Characterization of the exfoliative antispermatogenic agent 1-(2,4-dichlorobenzyl)-H-indazole-3-carboxylic acid in the rhesus monkey.

The effects of oral doses of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid (DICA) on spermatogenesis in the rhesus monkey (Macaca mulatta) was studied. Four animals given five daily 50 mg/kg doses or three or five daily 500 mg/kg doses showed that DICA was an exfoliating antispermatogenic compound. The inhibition of spermatogenesis was only partially reversible following 500 mg/kg doses of DICA. Weekly and monthly 50 mg/kg doses of DICA only partially inhibiting spermatogenesis as measured by electro-ejaculated sperm counts. Response in individual monkeys ranged from azoospermia to no effect. Testicular biopsies confirmed this finding. DICA did not affect serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), or testosterone concentrations. The blood absorption or urinary excretion rates of uniformly tritiated DICA in the animals that responded well did not differ from those monkeys that responded poorly. DICA metabolites were not detected in monkey urine. Serum testosterone concentrations appeared to vary with the season of the year, but FSH concentrations and ejaculated sperm count did not.     

Comparison of the effects of 15 and 60 micrograms/kg fentanyl used for induction of anesthesia in patients with coronary artery disease

We compared the effects of 15 and 60 micrograms/kg fentanyl used for induction in 40 patients, 50-72 yr old, with coronary artery disease and mildly impaired ventricular contractility. Morphine (0.1 mg/kg) and scopolamine (0.4 mg) were used for premedication. Crystalloid (500 ml) was administered before induction, and nitroglycerin (0.3 micrograms X kg-1 X min-1) was infused during the study. Fentanyl, 15 or 60 micrograms/kg, was administered at a rate of 1.2 micrograms X kg-1 X sec-1. Pancuronium (0.04 mg/kg) and metocurine (0.16 mg/kg) were used for muscle relaxation. Data were collected 2 min before induction (baseline), before intubation (3 min), at 6 min, and at 13 min. Responses to 15 and 60 micrograms/kg were similar. At 3 min the heart rate (HR) in patients given 15 micrograms/kg increased by 6; whereas the HR in those given 60 micrograms/kg increased by 14 (P less than 0.01). Subsequent differences in HR were not significant. There were no dose-related differences in mean arterial pressure, cardiac index, central venous pressure, or pulmonary capillary wedge pressure. The EEG showed high-voltage low-frequency activity within 2 min in all patients. Arterial plasma fentanyl concentrations at 3 min averaged 25.9 +/- 3.8 ng/ml with 15 micrograms/kg and 89.9 +/- 15.2 ng/ml with 60 micrograms/kg. At 4 hr, plasma concentrations averaged 0.4 +/- 0.2 ng/ml and 3.6 +/- 0.7 ng/ml, respectively. We conclude that anesthesia for induction and intubation is achieved by the rapid administration of 15 micrograms/kg fentanyl and that 60 micrograms/kg has no substantially different effect on cardiovascular responses.     

GnRH-A induced arrest of spermiogenesis in rats is associated with altered androgen binding protein distribution in the testis and epididymis.

This study examines the effects of a potent gonadotropin releasing hormone (GnRH)-antagonist (GnRH-A, Ac-D[2] Nal1, 4-CL-D Phe2, D-Trp3, D-Arg6, D-Ala10) upon the distribution of androgen binding protein (ABP) in serum, testis, and epididymis, and its relationship with the completion of spermatogenesis in Sprague-Dawley rats. After 2 weeks of daily injections of 10 micrograms/kg, 50 micrograms/kg, 100 micrograms/kg, or 500 micrograms/kg of GnRH-A, testicular ABP content was either unchanged or elevated (P less than 0.05), and serum ABP levels were elevated (P less than 0.01). Spermatogenesis was maintained in animals administered 10 micrograms/kg or 50 micrograms/kg GnRH-A, and epididymal ABP content remained unchanged. On the other hand, daily injections of 100 micrograms/kg or 500 micrograms/kg GnRH-A resulted in a significant decrease in epididymal ABP content (P less than 0.05), and spermatogenesis was arrested at early spermiogenesis. After 4 weeks of GnRH-A administration, both testicular and epididymal ABP were decreased in a dose-dependent manner in animals receiving doses of 50 micrograms/kg or higher of GnRH-A. In order to evaluate the normalcy of the bidirectional release of ABP in GnRH-A treated rats, additional rats were given daily injections of 25 micrograms/kg or 250 micrograms/kg of GnRH-A for 2 weeks. Concentrations of ABP in interstitial fluid (ITF) and seminiferous tubular fluid (STF) remained unchanged, but serum ABP levels were significantly increased (P less than 0.05) in rats administered 25 micrograms/kg GnRH-A. Qualitatively normal spermatogenesis was maintained and epididymal ABP content did not differ from that of control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sperm suppression with monthly injections of medroxyprogesterone acetate combined with testosterone enanthate at a high dose (500 mg)

The combination of an initial injection of 1000 mg of depot medroxyprogesterone acetate and 500 mg of testosterone enanthate, followed by monthly administration of 150 mg and 500 mg of the same drugs, was tested in 10 healthy males aged 28 through 39, with pre-treatment sperm counts of 50 x 10(6)/ml or more. Eight of the subjects achieved azoospermia, and the sperm counts of the other two declined 0.09 ad 5 million/ml. This last subject was highly refractory to treatment as his sperm density recovered to 27 million sperm/ml at the 6th month of continuous therapy. FSH was severely depressed during the entire treatment period. LH fell to 30--40% of normal values in the first two months and then showed a slow recovery during maintenance treatment. Testosterone measured one month after each injection was between 10 and 30% of pre-treatment values. Three of the subjects had increased libido and potency, none had decreased sexual drive or potency. All subjects gained weight with the average gain being 6 kg. The increase in the dose of testosterone enanthate to 500 mg/ng did not improve the results as compared to previous trials using lower doses of TE.     

5-Fluorouracil (5-FU) concentration in prostatic tissue of rats and in prostatic cancer patients after oral administration of 5-FU

5-FU has been widely used in the treatment of urogenital cancers. The concentration of orally administered 5-FU was investigated in both the serum and prostate of rats and prostatic cancer patients. In the experimental studies rats were divided into two groups. In rats in group 1 (single administration group), after oral administration of 20 mg/kg/day 5-FU, the 5-FU concentration in serum was 0 at 0 min., 0.916 +/- 0.694 at 10 min., 2.000 +/- 1.159 at 20 min., 1.029 +/- 0.570 at 30 min., 0.119 +/- 0.033 at 60 min., 0.020 +/- 0.020 at 2 hr., 0 at 4 hr. and 0 micrograms/ml at 24 hr.; the 5-FU concentration in prostatic tissue as 0 at 0 min., 0.324 +/- 0.190 at 10 min., 0.843 +/- 0.544 at 20 min., 0.469 +/- 0.252 at 30 min., 0.132 +/- 0.027 at 60 min., 0.094 +/- 0.024 at 2 hr., 0.057 +/- 0.020 at 4 hr. and 0 micrograms/g at 24 hr. In rats in group 2 (daily administration group), 20 mg/kg/day 5-FU was orally administered for seven days. On the seventh day, the 5-FU concentration in serum was 0 at 0 min., 1.877 +/- 0.957 at 10 min., 4.091 +/- 2.184 at 20 min., 1.692 +/- 1.033 at 30 min., 0.345 +/- 0.084 at 60 min., 0.036 +/- 0.019 at 2 hr., 0.005 +/- 0.011 at 4 hr. and 0 micrograms/ml at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultrapure, stroma-free, polymerized bovine hemoglobin solution: evaluation of renal toxicity

Because of recent concern about the safety of our national blood supply, there is increased interest in finding safe and effective blood substitutes. One option is the use of stroma-free hemoglobin (SFH) solutions. Recently, a SFH solution based on ultrapure, polymerized bovine hemoglobin (UPPBHg) has been shown to be effective in oxygen transport. We examined the potential renal toxicity of this material. Sprague-Dawley rats were infused with UPPBHg at doses of 25, 50, 75, and 100 ml/kg. Additional groups of rats were infused with UPPBHg at these doses with the addition of bicarbonate at a dose adequate to alkalinize the urine. Further groups of rats received UPPBHg intentionally contaminated with raw bovine blood lysate. Renal function was examined by subsequent determination of serum creatinine. UPPBHg infusion up to 50 ml/kg caused no significant change in serum creatinine; at higher doses, there was a reversible rise in creatinine at 24 hr following infusion. Addition of bicarbonate diminished the amount of reversible toxicity seen, even at doses of 100 ml/kg. In contrast, with hemolysate-contaminated UPPBHg, there were sharp increases in creatinine 24 hr after infusion of all doses tested, even at 25 ml/kg; these did not decrease significantly by 48 hr following infusion. At the higher doses tested, death occurred. These observations were not affected by simultaneous bicarbonate infusion. This study shows that UPPBHg may be administered in very large doses with only mild, reversible renal toxicity. The observation that urine alkalinization ameliorates this toxicity suggests that this may occur by hemoglobin precipitation or by a toxic effect in the renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine's effect on canine pancreatic endocrine function

This study was designed to investigate the mechanism, and reversibility, of glucose intolerance following the acute administration of cyclosporine (CsA) in a canine model. Three groups underwent a baseline intravenous glucose tolerance test (IVGTT; 0.5 g/kg of glucose), with simultaneous insulin determinations. In groups A and B, repeat IVGTTs were performed, at three-day intervals, after 2, 4, and 6 mg/kg of intravenous CsA + solvent (group A; n = 8), or the solvent alone (group B; n = 5). Repeat IVGTTs were performed in group A, 24 and 72 hr after the last CsA infusion. In group C (n = 5), IVGTTs were performed, 4, 24, 48, and 72 hr after oral CsA (12.5 mg/kg). In each group, the rate of glucose clearance (k value,--per cent min), and basal-to-peak insulin difference (uU/ml), for each IVGTT were compared with the baseline results. In group A, the basal-to-peak insulin difference was significantly lower than baseline (81.9 +/- 13.6) after 2 mg/kg (27.3 +/- 3.1; P less than 0.005), 4 mg/kg (22.7 +/- 3.7; P less than 0.001); and 6 mg/kg (16.8 +/- 3.2; P less than 0.001) of CsA, and returned to baseline within 24 hr (81.4 +/- 3.7). Corresponding K values were also significantly different in group A. In group B, there were no significant differences in these parameters from controls, at the equivalent doses of the solvent alone. At 4 hr after oral CsA (group C), there was a reduction in the basal-to-peak insulin difference (37.2 +/- 9.1 vs. 22.5 +/- 4.1) and K values (-3.20 +/- 0.4 vs. -1.96 +/- 0.3), with the change in K values being statistically significant (P less than 0.05). A return to baseline levels was present at 24 h. This study demonstrates that, in the canine model, therapeutic doses of intravenous and oral CsA acutely impair glucose regulation. This acute effect is secondary to decreased peripheral insulin levels, is reversible at 24 h, and is not evident with CsA solvent alone. The mechanism of decreased insulin secretion following CsA administration requires further elucidation.     

The ability of the rat epididymis to concentrate spermatozoa. Responsiveness to aldosterone

Experiments have been performed to determine if aldosterone is involved in the control of water reabsorption from the epididymal lumen in vivo. Micropuncture samples of lumen content were collected from the epididymides of control rats and those receiving aldrenalectomy, adrenalectomy + 25 micrograms aldosterone/day, 10 mg spironolactone/kg body weight/day, 10 mg spironolactone + 1 mg testosterone/kg body weight/day, 5 mg desoxycorticosterone acetate (DOCA)/day, 50 micrograms aldosterone/day, or 0.1 ml vehicle alone. The treatment period was three days. Seminal vesicles weights and testis weights were obtained. Sperm concentrations (SEM) in the caput, corpus, and cauda epididymidis of normal rats were 0.75 +/- 0.05, 1.24 +/- 0.13, and 1.99 +/- 0.15 x 10(9) sperm/ml, respectively. Both inhibition and removal of aldosterone caused significant reduction (P less than .01) of intraluminal sperm concentrations. Sham treatment had no effect. Sperm concentrations were normal in animals receiving aldrenalectomy plus aldosterone replacement. It is concluded that water resorption in the rat epididymis is responsive to aldosterone.     

Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation.

A variety of side effects are associated with the use of cyclosporine, the most relevant of which remains the renal toxicity. We did parallel studies on cyclosporine pharmacokinetics and renal function in patients who had a recent kidney transplant and were given cyclosporine as a part of their immunosuppressive therapy. Seven consecutive renal transplant patients were studied at the end of a month of treatment while on different oral cyclosporine doses (5, 3.5, 2.5, or 1.5 mg/kg, twice a day, respectively). Cyclosporine pharmacokinetics profiles and renal function parameters (GFR and renal plasma flow [RPF], as inulin and p-amino hippurate clearances, respectively) were determined before and over a 12-hr period after each single dose of cyclosporine. Plasma levels and urinary excretion rate of endothelin were also studied before and after the highest cyclosporine dose (5 mg/kg). Mean trough levels, area under the curve values, and maximum concentration of blood cyclosporine were comparable after 5 and 3.5 mg/kg cyclosporine and decreased in a dose-dependent manner after the lower doses (2.5 and 1.5 mg/kg). In the same patients GFR declined on average 63%, 53%, 35%, and 18%, 2-4 hr after maximum cyclosporine concentration was reached. As blood levels of cyclosporine returned to trough, GFR progressively increased to baseline. Similar results were found for RPF; 5 mg/kg cyclosporine did not modify endothelin plasma levels. By contrast, urinary excretion of the peptide increased significantly (P less than 0.01) in the 6 hr that followed cyclosporine administration and returned within the normal range in the subsequent 6 hr. Following each oral administration of cyclosporine, 2-4 hr after peak blood concentration was reached, patients showed renal hypoperfusion, transient and rapidly reversible. This was associated with an increased urinary endothelin excretion rate that was also transient. It is speculated that an excessive renal synthesis of endothelin is the cause of the daily renal hypoperfusion observed in patients with renal transplants given cyclosporine.     

Hematopoietic toxicity by cimetidine. Reexamination using the antimetabolite azathioprine

By using an in vitro quantitative clonal culture technique for bone marrow granulocyte/macrophage progenitor cells (GM-CFC), we studied the effects of cimetidine alone and cimetidine plus azathioprine on bone marrow toxicity in C57BL/6 mice. Femoral bone marrow showed no effect of cimetidine in doses from 31.25 to 500 mg/kg on either marrow cellularity or the number of GM-CFC. Cimetidine pretreatment with single doses of 62.5 mg/kg or 250 mg/kg had no effect on the bone marrow suppression of azathioprine at 100 mg/kg. Chronic cimetidine pretreatment at 62.5 mg/kg daily for 7 days also had no effects on the single-dose azathioprine toxicity. Cimetidine given either before or after azathioprine had no effect on the rate or final level of recovery of GM-CFC in the marrow after depletion by azathioprine. Cimetidine in vitro at doses of 3.1 to 200 micrograms/ml caused no alteration in the proliferative response of the GM-CFC. Analysis of the serum colony-stimulating activity 1 to 24 hr following doses of cimetidine of either 12.5 mg/kg or 31 mg/kg caused no change in the serum colony-stimulating activity. We could find no evidence that at clinically relevant doses, cimetidine increased the hematopoietic toxicity of the azathioprine or altered the rate of bone marrow recovery after azathioprine depletion.     

Improved immunosuppression for heart transplant patients using intravenous doses of cyclosporine

Inducing immunosuppression in heart transplant patients with intravenous doses of CsA may decrease the incidence of severe rejection in the 1st month after operation. In our initial series, 16 consecutive patients (group A) who had no contraindications to this type of therapy received an i.v. dose of CsA, 1 mg/kg/day, postoperatively, which was then increased by 1 mg/kg every 24 hr until a full maintenance dose of 4 mg/kg/day was achieved (total time, 72 hr). The gradual increase in dosage was designed to prevent nephrotoxicity associated with higher doses of CsA. Intravenous administration was continued for 2 weeks, at which time oral administration of CsA, 14 mg/kg/day, was begun. In a subsequent series, 21 similar patients (group B) received the same amount of CsA, except that doses were increased every 12 hr, so that the full maintenance dose was achieved 36 hr postoperatively. In group B, the i.v. dose of CsA was continued for only 1 week, at which time oral administration of CsA, 14 mg/kg/day, was begun. All patients received the same standard steroid taper (30 mg/day by day 10). Patients from both groups who were greater than or equal to 55 years old and had serum creatinine greater than or equal to 1.5 mg/dl and patients from group B who had creatinine clearance less than or equal to 55 ml/min also received azathioprine, 2 mg/day, which was adjusted to maintain the white blood cell count at a level greater than or equal to 5000/cc. There was a similar number of such patients in both groups. Severe rejection was defined by endomyocardial biopsy with frequent foci of myocyte degeneration. Three (18.7%) patients in group A experienced severe rejection, and 2 (9.4%) in group B did. No patients developed renal failure. All patients survived the 1st month. The overall survival rate for group A at 12.2 +/- 1.5 months was 94%, and for group B it was 86% at 7.5 +/- 1.4 months. Both these groups compared favorably with our historical control group of patients who received oral doses of CsA to induce immunosuppression, in which 59 of 165 (35.8%) had severe rejection in the 1st month, with a 1-year actuarial survival rate of 76%. Based on this experience, we believe that i.v. administration of CsA enhances the induction of immunosuppression, thereby reducing the incidence of severe rejection. This protocol is likely to be effective because it minimizes the problems of oral absorption in the perioperative period.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interactions between mezlocillin and sisomicin in vitro and in patients with normal and various degrees of impaired renal function

During in vitro experiments using pooled human plasma at 37 degrees C, sisomicin alone showed only a small loss of activity of 12% in 24 hr. Incubation with 80 micrograms/ml mezlocillin did not alter the rate of inactivation. But, after the addition of 300 micrograms/ml mezlocillin to either 5.0 or 2.5 micrograms/ml sisomicin, the sisomicin half-life was reduced by 50% and 100% respectively. When the mean drug concentration ratios are compared, inactivation of sisomicin by mezlocillin was significantly less than that reported for carbenicillin or ticarcillin. Sisomicin pharmacokinetics were studied in 27 patients with normal and various degrees of impaired renal function (Part A) and were not changed by the simultaneous administration of mezlocillin 60 mg/kg (Part B). Furthermore, even in far advanced renal insufficiency, sisomicin inactivation by mezlocillin could not be demonstrated. The differing results obtained with mezlocillin compared to carbenicillin or ticarcillin might be explained by differences in the physico-chemical properties of the drugs in addition to the different kinetic behavior of mezlocillin in patients with impaired renal function.     

The effects of the indazole carboxylic acid derivative, tolnidamine, on testicular function: I. Early changes in androgen binding protein secretion in the rat

The indazole carboxylic acid derivative, tolnidamine, has marked antispermatogenic activity in several animal species. In this study, we assessed the effect of tolnidamine on rat Sertoli cell function both in vivo and in vitro, using androgen binding protein (rABP) as a marker. Groups of six male rats were killed 2, 4, 8, 16, 32, 64 hours and 5, 8, and 12 days following tolnidamine administration (250 mg/kg by oral gavage). There was a progressive reduction in both testicular and epididymal weights. Serum FSH levels did not change and LH showed a transient increase between 64 hours and 8 days. Except for an initial increase at 2 hours, there were no changes in serum testosterone. Epididymal rABP concentration and content declined as early as 8 hours, with the lowest values occurring at 5 and 12 days. By 16 hours, there was an increase in testicular rABP, which was also evident at 8 days and 12 days. Within 16 hours after tolnidamine, there was a rise in serum rABP, which persisted until the end of the experiment. When another indazole carboxylic acid derivative, lonidamine, was administered (250 mg/kg), similar changes were evident in epididymal and serum rABP at 32 hours, but the rapid decrease in testicular rABP suggested a different mechanism of action. In another experiment, single oral doses of tolnidamine (50, 100, 250, and 500 mg/kg) were administered to other groups of rats and the animals were killed after 24 hours and 5 days. With increasing doses of tolnidamine, there was a reduction in epididymal rABP concomitant with an increase in testis and serum rABP levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sperm suppression with monthly injections of medroxyprogesterone acetate combined with testosterone enanthate at a high dose (500 mg)

The combination of an initial injection of 1000 mg of depot medroxyprogesterone acetate and 500 mg of testosterone enanthate, followed by monthly administration of 150 mg and 500 mg of the same drugs, was tested in 10 healthy males aged 28 through 39, with pre-treatment sperm counts of 50 times 10⁶/ml or more. Eight of the subjects achieved azoospermia, and the sperm counts of the other two declined 0.09 and 5 million/ml. This last subject was highly refractory to treatment as his sperm density recovered to 27 million sperm/ml at the 6th month of continuous therapy. FSH was severely depressed during the entire treatment period. LH fell to 30–40% of normal values in the first two months and then showed a slow recovery during maintenance treatment. Testosterone measured one month after each injection was between 10 and 30% of pre-treatment values. Three of the subjects had increased libido and potency, none had decreased sexual drive or potency. All subjects gained weight with the average gain being 6 kg. The increase in the dose of testosterone enanthate to 500 mg/ng did not improve the results as compared to previous trials using lower doses of TE.     

Coadministration of active phthalates results in disruption of foetal testicular function in rats

The reproductive effects of the coadministration of di-2-(ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) were studied in both foetal and adult male rat offspring exposed in utero . Pregnant Wistar rats were treated by oral gavage from gestation day 13 to 21 with vehicle control, 150 mg DEHP/kg body weight (bw)/day, 100 mg DBP/kg bw/ or a combination of the two compounds (DEHP 150 + DBP 100 mg/kg bw/day). An additional group of dams received 500 mg DBP/kg bw/day. A significant decrease in foetal testicular testosterone levels was observed in animals exposed to 500 mg DBP/kg/day or the phthalate mixture. Similarly, histological analysis of the foetal testis revealed that the coadministration of DEHP and DBP was able to increase the diameter of seminiferous cords and induce gonocyte multinucleation at doses that individually had no significant effects on these variables. However, in the phthalate mixture group, no significant changes were observed in anogenital distance and nipple retention, variables that are used to indicate possible anti-androgenic effects. Also, the adult endpoints investigated, that included reproductive organ weights and the number of spermatids per testis, were unaffected by any treatment regimen. Overall, coadministration of DEHP and DBP in utero significantly reduced testicular testosterone levels and resulted in misshapen seminiferous cords and gonocyte multinucleation in rat foetal testis. Our results also confirm that these foetal endpoints seem to be the most sensitive markers of prenatal phthalate exposure.     

Evaluation of the effect of experimental cyclosporine toxicity on male reproduction and renal function. Reversal by concomitant human chorionic gonadotropin administration

Administration of cyclosporine to rats has been shown to impair testicular function, resulting in a decrease in sperm counts and fertility. In order to determine whether or not the deleterious effects of CsA could be reversed by hormonal therapy, mature male Sprague Dawley rats were treated with CsA (40 mg/kg/day, s.c.) alone or in combination with human chorionic gonadotropin (hCG) (5 micrograms/day/r; s.c.) for 14 days. Cyclosporine administration decreased the body weight (290 +/- 5.30 vs. 339 +/- 8.7 g; P less than 0.05) and reproductive organ weights (testis 1.49 +/- 0.42 vs. 1.60 +/- 0.03 g; epididymis 0.41 +/- 0.02 vs. 0.49 +/- 0.002 g; seminal vesicle 0.61 +/- 0.09 vs. 1.60 +/- 0.05 g; prostate 0.28 +/- 0.04 vs. 0.60 +/- 0.06 g; P less than 0.05) testicular sperm counts (5.80 +/- 0.42 vs. 8.49 +/- 0.48 x 10(7)/100 mg tissue; P less than 0.05) and epididymal sperm counts, (28.2 +/- 0.95 vs. 51 51.62 +/- 2.17 x 10(7)/100 mg tissue; P less than 0.05) and fertility (25% vs. 100%). Serum levels of LH were elevated (101.98 +/- 21.48 vs. 25.6 +/- 5.18 ng/ml; P less than 0.05) and testosterone was decreased (0.48 +/- 0.07 vs. 2.06 +/- 0.56 ng/ml; P less than 0.05). The administration of hCG to the CsA-treated rats restored the reproductive organ weights (testis 1.56 +/- 0.043 g; seminal vesicle 1.04 +/- 0.05 g; prostate 0.70 +/- 0.06 g) and sperm counts (testicular 7.88 +/- 1.0 x 10(7)/100 mg tissue; epididymal 59.86 +/- 4.16 x 10(7)/100 mg tissue; P less than 0.05) Serum levels of testosterone (18.63 +/- 4.45 ng/ml) and LH (431.65 +/- 31.41 ng/ml) were significantly elevated, as compared with control and CsA-treated groups (P less than 0.05). All the rats in the gonadotropin-treated group were fertile, as compared with 25% in the CsA-treated group. CsA reduced the kidney weight (1.17 +/- 0.02 vs. 1.27 +/- 0.03 g; P less than 0.05) and increased the levels of serum creatinine (0.97 +/- 0.07 vs. 0.59 +/- 0.03 mg/dl; P less than 0.05): these changes were ameliorated by the administration of hCG (kidney weight 1.35 +/- 0.03 g; creatinine 0.76 +/- 0.09 mg/dl).     

Effect of intravenous glucagon on the survival of rats after acute occlusive mesenteric ischemia

The purpose of this study was to determine the optimal timing of intravenous glucagon infusion for the treatment of acute occlusive mesenteric ischemia. The superior mesenteric artery (SMA) was occluded for 85 min in 106 Sprague-Dawley anesthetized rats. The animals were divided into 12 treatment groups according to the timing of glucagon and saline administration, and survival was measured to 48 hr. Without treatment, all rats died within 24 hr. Intravenous saline (10 ml/kg/hr) for 2 hr did not significantly improve 48-hr survival (17-33%). Glucagon (1.6 micrograms/kg/min iv) plus saline (10 mg/kg/hr iv) for 2 hr after SMA occlusion significantly improved survival from 33% (saline control) to 83% (P less than 0.02). The same treatment begun 1 hr before SMA release (during ischemia) did not significantly improve survival (33% at 48 hr). Glucagon infusion during occlusive mesenteric ischemia was detrimental when added to effective postischemia treatment, reducing survival from 83 to 33% (P less than 0.02). Adequate saline infusion was required for glucagon efficacy after ischemia, as shown by an intermediate 48-hr survival of 50% when only maintenance saline (1.5 ml/kg/hr) was given. These data suggest that glucagon therapy should be delayed until after operative release of an acute SMA occlusion and should be accompanied by vigorous volume expansion.     

Pharmacokinetics of fentanyl in neonates

The pharmacokinetics of fentanyl were studied in fourteen neonates undergoing major surgical procedures. Five patients were less than 1 day of age, seven were 1-4 days old, and two were 7-14 days old. Fentanyl was given intravenously, 10 micrograms/kg (n = 1), 25 micrograms/kg (n = 4), or 50 micrograms/kg (n = 9), and plasma concentrations measured at intervals of up to 18 hr. Average weight was 2.9 kg. The injection of 25 or 50 micrograms/kg of fentanyl over 1-3 min was hemodynamically well-tolerated by all patients. Four newborns without respiratory impairment secondary to surgery or disease needed ventilatory support for an average of 24 hr (range 11-40 hr). Plasma concentrations of fentanyl were most appropriately described by a two-compartment model. The mean +/- SEM values of selected model parameters were volume of the central compartment, 1.45 +/- 0.34 L/kg; volume of distribution at steady state, 5.1 +/- 1 L/kg; clearance, 17.94 +/- 4.38 ml X kg-1 X min-1; and terminal elimination half-life (t 1/2 beta), 317 +/- 70 min. In seven patients transient rebound in plasma fentanyl concentrations of 0.5 ng/ml or greater occurred. In three patients with markedly increased intraabdominal pressure, the t 1/2 beta was 1.5-3 times the population mean. Thus fentanyl disposition in neonates is highly variable, but the t 1/2 beta is predictably prolonged in the presence of increased abdominal pressure.     

The immunosuppressive mode of action of mizoribine

Mizoribine (MIZ) suppressed the mitogen response and mixed lymphocyte reaction (MLR) significantly at doses of 100 micrograms/ml and 10 micrograms/ml in a dose-response analysis. The 50% inhibition dose (ID50) was between 10 micrograms/ml and 1.0 microgram/ml, both in the mitogen response and MLR. In a kinetic study of the MLR, the degree of suppression with MIZ at a given dosage was essentially the same as the degree of suppression observed in the dose-response analysis when MIZ was added to MLR cultures from day 0 to day 4. In addition, MLR was more susceptible to the suppressive activity of MIZ at 100 micrograms/ml when MIZ was added near the peak of lymphocyte proliferation. This experiment also showed that MLR suppression induced by MIZ at 10 micrograms/ml was reversible and MLR activity had completely recovered 6-8 hr after its removal. MIZ had no inhibitory action on MLR-derived cytotoxic cells or the effector phase of cell mediated lymphocytotoxicity. These results clearly demonstrate that MIZ suppresses lymphoproliferation, but has no effect on the recognition phase or effector phase of cytotoxic lymphocytes.     

Methylprednisolone disposition in renal transplant recipients receiving triple-drug immunosuppression

Renal transplant patients commonly receive triple-drug immunosuppression with standardized doses of cyclosporine, azathioprine, and methylprednisolone. Although cyclosporine may decrease the clearance of oral prednisone, data are lacking for methylprednisolone, a glucocorticoid commonly prescribed via a standardized protocol for intravenous therapy and during periods of acute rejection. The disposition of methylprednisolone (doses: 10-60 mg/day) was examined in nine renal transplant patients during the post-transplant period (0.8-14 months). Plasma samples were collected over 24 hr and analyzed for methylprednisolone via HPLC. Pharmacokinetic parameters were determined by noncompartmental analysis. The mean total clearance of methylprednisolone was 379 ml/hr/kg (range 105-672) and the volume of distribution was 1.4 +/- 0.5 L/kg. The mean plasma half-life was 2.7 +/- 1.1 hr. When normalized to a 1 mg dose of methylprednisolone, the mean peak concentration at 1 hr was 10.0 +/- 3.5 ng/ml with an 8 hr concentration ranging from 0.3 to 5.5 ng/ml. An appreciable variability in methylprednisolone metabolism thus exists in renal transplant recipients receiving triple-drug immunosuppression. This may partially explain the variable response to steroid therapy during acute rejection episodes and chronic immunosuppression as well as the unpredictable occurrence of chronic steroid toxicity.