EFFECTS OF LOCALLY ADMINISTERED ARGATROBAN ON RESTENOSIS AFTER BALLOON ANGIOPLASTY: EXPERIMENTAL AND CLINICAL STUDY

1. This study was undertaken to evaluate the preventive effects of locally administered argatroban, a competitive inhibitor of thrombin-induced platelet activation, on restenosis after balloon angioplasty. 2. A hydrogel-coated balloon catheter was immersed three times in argatroban/saline solution (1 mg/mL) for 60 s, inflated to a pressure of 606 kPa and left in the rabbit common carotid artery for 1 min. The same procedure was performed, without drug, as a control. The pharmacokinetics of delivered argatroban in the arterial wall were assessed using [¹⁴C]-argatroban. Platelet deposition 2h after balloon injury was quantified by fluorescence studies using antiplatelet antibody. Vascular smooth muscle cell (VSMC) proliferation 3 days after balloon injury was assessed by immunohistochemical staining for proliferative cell nuclear antigen (PCNA). In a clinical study, we divided 50 elective patients into two groups: argatroban and control. 3. In the experimental study, the mean quantities of argatroban at 0, 2 and 6 h after deflation wer. 24.63, 0.49 and 0.11 nmol/g wet weight of artery, respectively. Argatroban was undetected 24 h after deflation. Two hours after deflation, argatroban-treated arteries showed less platelet adhesion than saline-treated controls. The mean number of PCNA-positive cells was 16.9 and 43.8% in the argatroban and control groups, respectively (P < 0.01). In the clinical study, the mean late gain loss was 8.2 and 27.3% in the argatroban and control groups, respectively (P < 0.05). The mean late restenosis rate was 11.1 and 41.4% in the argatroban and control groups, respectively (P<0.05). 4. These data suggest that blood coagulation plays a significant role in VSMC proliferation after balloon injury and that locally administered argatroban using hydrogel-coated balloon catheter may prevent post-percutaneous transluminal coronary angioplast. restenosis.     

Effect of adrenergic blockade on gastric secretion altered by catecholamines in rats.

The effect of adrenergic blockade on gastric secretion altered by catecholamines was studied for 4 hr after injection in rats with chronic gastric fistulas. The alpha-adrenergic blockers phenoxybenzamine and phentolamine significantly inhibited the basal secretion of HCl and pepsin. Blockade of the beta-adrenergic receptors with propranolol did not change this secretion. Practolol in small doses slightly increased and in larger doses inhibited HCl out-put. Of the catecholamines, adrenaline and dopamine most markedly reduced HCl and pepsin secretion, while noradrenaline and isoprenaline had a weaker effect. Neither alpha- nor beta-adrenergic blockers prevented the inhibitory action of the catecholamines employed, but intensified the depression of the gastric secretion provoked by them. Adrenergic blockers inhibited secretion after catecholamines as well as basal secretion. This indicates that these two antagonistic groups of compounds act independently on the mechanism controlling gastric secretion. It is unlikely that this takes place indirectly through changes in the blood supply of the gastric mucosa.     

Components of root bark of morus lhou1 1. Structures of two new natural diels-alder adducts, kuwanons N and o

Kuwanons N and O, two new flavonoid derivatives with a fused dihydrochalcone partial moiety, and four known flavonoid derivatives, morusin, kuwanons G, H, and K, were isolated from the ethyl acetate extract of the root bark of MORUS LHOU (SER.) Koidz. The structures of kuwanons N and O were shown to be 1 and 2, respectively, on the basis of spectral data. They are regarded biogenetically as Diels-Alder adducts of a chalcone and a dehydroprenyl flavonoid.     

Structures of four new isoprenylated xanthones, cudraxanthones h,i,j, and k1,2

Four new isoprenylated xanthones, cudraxanthone H,I,J, and K were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Moraceae), collected in China. The structures of cudraxanthones H,I,J, and K were shown to be 1- 4, respectively, on the basis of chemical and spectral evidence.     

Structures of three new isoprenylated xanthones, cudraxanthones e, f, and g 1,2

Three new isoprenylated xanthones, cudraxanthones E, F, and G along with a known xanthone, 6-deoxyisojacareubin, were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Moraceae), collected in China. The structures of cudraxanthones E, F, and G were shown to be 1-3, respectively, on the basis of spectral evidence.     

Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up

Summary Plasma concentration-time profiles of nimustine hydrochloride, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), in the mouse, rat, rabbit, and dog were determined by high-performance liquid chromatographic analysis. The pharmacokinetic parameters for these four animal species and previously reported clinical data were analyzed for investigation of interspecies correlation. Loglog plots of body weight (W; kg) vs total plasma clearance (CLtot, p; ml/min) and steady-state distribution volume (Vd, ss; 1) for the four animal species were linear, with high correlation coefficients (r 0.996 for both parameters), despite the fact that the nonrenal clearance was >97% in these species. Linear regression on the plots excluding human data yielded allometric equations (CL_tot,p=50.6 W^0.957; Bd, ss=1.29 W^1.03) that were extrapolated to predict ACNU pharmacokinetic parameters in humans. For both parameters, however, there were 3-fold differences between the predicted and observed parametric values. To investigate these discrepancies, we measured serum protein binding of ACNU in these animal species and in humans. The values of CLtot,p and Vd,ss were converted into those of CL^u _tot,p and Vd,^u _ss, which correspond to the parameters for unbound ACNU. In this case, correlation coefficients of the log-log plots excluding human data (CL^u _tot,p=71.7 W^0.891; Bd,^u _ss=1.82 W^0.966) were also high (r0.991). The extrapolated values vs those observed in a 70-kg human were the following: CL^u _tot,p, 3,160 vs 2,290 ml/min; Vd,^u _ss, 110 vs 1061. Thus, the animal data were successfully extrapolated to yield better predictions of human pharmacokinetic parameters if the analysis was based on the unbound plasma concentration of ACNU. In addition, the predicted plasma concentration-time profile for humans also showed good agreement with the observed ones. These results suggest the importance of measuring unbound fractions of drugs for more accurate prediction of human pharmacokinetic parameters by extrapolation of animal data to the human situation.     

Constituents of the chinese crude drug "Sāng-Bái-Pí" (morus root bark)

From the benzene extract of the Chinese crude drug "Sāng-Bái-Pí" (Japanese name Sōhakuhi), the root barks of MORUS sp. (Moraceae), a novel isoprene substituted flavanone derivative, named sanggenon B, was isolated; its structure was shown to be I on the basis of spectral and chemical data. Sanggenon B (I) is regarded biogenetically as a variation of a Diels-Alder adduct of a chalcone derivative and a dehydroprenylflavanone derivative.     

Constituents of the Chinese crude drug "sāng-bái-pí" (Morus root bark)

From the benzene extract of the Chinese crude drug "Sāng-Bái-Pí" (Japanese name Sōhakuhi), the root bark of MORUS sp. (Moraceae), a novel isoprene substituted flavanone, named sanggenon A, was isolated whose structure was shown to be I on the basis of spectral data. A known isoprene substituted flavone derivative, morusin (II), was also obtained from the extract.     

Relationship between HLA-DRB1*0101, DRB1*0301 alleles and interleukin-12 in haemophilic patients and hepatitis C virus positive hepatocellular carcinoma patients

The immune system can effectively eliminate hepatitis C virus (HCV) in 15 % of acute hepatitis cases. It is assumed that certain HLA-DR alleles present HCV epitopes more effectively to CD4 helper T cells than do others resulting in vigorous proliferative response to these epitopes and probably HCV recovery. So, we aimed at investigating the frequency of HLA-DRB1*0101 and DRB1*0301 alleles in child and adult haemophilics and in HCV positive hepatocellular carcinoma (HCC) patients in a trial to predict patients who require early therapeutic intervention. We also evaluated interleukin (IL)-12 levels in these patients since IL-12 induces interferon (IFN)-gamma production. This study was conducted on 50 antiHIV negative male patients subdivided into: 25 HCV negative haemophilics (group I), 10 HCV positive haemophilics (group II) and 15 HCV positive HCC (group III). Fifteen healthy persons of matched age and free of HCV and HIV infections were chosen as controls (group IV). All patients and controls were subjected to thorough history taking and clinical examination, routine and diagnostic investigations, viral markers, DRB1*0101 and DRB1*0301 amplification by polymerase chain reaction and plasma IL-12 quantitation by enzyme linked immunosorbent assay (ELISA). The frequencies of DRB1*0101 and DRB1*0301 were 20% and 30% respectively in HCV positive haemophilics and 13.3% and 40%, respectively in HCC. IL-12 levels were significantly lower in HCC cases than in HCV positive haemophilics. Among the haemophilics, IL-12 levels were non-significantly higher in children than in adults and were associated with the given number of blood product bags. DRB1*0101 and DRB1*0301 may have a role in HCV clearance and persistence in Egyptian patients with haemophilia and HCC. Low IL-12 levels encountered in HCV positive haemophilics suggest its relation to immunopathogenesis and outcome of HCV infection.     

Frequent loss of heterozygosity in two distinct regions,8p23.1 and 8p22, in hepatocellular carcinoma

AIM: To identify the precise location of putative tumor suppressor genes (TSGs) on the short arm of chromo- some 8 in patients with hepatocellular carcinoma (HCC). METHODS: We used 16 microsatellite markers informative in Japanese patients, which were selected from 61 pub- lished markers, on 8p, to analyze the frequency of loss of heterozygosity (LOH) in each region in 33 cases (56 lesions) of HCC. RESULTS: The frequency of LOH at 8p23.2-21 with at least one marker was 63% (20/32) in the informative cases. More specifically, the frequency of LOH at 8p23.2, 8p23.1, 8p22, and 8p21 was 6%, 52%, 47%, and 13% in HCC cases. The LOH was significantly more frequent at 8p23.1 and 8p22 than the average (52% vs 22%, P = 0.0008; and 47% vs 22%, P = 0.004, respectively) or others sites, such as 8p23.2 (52% vs 6%, P = 0.003; 47% vs 22%, P = 0.004) and 8p21 (52% vs 13%, P = 0.001; 47% vs 13%, P = 0.005) in liver cancer on the basis of cases. Notably, LOH frequency was significantly higher at D8S277, D8S503, D8S1130, D8S552, D8S254 and D8S258 than at the other sites. However, no allelic loss was detected at any marker on 8p in the lesions of nontumor liver tissues. CONCLUSION: Deletion of 8p, especially the loss of 8p23.1-22, is an important event in the initiation or promotion of HCC. Our results should be useful in identi- fying critical genes that might lie at 8p23.1-22.