoxic concentrations (AD 198, 1.0 microM; ADR, 0.1 microM), a number of differences were apparent. Under conditions of continuous 24-h drug exposure, a slow cellular accumulation and equilibration was observed with ADR (cell: medium equilibrium, 1:11 after 4-6 h), whereas the uptake of AD 198 was rapid and extensive (cell: medium equilibrium, 3:1 within 30 min). In drug-retention studies, when cells were pretreated at the same drug concentrations as before (AD 198 for 1 h; ADR for 4 h) and then transferred to drug-free media, both compounds re-equilibrated their intracellular drug content with the fresh media, losing about 50% of their respective anthracycline levels. Liquid chromatographic analysis of ADR-treated cultures under both sets of conditions showed the parent drug to be the only intracellular anthracycline species, whereas analysis of AD 198-treated cultures revealed two fluorescent signals corresponding to the parent drug and its 14-de-esterified biotransformation product, N-benzyladriamycin (AD 288). Levels of AD 288 rose from 2% of the total intracellular anthracycline content immediately on drug admixture to 61% following 24 h continuous drug exposure and to 69% at 24 h in cells exposed to drug for 1 h and then continued in drug-free media for 24 h. At all times, the balance of the intracellular anthracycline fluorescence was attributable to the parent drug; no ADR was detectable in AD 198-treated cells by either fluorescence detection or radioassay.(ABSTRACT TRUNCATED AT 400 WORDS)

Biotransformation↗