Abstract Opiate addiction and stress have been associated with altered immune responses. In this study, we evaluated the influence of morphine and the stress responsive opioid peptide beta-endorphin (beta-END) on O-2 and H2O2 production by cultured human peripheral blood mononuclear cells. Exposure of these cells during 48 hr of culture to morphine and beta-END at pharmacologically (10(-8) M) and physiologically (10(-12) M) relevant concentrations, respectively, markedly suppressed peripheral blood mononuclear cell O-2 and H2O2 release in response to the respiratory burst stimuli opsonized zymosan and phorbol myristate acetate. Both opioids also induced a minimal, but statistically significant, increase in resting O-2 and H2O2 generation. The modulatory effects of morphine and beta-END on peripheral blood mononuclear cell oxygen metabolism appeared to involve a classical opioid receptor, because opioid activity was blocked by naloxone and was not observed with N-acetylated-beta-END. Using purified lymphocyte and monocyte preparations, we determined that although opioids directly increase monocyte-resting oxygen metabolism, lymphocytes are the primary target cell in opioid-mediated suppression of monocyte respiratory burst activity. The release of a suppressive product from opioid-triggered lymphocytes was inhibited by cyclosporine. Based on the results of this study, we propose that opioid-mediated suppression of mononuclear phagocyte respiratory burst activity is another factor to be considered in the immunodeficiency of opiate addiction and stress.
The pharmacokinetics of cefsulodin were characterized in 19 patients with different degrees of renal function after a single 500-mg, 30-min intravenous infusion. Six subjects had a creatinine clearance (Clcr) of greater than 100 ml min-1 (group I), eight had a Clcr of between 12 and 42 ml min-1 (group II), and five had a Clcr of less than 10 ml min-1 (group III). Nine plasma and four urine samples were collected in the first 36 h. The plasma concentration-time data were fitted to a two-compartment open model. The mean beta-phase half-life was 1.77, 6.37, and 10.12 h in groups I, II, and III, respectively. A significant decline in plasma clearance (Clp) was also noted between the three groups: 136 to 49.6 to 27.2 ml min-1 in groups I, II, and III, respectively. Steady-state volume of distribution was 0.26 liter kg-1, regardless of renal function. The observed linear relationship between Clp and Clcr (Clp = 24.09 + 0.765 Clcr; r = 0.9566) can be utilized to revise dosage schedules for patients with any degree of renal impairment. The nonrenal clearance of cefsulodin was also noted to be significantly lower in groups II and III than in group I. Further investigations will be necessary to elucidate the mechanism(s) responsible for the decrease in the nonrenal clearance of cefsulodin.
Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.
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