The role of ethyl acrylate induced GSH depletion in the rodent forestomach and its impact on MTD and in vivo genotoxicity in developing an adverse outcome pathway (AOP).

Adverse outcome pathways (AOP) and mode of action (MOA) frameworks help evaluate the toxicity findings of animal studies and their relevance to humans. To effectively use these tools to improve hazard identification and risk assessments for ethyl acrylate (EA), knowledge gaps in metabolism and genotoxicity were identified and addressed. For EA, hypothesized early key events relate to its irritation potential: concentration dependent irritation and cytotoxicity, progressing to regenerative proliferation and forestomach carcinogenicity after repeated oral bolus application in rodents. The current research quantitated glutathione (GSH) depletion to assess a kinetically-derived maximum tolerated dose (MTD) in the target tissue and used this information to conduct an in vivo genotoxicity study using current methods. In the mouse forestomach, gavage doses of EA caused GSH depletion to 47% of control at 20 mg/kg and 28% at 100 mg/kg. Cellular redox changes and histopathology support saturation of metabolism and an MTD of ∼50 mg/kg. No increases in point mutations or deletions occurred in the stomach or liver following a 28 day treatment of gpt delta transgenic mice at gavage doses up to 50 mg/kg/day. These results provide valuable information for evaluating AOP molecular initiating events or MOA key events for EA and other GSH depleting materials.

Peripheral vascular tone in patients with cirrhosis: role of the renin-angiotensin and sympathetic nervous systems.

OBJECTIVE: The aims of the study were to establish the roles of angiotensin II and of the cardiopulmonary baroreceptor reflex in the regulation of peripheral vascular tone in patients with cirrhosis. METHODS: Forearm blood flow responses to subsystemic, locally active intrabrachial infusions were measured in patients with Child's Grade C cirrhosis and matched controls using bilateral venous occlusion plethysmography. Responses were determined to the angiotensin II type I receptor antagonist, losartan, noradrenaline, angiotensin II and the nitric oxide synthase inhibitor, L-NG-monomethyl arginine. RESULTS: Losartan at 30 and 90 micrograms/min caused no significant change in blood flow in controls, but caused 23 +/- 6% and 27 +/- 5% increases in patients respectively (p < 0.001). Lower body negative pressure caused a mean bilateral reduction in forearm blood flow of 20 +/- 4% in controls (p < 0.001) but only tended to reduce flow (9 +/- 5%; p = 0.06) in patients (p < 0.001; controls vs. patients). Noradrenaline, angiotensin II and L-NG-monomethyl arginine caused significant vasoconstriction (p < 0.001) in both patients and controls although angiotensin II caused significantly less vasoconstriction in patients (p = 0.01). CONCLUSIONS: We conclude that angiotensin II makes an important contribution to basal peripheral vascular tone in patients with cirrhosis in the face of reduced vascular responses to its local administration. In addition, the vasoconstrictor response to cardiopulmonary baroreceptor unloading is attenuated despite normal vascular responses to noradrenaline. These responses are consistent with chronic activation of the renin-angiotensin and sympathetic nervous systems in patients with advanced cirrhosis.

Endogenous angiotensin II does not contribute to sympathetic venoconstriction in dorsal hand veins of healthy humans.

BACKGROUND: Sympathetically mediated venoconstriction is augmented by exogenously administered angiotensin II. This study was designed to assess whether endogenous angiotensin II influences sympathetically mediated venous tone. METHODS: Responses of dorsal hand veins to local intravenous administration of subsystemic doses of losartan, an angiotensin II type-1 receptor antagonist, were assessed with use of a well-validated displacement technique in eight healthy male volunteers. In a four-phase study, responses to local infusions of angiotensin II (4 to 64 ng/min) and norepinephrine (1 to 128 ng/min) or to sympathetic venoconstriction produced by a single deep breath were compared in the presence of either saline placebo or 30 microg/min losartan. Each phase of the study was conducted on a separate day, in random order, and each phase was separated by at least 1 week. RESULTS: Angiotensin II (p = 0.03) and norepinephrine (p < 0.001) caused dose-dependent venoconstriction. Losartan attenuated the venoconstriction induced by angiotensin II (p = 0.048) but had no effect on the responses to norepinephrine or the venoconstriction induced by a single deep breath. CONCLUSIONS: In contrast to exogenously administered angiotensin II, basal endogenous angiotensin II does not influence sympathetically mediated venoconstriction in healthy humans. However, endogenous angiotensin II may have a role in circumstances of renin-angiotensin system activation, such as salt depletion.

Amino acid losses and nitrogen balance during slow diurnal hemodialysis in critically ill patients with renal failure.

OBJECTIVE: The effects of slow diurnal hemodialysis (slow HD) on amino acid losses and nitrogen balance were studied. DESIGN: Slow HD was conducted for 10 h during the day at the dialysate flow rate of 30 ml/min. The patients received total parenteral nutrition including 40 g of amino acids (6.08 g of nitrogen). The amino acid concentrations in plasma and dialysate were determined and the daily nitrogen balance was calculated from the urea nitrogen appearance. PATIENTS: Six critically ill patients with renal failure were entered into the study. RESULTS: Slow HD eliminated 48.5 +/- 4.4 mmol (6.2 +/- 0.6 g) of amino acids, representing 16% of the daily amino acid load. The estimated nitrogen balance was -2.3 +/- 1.3 g/day. Amino acid nitrogen lost in the dialysate was 1.0 +/- 0.1 g, contributing 43% of the daily negative nitrogen balance. CONCLUSION: The amount of amino acid losses during slow HD should be taken into consideration when designing nutritional schedules for maintaining positive nitrogen balance in critically ill patients.

Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man.

OBJECTIVE: Both endothelin-1 and nitric oxide make important contributions to the maintenance of basal peripheral arteriolar tone. However, the role of angiotensin II, a key hormone regulating cardiovascular and renal function, in the regulation of peripheral vascular tone has not been fully characterised. METHODS: Using local intra-arterial administration of losartan, a selective angiotensin II type 1 (AT1) receptor antagonist, we examined the contribution of endogenous angiotensin II to the maintenance of basal and sympathetically stimulated vascular tone in the forearm of healthy man under conditions of sodium repletion and depletion. The effects of losartan on responses to exogenous angiotensin I, angiotensin II, bradykinin and noradrenaline were also determined. RESULTS: Losartan, in keeping with its actions as a selective AT1 receptor antagonist, inhibited responses to angiotensin I and II, but had no effect on responses to bradykinin or noradrenaline. The dose of angiotensin II required to cause a 20% vasoconstriction was 40- and 250-fold greater with 30 and 300 micrograms/min of losartan, respectively. However, in sodium replete subjects, losartan alone caused no significant changes in basal forearm blood flow (95% confidence interval of -7.2 to +8.0%), forearm vascular resistance or sympathetically stimulated forearm vasoconstriction. Sodium depletion elevated plasma renin activity and angiotensin II concentrations (p < or = 0.002) after which acute local administration of losartan increased forearm blood flow in a dose dependent manner (maximum of 69 +/- 17%; p < 0.001). CONCLUSIONS: Endogenous angiotensin II does not contribute to the acute local maintenance of basal peripheral vascular tone in healthy man except under conditions of renin-angiotensin system activation such as sodium depletion.

Pharmacokinetics and pharmacodynamics of nisoldipine in hypertensive patients with normal and mild to moderate impaired renal function.

The pharmacokinetics and pharmacodynamics of nisoldipine (CAS 63675-72-9, isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate, Bay k 5552), a calcium antagonist, were investigated after administration of a single oral 10 mg dose and after 7 same doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with mild to moderate renal dysfunction (impaired renal function, IRF). A significant decrease in blood pressure was observed after consecutive dosing of nisoldipine compared to baseline values over 24 h in both groups. There were no significant differences in plasma profiles of nisoldipine in both groups after either single or consecutive dosing. The plasma concentration-time profiles of the active metabolite, Bay r 9425, were similar to those of nisoldipine in both groups. The pharmacokinetic parameters of nisoldipine and its active metabolite in the NRF and IRF groups did not differ after the single and the consecutive dosing. In addition, there were neither prolongation of apparent elimination half-life (t1/2), nor increases in peak plasma levels (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) after consecutive dosing in both groups. Cumulative urinary excretion rates of the major metabolites, Bay s 4755 and Bay s 1869, did not differ significantly between the NRF and IRF groups in both single and consecutive studies. In the present study, mild flushing was observed in one patient with IRF. There was no deterioration in renal function during the study. These results suggest that nisoldipine may have a long-lasting antihypertensive effect during consecutive dosing and that it can be used in hypertensive patients regardless of presence of renal dysfunction.

Pharmacokinetics of single-dose intravenous amikacin in critically ill patients undergoing slow hemodialysis.

OBJECTIVE: The pharmacokinetics of amikacin were studied in patients undergoing slow hemodialysis (HD). DESIGN: Slow HD was performed at the dialysate flow rate of 30 ml/min. After a single intravenous dose of amikacin 5 mg/kg, pharmacokinetic variables were calculated by fitting individual concentration-time curves to a two-compartment open model. PATIENTS: 6 critically ill patients with renal failure were entered into the study. RESULTS: The volume of distribution was 0.35 +/- 0.03 l/kg. Total body clearance was 35.1 +/- 2.3 ml/min with an elimination half-life of 10.5 h. During a 10.5 h session of slow HD, the serum amikacin concentration decreased from the peak level of 21.3 +/- 1.2 mg/l to 7.2 +/- 0.9 mg/l. CONCLUSION: Slow HD eliminate amikacin more efficiently than other types of slowly performed renal replacement therapy and had profound effects on the pharmacokinetics. Amikacin elimination by this approach should be taken into consideration for designing a dosage schedule during the treatment.

Pharmacokinetic profiles of intravenous imipenem/cilastatin during slow hemodialysis in critically ill patients.

The pharmacokinetics of imipenem/cilastatin were determined in 7 critically ill patients undergoing slow hemodialysis (HD). All patients were anuric. Following intravenous administration of 500 mg of imipenem/cilastatin, concentrations of the drugs in the serum and dialysate were monitored during slow HD. The elimination phase half-life of imipenem was 3.1 +/- 0.3 h and that of cilastatin was 9.7 +/- 1.2 h. The total body clearance of imipenem and cilastatin was 84.0 +/- 7.2 and 32.2 +/- 2.4 ml/min, respectively. Clearance of imipenem and cilastatin during slow HD was 24.3 +/- 2.4 and 54.3 +/- 3.1%, respectively, of total body clearance. After the 10.5-h session of slow HD, serum concentrations of imipenem and cilastatin were 2.3 +/- 0.4 and 16.0 +/- 1.2 mg/l, respectively. It appears that at least 500 mg of imipenem may be needed as a supplemental dose after a session of slow HD or the application interval should be shortened to maintain a therapeutic concentration.

[Maintenance hemodialysis in IgD- lambda -type multiple myeloma associated with severe renal failure].

A 52-year-old man was admitted to our hospital because of oliguric renal failure. The patient was well until four weeks earlier, when he developed nausea and anorexia. The urea nitrogen was 179 mg/dl, creatinine 29.2 mg/dl, uric acid 19.0 mg/dl and potassium 8.6 mEq/1. Hemodialysis was started immediately after admission. Bone marrow aspiration showed atypical plasma cell infiltration consistent with multiple myeloma. The immunoelectrophoresis revealed urinary lambda -type Bence Jones protein and serum IgD- lambda -type M protein. The findings of renal biopsy study were consistent with myeloma kidney. On the fourth hospital day, administration of prednisolone 40 mg and melphalan 2 mg was started. The patient also underwent double filtration plasma-pheresis (DFPP). Serum IgD level was decreased from 950 to 113 mg/dl. After a course of chemotherapy, however, he developed severe leukopenia and was complicated with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This complication was successfully treated with imipenem/cilastation and vancomycin combined with granulocyte colony stimulating factor (G-CSF). The patient was discharged and returned to work on maintenance hemodialysis. Fifteen months after the presentation, he manifested progressive peripheral nerve disturbances. Three months later, the patient died--not from renal failure, but from ventricular arrhythmia. The application of maintenance dialysis therapy to myelomatosis has until now been questioned. The present case, however, suggests that aggressive treatment consisting of chronic dialysis therapy as well as chemotherapy and plasma exchange should be administered even in patients with established renal failure.

Slow hemodialysis performed during the day in managing renal failure in critically ill patients.

Slow hemodialysis (HD) was performed for 10 h during the day in 11 critically ill patients with renal failure. The dialysis method was a modification of the pump-driven continuous venovenous HD. A nonsterile bicarbonate-containing hemodialysate was passed into the EVAL membrane dialyzer at a flow rate of 30 ml/min. No patient developed further hemodynamic instability during the treatment. The serum urea level was maintained below 20 mmol/l within 4 days of initiating the treatment. It allowed the patients to rest without interruption at night. This method was safely conducted by general nursing staff under the supervision of nephrologists on duty during the day. This schedule offers an approach to renal replacement therapy for hemodynamically unstable patients without any potential problem in the extracorporeal circulation at night.

Well-differentiated adenoma at the anorectal junction.

Twenty-six cases of patients having adenomatous polyps at the anorectal junction are presented. Most polyps in this region were well-differentiated, and atypical polyps were infrequently seen. Well-differentiated adenomatous polyps in the anorectal junction were larger in average size than ordinary colorectal polyps having the same grade of epithelial pseudostratification. The reason adenomatous polyps at the anorectal junction grow to large sizes with only a relatively rare occurrence of malignant degeneration is discussed in relation to their specific location. Some well-differentiated adenomas were considered to develop secondarily in the bases of hemorrhoids or in pre-existing fibrous polyp that were the end result of hemorrhoids.

Is rectal carcinoid argyrophilic? Application of Grimelius' silver nitrate stain in four cases.

In four cases, small rectal carcinoids from patients who did not have accompanying significant clinical signs or metabolic disturbances were found to give a definite argyrophil reaction by double or triple impregnation of Grimelius' silver nitrate stain, but not by other silver methods for argyrophil or argentaffin granules, regardless of variations of cellular arrangement in ribbon-like, solid, and sclerosing patterns. The implication that the carcinoid tumor occurring in the rectum may constitute a group distinct from carcinoids arising from other sites is discussed.