Combined Infusion Research Articles

Effect of intravenous glucose and lipid on proteolysis and glucose production in normal newborns.

To determine whether nonprotein substrate can suppress proteolysis in normal newborns and to assess the effect of this substrate on glucose production, the rates of appearance (Ra) of leucine (reflecting proteolysis) and glucose were measured in healthy 2-day-old full-term newborns during fasting, an intravenous glucose infusion (5.5 mg.kg-1.min-1), an intravenous lipid infusion (2.5 mg.kg-1.min-1), and a combined glucose plus lipid infusion (5.5 mg.kg-1.min-1 glucose + 2.5 mg.kg-1.min-1 lipid). Leucine RA was not reduced from fasting values during any of the substrate infusions. Intravenous lipid infusion alone neither suppressed nor increased glucose production. In contrast, glucose production was nearly completely suppressed (approximately 90%) during intravenous infusions of glucose provided either alone or in combination with lipid; this suppression was achieved at glucose concentrations of approximately 90 mg/dl and insulin concentrations of approximately 6 microU/ml. Thus normal newborns respond to intravenous glucose with sustained nearly complete suppression of glucose production, even at moderate levels of glycemia and at low insulin concentrations; however, nonprotein substrate infusion does not result in suppression of proteolysis. It remains unclear to what extent any potential regulator can suppress proteolysis in this population.

Cortisol feedback in adrenalectomized adult sheep.

These experiments tested the sensitivity of cortisol feedback on adrenocorticotropic hormone (ACTH) secretion in adult sheep. In series I, five bilaterally adrenalectomized (ADX) adult sheep were maintained on "low" (125 micrograms/h) or "high" (500 micrograms/h) intravenous cortisol replacement, and dose-response curves were obtained with corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). CRF caused incremental increases in plasma ACTH at the low but not the high dose of cortisol. AVP was similarly ineffective in stimulating ACTH at the high dose of cortisol. However, in series II, where ADX animals were again maintained on low or high cortisol infusions, a combined infusion of CRF and AVP was able to stimulate a robust ACTH response during both steroid replacement regimens. These studies demonstrate that the pituitary represents a major site of steroid feedback in the sheep, with a relatively small increase in the concentration of cortisol, within the normal unstressed physiological range, being able to inhibit ACTH secretion in response to exogenous CRF and AVP. However, under these conditions, inhibition of ACTH release can be overcome by the combined action of CRF and AVP. Further studies in series III, concerned with the nature of glucocorticoid inhibition of AVP release, demonstrate that whereas exposure to maximal cortisol levels (5,000 micrograms/h) completely abolishes the ACTH response to severe hemorrhage (15 ml/kg over 15 min), AVP release is maintained, suggesting that the system controlling AVP release during hemorrhagic stress is less sensitive to the negative influences of glucocorticoids than is the system controlling ACTH release.

Dose-finding study of paclitaxel (Taxol) plus cisplatin in patients with non-small cell lung cancer: Klastersky J, Sculier JP. Department of Medicine, Institut Jules Bordet, I Rue Heger-Border, 1000 Brussels. Semin Oncol 1994;21:Suppl 8:39–43

We present preliminary results of a study undertaken in previously untreated patients with non-small cell lung cancer to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when administered as a 3-hour intravenous infusion in combination with cisplatin every 3 weeks; to evaluate the nature, frequency, severity, and duration of adverse events associated with this drug combination; and to evaluate the combination's antitumor efficacy. Thus far, we have treated 10 patients with cisplatin (100 mg/m2) and increasing doses of paclitaxel (135, 170, and 200 mg/m2). Among nine evaluable patients, four partial responses have been obtained, disease in three patients progressed after three courses, and no changes were seen in one patient. One patient had two cardiac arrests within 8 days of the onset of therapy, from which he recovered; he died 1 month later of massive hemoptysis. Thrombocytopenia was not seen in these patients, and neutropenia (< 1,000 granulocytes/microL) was seen in only three patients. Infections were seen in these patients and were manageable in all cases. Other toxicities consisted mainly of World Health Organization grades II and III alopecia and nausea and/or vomiting. No grade III nephrotoxicity, neurotoxicity, hypersensitivity, mucositis, or infection was seen in this series after one to three courses of chemotherapy; one patient presented with grade IV cardiotoxicity 6 days after the onset of therapy. So far, the maximum tolerated dose of the cisplatin/paclitaxel combination has not been reached; however, definitive conclusions await the full treatment of additional patients. Moreover, the possibility of cumulative and delayed toxicity must be evaluated after a sufficient duration of follow-up in adequate numbers of patients.

Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer: First results of a randomized multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO)

High-dose 5-FU given weekly as a 24-h infusion in combination with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combination with FA has also improved treatment results by modulating 5-FU activity. We therefore initiated a randomized multicenter trial comparing the ability of FA or IFN to modulate infusional 5-FU. The statistical design using a sequential analysis allows us to report on the comparison of 5-FU/FA vs. 5-FU/FA/IFN while randomization of patients into 5-FU/FA vs. 5 FU/IFN continues. Chemotherapy-naive patients with advanced progressive colorectal cancer and measurable metastatic lesions were randomized to receive 5-FU 2600 mg/m2 i.v. as a 24-h infusion, combined with either FA 500 mg/m2 as a 2-h infusion (A), or IFN 3 x 10(6) U s.c. 3 x/week (B), or the combination of FA plus IFN as in arms A and B (C). Treatment arms were repeated weekly for 6 weeks followed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths among the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m2 for all patients in arm C. Sequential analysis according to Whitehead for objective response was planned with alpha = 0.05/3 and a power of 80% (beta = 0.2) to detect a difference of > or = 25% (delta = 0.25) or equivalence of response rates. For pairwise comparison of treatment arms a minimum of 30 patients per arm and a maximum of 90 patients per arm were expected in case of equivalence or difference. An interim analysis was performed after the first 93 of 149 randomized patients were evaluable for response and toxicity (A 31 pts, B 33 pts, C 29 pts). Despite the 5-FU dose reduction in arm C, 28% of patients experienced grade 3/4 toxicity (CTC) including diarrhea, mucositis and handfoot syndrome compared to 16% in arm A and 12% in arm B (not significant). No treatment related toxic death occurred in arms A or B, but 3 patients (10%) in arm C died of diarrhea and septicemia. Among patients treated with 5-FU/FA objective tumor response occurred in 12/31 patients (39%) (21%-56%, 95% confidence interval) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patients. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) receiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patients) remissions, 10/29 patients (34%) had stable disease and 8/29 patients (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/FA or 5-FU/FA/IFN were equivalent. This interim analysis allows the conclusion that infusional 5-FU plus FA/IFN is no more active than infusional 5-FU plus FA alone. However, 5-FU/FA/IFN despite 5-FU dose reduction was associated with unacceptably high toxicity, including 10% deaths. Therefore, further investigation of this regimen is not justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.

Cholecystokinin does not act on the efferent pathway of cholinergic and adrenergic nerves to inhibit ruminal contractions in sheep (Ovis aries).

The effect of exogenous cholecystokinin-octapeptide (CCK-8) on ruminal contractions and the role of efferent pathways of cholinergic and adrenergic nerves on the effect were studied in sheep. Intravenous infusion of CCK-8 at 11.4 and 45.6 pmol/kg/min significantly inhibited the frequency and amplitude of ruminal contractions in conscious sheep. After bilateral cervical vagotomy, intravenous infusion of CCK-8 at 45.6 mol/kg/min had no detectable effect on amplitude of ruminal contractions induced by electric stimulation to the cervical vagus nerve (1 msec, 20 Hz, 5 mA, for 10 sec at 1-min intervals) in anesthetized sheep. The amplitude of contractile responses of ovine ruminal muscle strips to acetylcholine at 5 x 10(-5) M was not inhibited by CCK-8 applied simultaneously at 1 x 10(-9) M. Intravenous infusion of phentolamine at 53.0 nmol/kg/min, propranolol at 101.4 nmol/kg/min, or their combined infusion did not alter the inhibitory action of CCK-8 at either dose on ruminal contractions in conscious sheep. These results suggest that CCK-8, which does not act on the efferent pathway of cholinergic and adrenergic nerves, may reflexively inhibit reticuloruminal contractions via vagal afferent fibers in sheep.

Synergistic regulation of ANF in isolated rat hearts

The interaction between cardiac sympathetic stimulation of atrial natriuretic factors (ANF) release and left atrial stretch was examined in groups (n = 5 or 6) of isolated, perfused (10 ml/min), paced rat hearts. Left atrial stretch, produced by an increase in atrial pressure of 1.1 +/- 0.2 mmHg over 8 min, transiently (4 min) increased ANF release by 46 +/- 4% over baseline (220 pg/ml buffer; P < 0.05). Infusion of 1 microM norepinephrine (NE) over 28 min caused a sustained increase in ANF release of 76 +/- 10% (P < 0.05). Atrial stretch plus NE caused additive effects on ANF release during stretch but 2.4 times the additive effects after stretch (P < 0.05). To examine whether resting tension modulates the ANF response to sympathetic stimulation, the left atrium was stretched throughout the experiment by increasing the atrial pressure by 1-1.5 mmHg. Infusion of 1 microM NE over 28 min increased ANF release by 216 +/- 46% (P < 0.01) in the prestretched heart, compared with a calculated summed increase of 85% due to NE alone plus prestretch alone. Infusion of 0.5 microM veratridine, known to stimulate ANF via mechanical effects on the heart, increased ANF release by 88 +/- 3% (P < 0.01). Scorpion venom, known to dose dependently stimulate ANF secretion via activation of neuronal sodium channels, elicits a negligible increase in ANF release at the threshold concentration of 0.1 microM. The combined infusion of 0.5 microM veratridine plus 0.1 microM venom increased ANF release by 239 +/- 53% (n = 6, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Do vasopressin and oxytocin have synergistic renal effects in the conscious rat?

The renal effects of arginine vasopressin and oxytocin were studied in the conscious unrestrained rat infused with 0.077 M NaCl. Peptides were infused at rates of 24 and 160 pmol/min (vasopressin) or 30 and 200 pmol/min (oxytocin) either alone or as a combination of the two lower or two higher doses. The rates of infusion were selected to give ratios of oxytocin:vasopressin similar to those seen in the plasma of euhydrated and dehydrated rats. Vasopressin produced dose-dependent antidiuretic and natriuretic responses, the natriuresis commencing after 15-30 min infusion. Oxytocin produced dose-dependent diuretic and natriuretic responses, the natriuresis commencing within the first 15 min of infusion. Combined infusion of vasopressin and oxytocin produced dose-dependent antidiuretic responses which were comparable to those seen with vasopressin alone. The natriuretic response from combined infusion at the higher rate appeared to have the greater magnitude for individual 15-min periods of the vasopressin response combined with the longer duration of the oxytocin response. Although the total natriuretic response was therefore greater, this difference failed to reach significance. Only the higher rates of infusion of vasopressin and oxytocin significantly increased the clearance of sodium, by 53 +/- 23 and 62 +/- 18% and glomerular filtration rate (GFR) by 23 +/- 4 and 23 +/- 4% respectively. The clearance of sodium during the combined hormone infusion was significantly greater (109 +/- 21%), while the rise in GFR at 23 +/- 5% was comparable to that seen when each hormone was given separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Water intake and activity of hypothalamoneurohypophysial system during osmotic and sodium stimulation in rats.

Intrajugular infusion (200 microliters/min for 10 min) of 0.85 M NaCl or 1.7 M mannitol in conscious adult male Sprague-Dawley rats increased plasma osmolality similarly and had an additive effect when combined. Plasma Na+ concentration, however, increased with infusion of 0.85 M NaCl, decreased with 1.7 M mannitol, and was not significantly altered by the combined solution. Irrespective of changes in plasma Na+ concentration, plasma vasopressin and oxytocin concentrations were elevated to a similar degree after independent infusion of 0.85 M NaCl or 1.7 M mannitol. With the combined infusion, the change in plasma vasopressin was additive but the change in oxytocin tended to be greater. Accordingly, glucose utilization increased throughout the hypothalamoneurohypophysial system after infusion of 0.85 M NaCl and 1.7 M mannitol. With the combined infusion, however, the change in glucose utilization in the paraventricular nucleus was additive but a synergistic effect occurred in the supraoptic nucleus and neural lobe. Drinking responses were similar in all groups receiving hypertonic solutions, with no additive effect after the combined stimulus. Although our results do not completely rule out the participation of cerebrospinal fluid sodium receptors, it is more likely that osmoreceptors regulate the activity of the hypothalamoneurohypophysial system and drinking behavior. Unlike the magnocellular system, however, drinking behavior seems to be negatively influenced by a stress component of the osmotic stimulation.

Role of nitric oxide on cardiac hormone secretion: effect of NG-nitro-L-arginine methyl ester on atrial natriuretic peptide and brain natriuretic peptide release.

Endocardial cells, like endothelial cells, release nitric oxide (NO) and may play a role in modulating the contractility of cardiac muscle. We have studied the effects of NG-nitro-L-arginine methyl ester (L-NAME), a selective NO synthase inhibitor, on basal and volume expansion-induced secretion of two cardiac hormones, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in vivo. In conscious chronically cannulated rats, bolus injection of L-NAME at doses of 1, 3, and 10 mg/kg, iv, caused a dose-dependent increase in mean arterial pressure and sustained bradycardia, whereas right atrial pressure remained unchanged. The hemodynamic effects of L-NAME were reversed by simultaneous administration of L-arginine, a precursor of NO. Administration of 3 and 10 mg/kg L-NAME alone increased plasma levels of immunoreactive ANP (IR-ANP) from 30 +/- 5 to 52 +/- 9 pmol/liter and from 38 +/- 6 to 91 +/- 16 pmol/liter (P < 0.01), respectively, but had no effect on plasma levels of immunoreactive BNP (IR-BNP). The increase in plasma IR-ANP concentration in response to L-NAME infusions showed a positive linear correlation (P < 0.01) with the increase in mean arterial pressure and a negative correlation (P < 0.01) with the changes in heart rate. Acute volume expansion with 0.9% saline in conscious animals resulted in a 3.2-fold increase in plasma IR-ANP levels (from 35 +/- 7 to 113 +/- 15 pmol/liter; P < 0.01), but plasma IR-BNP levels did not change. In the rats pretreated with L-NAME, the relation between the changes from control in plasma IR-ANP and right atrial pressure shifted to the left; the absolute increases corresponding to the 3 mm Hg increase in right atrial pressure were 66 +/- 13, 76 +/- 15, 135 +/- 33, and 148 +/- 24 pmol/liter in the control and 1 mg/kg L-NAME, 3 mg/kg L-NAME-, and 10 mg/kg L-NAME-treated groups, respectively. The combined infusion of L-NAME and L-arginine attenuated the L-NAME-induced increase in ANP release. Our results show that L-NAME increases basal plasma IR-ANP levels and enhances stretch-induced ANP release, suggesting that secretion of ANP in response to volume load may be modulated by the locally released nitric oxide from the endothelium. Further, acute regulation of BNP secretion in response to inhibition of nitric oxide synthase and volume load differs from that of ANP.

Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20s schedule of food reinforcement

Previous studies have shown that long-term 5-hydroxytryptamine (5-HT) depletion induced by combined dorsal and median raphe injections of 5,7-dihydroxytryptamine (5,7-DHT) leads to impairments in the acquisition and performance of behaviour maintained under a differential-reinforcement-of-low-rate (DRL) schedule of reinforcement. The present studies examined the relative importance of dorsal versus median raphe 5-HT projections in mediating these effects by investigating the impact of separate versus combined infusions of 5,7-DHT into these sites on DRL responding. Adult male rats received injections of 3 μg 5,7-DHT into both dorsal raphe and median raphe, dorsal raphe only, or median raphe only. Sham-operated controls received vehicle injections. Animals were then trained to respond on a DRL 20s schedule for 36 days. Combined dorsal raphe and median raphe 5,7-DHT infusions depleted striatal and hippocampal 5-HT by >90%, increased responding, decreased the number of reinforcers earned, lowered the mean inter-response time (IRT), and shifted the frequency distribution of IRTs to the left. Median raphe 5,7-DHT infusions induced similar behaviouraleffects and reduced hippocampal 5-HT by 64%. Dorsal raphe 5,7-DHT lesions, that depleted striatal 5-HT by 56%, and hippocampal 5-HT by 30%, had no effect on behaviour. In a final experiment it was shown that providing an external cue light to signal food availability, and that removed the need to rely on internal timing processes, resulted in rapid acquisition of responding, and prevented the behavioural deficits in 5,7-DHT-lesioned rats. Following removal of this cue, responding deteriorated, and the 5,7-DHT treated animals performed worse than controls. These results suggest that destruction of 5-HT neurons arising from the median raphe is sufficient to disrupt behaviour maintained by a DRL 20s schedule, and that the behavioural changes observed may involve a deficit in timing.

Propofol infusion technique for outpatient general anesthesia

Purpose: The purpose was to evaluate the suitability of a continuous propofol infusion in combination with alfentanil for outpatient general anesthesia in an oral and maxillofacial surgery practice. Materials and Methods: Twenty-seven ASA 1 patients were selected to undergo oral and maxillofacial surgery outpatient procedures of short duration. Induction of anesthesia was accomplished with 1 mg/kg intravenous (IV) propofol and 10 μg/kg IV alfentanil. Local anesthesia was administered. General anesthesia was maintained with a continuous infusion of 150 μg/kg/min of propofol. Various physical and psychomotor responses were recorded during induction, maintenance, emergence, and recovery. Results: Anesthesia was successfully induced in all patients with single, slowly titrated, bolus doses of 1 mg/kg of propofol and 10 μg/kg of alfentanil. Induction of general anesthesia occurred in less than 1 minute in all cases and no excitatory phenomena, tremor, or hypertonus were observed. Maintenance of anesthesia was adequately accomplished and cardiovascular parameters remained within acceptable limits throughout the procedure. The average length of surgery was 22 minutes. Movement to surgical stimulus was minimal and easily managed with additional local anesthetic and/or a 10-mg bolus of propofol. Time to eye opening was approximately 5 minutes from the discontinuation of the propofol infusion. No emergence phenomena were observed. All patients were ready for discharge with baseline psychomotor activity within 30 minutes following the end of the procedure. The average total dose of propofol was 350 mg and the average dose of alfentanil was 750 μg. Conclusion: This anesthetic technique has numerous advantages with minimal side effects, and should be considered for routine use for outpatient general anesthesia in oral and maxillofacial surgery.

Deoxycholate and cholate modulate the source of cholesterol substrate for bile acid synthesis in the rat

In the current study, the role of the supply of preformed and newly synthesized cholesterol for the feedback control of the synthesis of different bile acids and the secretion of biliary cholesterol was investigated. To define these cholesterol fluxes and the possibility of a different modulation by bile acids with different suppressive capacities, a continuous labeling with tritiated water was used in rats with an extracorporeal bile duct receiving intraduodenal infusions of taurocholate or taurocholate plus deoxycholate. After bile acid pool depletion (6 to 9 hours) total muricholate, cholate, and chenodeoxycholate synthesis was variably increased (24% to 93%) during an infusion of 304 μmol taurocholate/kg per hour. The increase in bile acid synthesis and biliary cholesterol output was predominantly due to the utilization of preformed (unlabeled) cholesterol. The addition of 52 μmol/kg per hour of deoxycholate to 258 μmol/kg per hour of taurocholate had a comparable effect. In the late period (30 to 54 hours), the taurocholate infusion had little impact on total muricholate and chenodeoxycholate synthesis but caused by a significant increase of the proportion from preformed cholesterol. Both total cholate production and its synthesis from de novo (labeled) cholesterol was inhibited by 30% ( P < .05) and 64% ( P < .01), respectively. The secretion rate of total and de novo biliary cholesterol was higher (65% and 72%; P < .01) compared with controls. In comparison, the combined bile acid infusion led to a further increase of total muricholate synthesis ( P < .05), which was again due to an enhanced synthesis from preformed cholesterol ( P < .001). Similar changes were observed in chenodeoxycholate. The more pronounced suppression of total cholate synthesis by 81% ( P < .05) was due to a diminished cholate synthesis from both de novo cholesterol by 72% ( P < .001) and preformed cholesterol by 91% ( P > .05). We conclude that the modulation of the synthesis of the various primary bile acids in the rat differs and feedback regulation of cholate synthesis by taurocholate and deoxycholate is mediated by different mechanisms of control, including inhibition of cholesterol 7α-hydroxylase, HMG-CoA reductase, and uptake of lipoprotein cholesterol.

Deoxycholate and cholate modulate the source of cholesterol substrate for bile acid synthesis in the rat

In the current study, the role of the supply of preformed and newly synthesized cholesterol for the feedback control of the synthesis of different bile acids and the secretion of biliary cholesterol was investigated. To define these cholesterol fluxes and the possibility of a different modulation by bile acids with different suppressive capacities, a continuous labeling with tritiated water was used in rats with an extracorporeal bile duct receiving intraduodenal infusions of taurocholate or taurocholate plus deoxycholate. After bile acid pool depletion (6 to 9 hours) total muricholate, cholate, and chenodeoxycholate synthesis was variably increased (24% to 93%) during an infusion of 304 mumol taurocholate/kg per hour. The increase in bile acid synthesis and biliary cholesterol output was predominantly due to the utilization of preformed (unlabeled) cholesterol. The addition of 52 mumol/kg per hour of deoxycholate to 258 mumol/kg per hour of taurocholate had a comparable effect. In the late period (30 to 54 hours), the taurocholate infusion had little impact on total muricholate and chenodeoxycholate synthesis but caused by a significant increase of the proportion from performed cholesterol. Both total cholate production and its synthesis from de novo (labeled) cholesterol was inhibited by 30% (P < .05) and 64% (P < .01), respectively. The secretion rate of total and de novo biliary cholesterol was higher (65% and 72%; P < .01) compared with controls. In comparison, the combined bile acid infusion led to a further increase of total muricholate synthesis (P < .05), which was again due to an enhanced synthesis from performed cholesterol (P < .001). Similar changes were observed in chenodeoxycholate. The more pronounced suppression of total cholate synthesis by 81% (P < .05) was due to a diminished cholate synthesis from both de novo cholesterol by 72% (P < .001) and preformed cholesterol by 91% (P > .05). We conclude that the modulation of the synthesis of the various primary bile acids in the rat differs and feedback regulation of cholate synthesis by taurocholate and deoxycholate is mediated by different mechanisms of control, including inhibition of cholesterol 7 alpha-hydroxylase, HMG-CoA reductase, and uptake of lipoprotein cholesterol.

Role of renal dopamine D1 receptors in natriuresis induced by calcium channel blockers

The direct tubular natriuretic effect of calcium channel blockers (CCBs) may be due to an interaction between CCBs and a renal tubular dopamine receptor. We therefore studied the effects of two chemically unrelated CCBs, diltiazem and isradipine, infused into the right renal artery of 5% saline-loaded anesthetized rats alone or in the presence of a D1 antagonist, SKF-83742. Isradipine (0.03 microgram.kg-1.min-1) or diltiazem (20 but not 10 micrograms.kg-1.min-1) alone produced an increase in urine flow and an approximate doubling of absolute and fractional sodium excretion, which was not seen in the left kidney or in the control animals (analysis of variance, Scheffé's test, P < 0.05). SKF-83742 alone given systemically or into the right renal artery did not affect these parameters but did block the actions of diltiazem or isradipine. There was no change in mean arterial pressure, renal blood flow, or glomerular filtration rate in any of the experiments. In additional studies, we found that a combined infusion of dopamine (0.1 microgram.kg-1.min-1) and diltiazem (10 micrograms.kg-1.min-1) (doses that by themselves did not alter renal function) produced a twofold or greater increase in urine flow and absolute and fractional sodium excretion; glomerular filtration rate was not significantly changed. Intrarenal arterial CCBs, without a change in renal hemodynamics, produce a natriuresis that is blocked by a D1 antagonist. Concomitant administration of diltiazem and dopamine (each in subeffective doses when used alone) produces a synergistic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer

A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation.

Metabolism of nicotine to cotinine studied by a dual stable isotope method

(1) To determine the disposition kinetics of nicotine and cotinine, including the fractional conversion of nicotine to cotinine, (2) to compare the disposition kinetics of deuterium-labeled and unlabeled cotinine, and (3) to develop a pharmacokinetically based method for estimating daily intake of nicotine from cigarette smoking. Twenty cigarette smokers received a combined infusion of deuterium-labeled nicotine (d2) and cotinine (d4). Six nonsmokers received a combined infusion of unlabeled cotinine, cotinine-d2 and cotinine-d4. Daily intake of nicotine was estimated with use of the plasma cotinine concentration during ad libitum smoking, clearance of labeled cotinine, and fractional conversion of nicotine to cotinine. The kinetics of labeled versus unlabeled cotinine and of cotinine in smokers versus nonsmokers were similar. On average, 72% of nicotine was converted to cotinine, with a range from 55% to 92%. Subjects with lower clearances of nicotine had lower fractional conversion of nicotine to cotinine, indicating that this is the most rapid of the proximate metabolic pathways for nicotine. The equation for estimating daily intake of nicotine from smoking was: Dnic (mg/24 hr) = K x (Plasma Cot) (ng/ml), where K averaged 0.08, with a range from 0.047 to 0.102. Individual variability in the clearance of cotinine (coefficient of variation, 27.5%) accounts for more of the variability in K than does variability in the fractional conversion of nicotine to cotinine (coefficient of variation, 12.3%). Our study provides quantitative data on individual variability in the extent of C-oxidation of nicotine to cotinine and a quantitative perspective on the use of plasma cotinine as an indicator of daily intake of nicotine from tobacco.

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Synergistic effect of rhTNF-alpha and rhIL-1 alpha in inducing anorexia in rats

To investigate whether there is a synergistic effect of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and recombinant human interleukin-1 alpha (rhIL-1 alpha) in inducing anorexia, 32 rats with jugular catheters were studied (8 rats/group): controls received normal saline; the IL-1 group received rhIL-1 alpha (10 micrograms/kg); the TNF group received rhTNF-alpha (30 micrograms/kg); and the IL-1 + TNF group received the same concentration of both rhIL-1 alpha+rhTNF-alpha for 3 days; solutions were then switched to normal saline. No significant decrease in light- and dark-phase food intake occurred during infusion of subeffective rhTNF-alpha. Food intake was decreased on the first rhIL-1 alpha infusion day because of a decreased meal number during the dark phase. A significant decrease in food intake occurred with combined infusion of rhIL-1 alpha+rhTNF-alpha because of a reduction in meal number during dark phase and meal size during light phase. Our results show that rhIL-1 alpha and rhTNF-alpha, when administered concurrently, had a synergistic effect in inducing anorexia, suggesting that low concentrations of these cytokines as produced endogenously may have potential effects on other biological functions in vivo.

Renal allograft survival in outbred mongrel dogs using rabbit anti-dog thymocyte serum in combination with immunosuppressive drug therapy with or without donor bone marrow.

Therapeutic renal transplantation in dogs is currently being investigated as a treatment for endstage renal disease. This pilot study examines the effect of donor bone marrow (DBM) infusion and antithymocyte serum (ATS) in combination with immunosuppressive drug therapy in prolonging renal allograft survival in dogs. Seven normal outbred mongrel dogs received an unmatched renal allograft. All dogs received rabbit anti-dog thymocyte serum (RADTS), prednisone (Pr), cyclosporine-A (CsA) and azathioprine (Aza). In addition, three dogs (group 1 test) received DBM and four dogs (group 2 control) did not receive DBM. Serum CsA levels were measured throughout the study. Immunosuppressive therapy was gradually reduced with Pr, CsA, and Aza withdrawn at 200, 450, and 680 days, respectively. Allograft rejection was treated with prednisolone sodium succinate. One dog in group 1 and one in group 2 died as a result of infectious canine rhinotracheitis and rejection early in the study. Renal allograft torsion occurred in one group 1 dog. The remaining four dogs survived the 2 years of the study. The dogs in group 2 (three dogs) all rejected the renal allograft after total drug withdrawal, the surviving dog in group 1 did not. This study demonstrates that RADTS, Pr, CsA, and Aza in combination can prolong renal allograft survival in mongrel dogs, whereas DBM may enhance the unresponsive state.

Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure

It is commonly assumed that thiazide diuretics are ineffective in patients with advanced renal failure (GFR < 30 ml/min/1.73 m2). Thiazides act on the nephron segment distal to the ascending thick loop of Henle, that is, the site of action of loop diuretics. Blockade of sodium reabsorption in the thiazide-sensitive segment should therefore obliterate the compensatory increase in sodium reabsorption seen after administration of loop diuretics and thus potentiate the natriuretic efficacy of loop diuretics even in advanced renal failure. In a single-blind, randomized, placebo controlled crossover study we compared the natriuretic and chloruretic effect of the loop diuretic, torasemide, given alone or in combination with the thiazide diuretic, butizid, in 10 patients with advanced renal failure (mean CIn 13.1 +/- 5.9 ml/min/1.73 m2). For two weeks patients adhered to a diet containing a standardized amount of Na+ and K+. On the 6th and 13th study days, two sham infusions were given to patients in order to assess basal 24-hour urinary electrolyte excretion. On the 7th and 14th days they were randomly allocated to receive either 50 mg i.v. torasemide in combination with a sham infusion or torasemide in combination with 20 mg i.v. butizid. Administration of torasemide alone significantly (P < 0.01) increased mean cumulative 24-hour excretion of sodium (from 154 +/- 30 to 232 +/- 59 mmol/24 hr) and chloride (from 128 +/- 21 to 233 +/- 84 mmol/24 hr) as compared with baseline.(ABSTRACT TRUNCATED AT 250 WORDS)