Effects of hypertrophy and allylamine-induced fibrosis on mechanical properties of isolated rat heart muscles with references to the pumping function of the intact heart in the same models

To examine the effects of hypertrophy and fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 6-month-old male SHR and allylamine-fed rats. In SHR, the peak developed tension (DT) and the maximum rate of tension development (dT/dt) were higher compared to control male Wistar-Kyoto rats (WKY). With 15 min of hypoxia, the DT and the dT/dt declined similarly in both groups and the ratios of DT and dT/dt to their prehypoxic values after 15 min of hypoxia were not different in the two groups. From allylamine-fed rats, only 4 papillary muscles had more than 25% interstitial fibrosis by point-counting (AL-B group), but 9 muscles had no fibrotic involvement and their left ventricular hydroxyproline concentration was normal (AL-A group). The myocardial diameters, the passive stiffness constant and the duration of isometric contractions at Lmax were increased in AL-B group, but the resting tension, the DT at Lmax and the force-velocity relations did not differ from controls. The mechanical properties of the AL-A group muscles were not different from controls. However, when pumping function was examined in the intact heart from the AL-A group, the LVEDP was increased and the peak cardiac output normalized by body weight was decreased. Thus, hypertrophied muscle from SHR shows hyperfunction without an increase in susceptibility to hypoxic stress. Even if fibrosis progresses, hypertrophy can compensate for the reduction in contractile component up to a certain degree.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavior of chlorpheniramine in vivo after administration of d- and l-chlorpheniramine maleate

A high performance liquid chromatographic (HPLC) method was developed for the determination of chlorpheniramine (I) in the plasma. By this method, 1 ng of I could be measured. Plasma levels of I were determined by the HPLC method after oral administration of d-chlorpheniramine maleate (II) or l-chlorpheniramine maleate (III) to healthy subjects and dogs. Plasma levels of I brought about by oral administration of II were evidently higher than those by III both in humans and dogs. On the other hand, there was no difference in plasma levels of I when II or III was injected intravenously into dogs. Therefore, it was considered that the discrepancy in plasma levels of I after oral administration of II and III to dogs was neither due to a difference in elimination rate nor a distribution volume but rather in first-pass effect in absorption process. The result observed in the human study could be also explained in the same way as that in dogs.     

A new antitumor complex, WF-1360, WF-1360A, B, C, D, E and F

A complex of the new antitumor antibiotics (WF-1360, WF-1360A, B, C, D, E and F) was produced by Rhizopus sp. No. F-1360. Structural studies of these compounds suggested that they were novel 16-membered-ring lactones having an oxazole ring in their structures. WF-1360 was found to be identical with rhizoxin (1) and WF-1360B, C, E and F were determined to be homologues of 1 with structures 2, 3, 4 and 5, respectively. These compounds were cytotoxic when tested on P388 leukemia cells in vitro. WF-1360 was highly active against leukemia L1210 and melanoma B16. They also exhibited potent antifungal activities, but weak antimicrobial activities against some Gram-positive or negative bacteria.     

Chronic herpes simplex encephalitis with somnambulism: CT, MR and SPECT findings

A 64-year-old male with herpes simplex encephalitis had shown somnambulism and memory disturbance for nine months before consciousness disturbance appeared. Brain CT, MR and SPECT revealed lesions in the right temporal lobe. The atypical clinical course of this patient, including chronicity and focal symptom, is discussed.     

Thrombolytic properties of a novel modified human tissue-type plasminogen activator (E6010): a bolus injection of E6010 has equivalent potency of lysing young and aged canine coronary thrombi.

The thrombolytic properties of a novel modified human tissue plasminogen activator (E6010), in which cystein 84 in the epidermal growth factor domain is replaced by serine and that has a prolonged biological half-life, were examined. The thrombolytic efficacies of E6010 and recombinant human tissue plasminogen activator (rt-PA) on the duration of coronary artery thrombus were evaluated in a canine model (123 anesthetized dogs) with copper coil-induced left anterior descending coronary artery thrombus. Thrombi established for periods of 1, 3, or 6 h, as documented by coronary arteriography, were employed. A single bolus i.v. injection of E6010 or rt-PA and an i.v. infusion of rt-PA over 60 min were compared (n = 6). Thrombolytic efficacy was evaluated by three criteria: time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rate at 60 min after reperfusion (OR). With a bolus i.v. injection of E6010 at a dose of 0.2 mg/kg or an i.v. infusion of rt-PA at a dose of 0.6 mg/kg/h, these parameters were as follows: TR, 30.0 +/- 15.3 and 27.5 +/- 4.8 min; RR, 100 and 100%; OR, 17 and 33% for 1-h aged thrombi; TR, 30.0 +/- 9.5 and 35.0 +/- 8.2 min; RR, 83 and 50%; OR, 20 and 67% for 6-h aged thrombi. These data indicate that a bolus injection of E6010 is almost equally efficacious in lysing thrombi aged both 1 and 6 h. On the other hand, in the case of rt-PA, the thrombi aged 6 h were lysed significantly less than the thrombi aged 1 h. Plasma half-lives of E6010 were t1/2 alpha, 4.8 +/- 0.95 (estimated by antigen level) and 3.0 +/- 0.78 min (estimated by activity), and t1/2 beta, 51 +/- 5.4 (antigen level) and 22 +/- 7.0 min (activity). The half-lives of rt-PA were t1/2 alpha, 3.6 +/- 0.23 (antigen level) and 2.1 +/- 0.61 min (activity), and t1/2 beta, 36 +/- 2.3 (antigen level) and 7.0 +/- 3.5 min (activity). We conclude that a bolus injection of E6010 may have a more potent and longer-lasting effect than i.v.-infused rt-PA in clot lysis therapy.     

Four Stages and Lack of Stable Accommodation in Chronic Alloantibody-Mediated Renal Allograft Rejection in Cynomolgus Monkeys

The etiology of immunologically mediated chronic renal allograft failure is unclear. One cause is thought to be alloantibodies. Previously in Cynomolgus monkeys, we observed a relationship among donor-specific alloantibodies (DSA), C4d staining, allograft glomerulopathy, allograft arteriopathy and progressive renal failure. To define the natural history of chronic antibody-mediated rejection and its effect on renal allograft survival, we now extend this report to include 417 specimens from 143 Cynomolgus monkeys with renal allografts. A subset of animals with long-term renal allografts made DSA (48%), were C4d positive (29%), developed transplant glomerulopathy (TG) (22%) and chronic allograft arteriopathy (CAA) (19%). These four features were highly correlated and associated with statistically significant shortened allograft survival. Acute cellular rejection, either Banff type 1 or 2, did not correlate with alloantibodies, C4d deposition or TG. However, endarteritis (Banff type 2) correlated with later CAA. Sequential analysis identified four progressive stages of chronic antibody-mediated rejection: (1) DSA, (2) deposition of C4d, (3) TG and (4) rising creatinine/renal failure. These new findings provide strong evidence that chronic antibody-mediated rejection develops without enduring stable accommodation, progresses through four defined clinical pathological stages and shortens renal allograft survival.