Combined Infusion Research Articles

Role of nitric oxide in modulating systemic pressor responses to different vasoconstrictors in man

Animal studies suggest that nitric oxide (NO) attenuates responses to endogenous vasoconstrictors. We investigated whether this also holds true in man by monitoring pressor responses to different vasoconstrictors during nitric oxide synthase (NOS) inhibition. Systemic hemodynamic responses to intravenous infusions of three doses (each for 5 min) of angiotensin II (AngII) (2, 4 and 8 ng/kg per min), noradrenaline (NOR) (10, 30 and 70 ng/kg per min) and phenylephrine (PE) (0.5, 1.0 and 1.5 microg/kg per min) were monitored in 44 healthy subjects during saline. A second dose-response curve was obtained during NOS inhibition with a subpressor dose of N- nitro-L-arginine-methyl ester (L-NAME) (5 microg/kg per min) or during a systemic NO clamp using combined systemic infusions of L-NAME (12.5 microg/kg per min) and nitroprusside. Blood pressure was measured in the brachial artery and other hemodynamic parameters were derived from this signal. Mean arterial pressure (MAP) increased 2 +/- 2, 6 +/- 1 and 16 +/- 2 mmHg in response to AngII during saline, 7 +/- 6, 15 +/- 5 and 26 +/- 6 mmHg during the subpressor dose of L-NAME (P < 0.05) and 11 +/- 10, 18 +/- 7 and 25 +/- 6 mmHg during the systemic NO clamp (P < 0.001). These augmented responses of MAP were due to enhanced increments in systemic vascular resistance. Infusions of NOR and PE during saline resulted in dose-dependent increments in MAP and systemic vascular resistance. These increments were of comparable magnitude as those seen during AngII, but were not affected by NOS inhibition. Our findings show that the systemic pressor response evoked by AngII, but not by NOR or PE, is enhanced during NOS inhibition, suggesting that AngII is associated with increased NO release that counteracts its blood pressure rising effect.

Combined Systemic Chronotherapy and Hepatic Artery Infusion for the Treatment of Metastatic Colorectal Cancer Confined to the Liver

Background: The optimal treatment of patients with metastatic colorectal cancer is still a clinical challenge. We describe the use of combined hepatic arterial infusion (HAI) of irinotecan (CPT-11) in conjunction with systemic chronotherapy infusion of 5-fluorouracil (5FU), folinic acid and carboplatin in patients with colorectal liver metastases. Methods: Twenty-three patients with colorectal cancer and isolated liver metastases were enrolled in this trial. Intraoperative insertion of an intra-arterial catheter into the hepatic artery was accomplished during the colon operation (in cases of synchronous tumor) or as a separate procedure in colorectal cancer patients with newly diagnosed liver metastases. A systemic double-lumen double-chamber port was inserted via the subclavian vein as a separate procedure. The treatment plan included irinotecan given by intra-arterial infusion at 150 mg/m² for 1 h. After 2 weeks of rest chronomodulated 5FU (700 mg/m²; peak delivery rate at 04:00 h), leucovorin (175 mg/m²; peak delivery rate at 04:00 h) and carboplatin (40 mg/m²; peak delivery rate at 16:00 h) for 4 days was followed by 10 days’ rest and then given again. After 10 days’ rest another HAI was introduced using the same method. Each cycle of therapy included 2 HAI courses and 2 chronotherapy courses in between. After 2 complete cycles, patients were evaluated for their response with weekly accessed toxicity recording. Results: Seven women, 8 men, median age 61 years (range 46–72). Eight patients had synchronous colon and hepatic disease and 7 patients had metachronous disease. Ten patients had previously been treated with 5FU and leucovorin while 5 patients were chemonaive. The mean number of cycles were 11.6 per patient (range 8–19). Partial response was achieved in 6 patients (40%) and was followed by laparoscopic radiofrequency ablation in 5 patients (33%). Disease stabilization was observed in 2 patients (13%) and disease progression in 7 patients (47%) mainly after previous chemotherapy failure. Side effects were infrequent and mild including grade 2 GIT complaints (5 patients), RUQ pain during HAI (9 patients) and grade 2 hematological complaints in 2 patients. Conclusion: A combined chemotherapy protocol (HAI and chronotherapy) with irinotecan (CPT-11) together with chronomodulated infusion of 5FU, folinic acid and carboplatin can be used in metastatic colorectal patients with a high efficacy rate and minor side effects especially in pretreated patients.

Effective stimulation of daily LH secretion by the combined treatment with melatonin and naloxone in luteal-phase ewes

This study was designed to test the hypothesis that melatonin would intensify daily LH release after central blockade of the opiate receptors in sexually active ewes. The intracerebroventricular infusions of vehicle (control), melatonin, naloxone and melatonin in combination with naloxone were made in ewes in the luteal phase of the estrous cycle, from 2:00 P.M. to 5:00 P.M. Blood samples were collected from 11:00 A.M. to 8:00 P.M. at 10-min intervals. The mean plasma LH concentrations were measured before, during and after the infusions. The frequency and amplitude of LH pulses were determined during the whole experimental period. The LH concentrations recorded during melatonin or naloxone infusions were significantly higher than the concomitant concentration in vehicle-infused animals. The mean LH pulse amplitude in melatonin- and naloxone-treated ewes was also significantly higher than in controls. The LH concentration measured during the combined infusion of melatonin and naloxone was significantly higher than that during vehicle infusion. The LH concentration recorded in turn after the treatment was significantly higher than the concomitant concentrations in vehicle-, melatonin- and naloxone-infused animals. The mean LH pulse amplitude in this group was significantly higher than in the vehicle-infused group. These results indicate that blockade of the opiate receptors within the CNS facilitated effective stimulation of daily LH secretion by exogenous melatonin. In conclusion, a relationship between melatonin and endogenous opioid peptides may be crucial in enabling melatonin to exhibit stimulatory action on LH secretion during the luteal phase of the estrous cycle in ewes.

Influence of menstrual cycle on cytochrome P450 2A6 activity and cardiovascular effects of nicotine*

The phase of the menstrual cycle has been reported to affect frequency of smoking, withdrawal symptoms, and the likelihood of smoking cessation in women. Cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Our objective was to evaluate the effect of the phase of the menstrual cycle on the activity of CYP2A6 and the cardiovascular effects of nicotine. Eleven healthy, nonsmoking women received a 30-minute combined infusion of deuterium-labeled nicotine and cotinine (0.5 microg . kg(-1) . min(-1) of each compound) during the midfollicular and midluteal phases of the menstrual cycle. Nicotine and cotinine pharmacokinetic parameters and plasma adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine responses were measured over time. There were no biologically or statistically significant differences in the comparison of menstrual cycle phases with regard to the pharmacokinetics of nicotine and cotinine. Nicotine clearance was 1000 +/- 315 mL/min and 1047 +/- 271 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.06; 90% confidence interval, 0.87-1.29). Cotinine clearance was 44 +/- 20 mL/min and 55 +/- 42 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.13; 90% confidence interval, 0.90-1.41). Nicotine infusion increased blood pressure, heart rate, and epinephrine concentrations. There were no differences in catecholamine, ACTH, or hemodynamic responses to nicotine infusion between menstrual cycle phases, although norepinephrine concentrations were constantly higher in the luteal phase compared with the follicular phase. CYP2A6 activity is not affected by menstrual cycle phase, and it is unlikely that menstrual cycle-related smoking habits of women are determined by changes in nicotine pharmacokinetics. The effects of nicotine on plasma ACTH and catecholamine levels and hemodynamic parameters are not altered by menstrual cycle phase in healthy, nonsmoking women.

Pilot study of combined intra-arterial infusion therapy with gemcitabine plus heptaplatin for unresectable hepatocellular carcinoma: Young Min Park, Sihyun Bae, Woochul Chung, Byunghun Byun, Jongyoung Choi, Sangbok Cha, Kyuwon Chung, Heesik Sun, Dooho Park, Byungkil Choi, Catholic University Medical College, Seoul South Korea

Pilot study of combined intra-arterial infusion therapy with gemcitabine plus heptaplatin for unresectable hepatocellular carcinoma: Young Min Park, Sihyun Bae, Woochul Chung, Byunghun Byun, Jongyoung Choi, Sangbok Cha, Kyuwon Chung, Heesik Sun, Dooho Park, Byungkil Choi, Catholic University Medical College, Seoul South Korea

Regimens for Patient-controlled Epidural Analgesia during Labor

We would like to thank Dr. Paech for his comment on our study, and to apologize for not having cited his previous study devoted to the role of background infusion during labor patient-controlled analgesia performed more than 10 yr before ours.1,2Although a smaller sample size, a different anesthetic solution (0.125% bupivacaine and fentanyl 3 μg/ml) and only one rate of background infusion were studied, Paech had shown no benefit of using a background infusion in combination with self-administered boluses with equivalent analgesia and satisfaction in both groups, low rates of bupivacaine usage, and similar maternal and neonatal outcomes. No differences were observed in the mean ± SD hourly bupivacaine doses (11 ± 5 mg in the bolus groups and 13 ± 7 mg in the bolus plus 4-ml/h background infusion group, not significant), which was similar to our study, where no differences were observed in the hourly consumption of anesthetic solution between the 0-ml/h and 3-ml/h groups. This might be explained by insufficient power of both studies to detect small differences in the hourly requirements. However, the results from both studies and from the two previous studies devoted to this subject provide evidence that background infusion may not be routinely used during labor patient-controlled analgesia.3,4* Hôtel-Dieu Hospital, Lyon, France. dominique.chassard@chu-lyon.fr

Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l(-1) for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl(-1).min(-1) ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.

Tamoxifen increases methamphetamine-evoked dopamine output from superfused striatal tissue fragments of male mice

The antiestrogen, tamoxifen (TMX), has been shown to function as a neuroprotectant against the nigrostriatal dopaminergic (NSDA) neurotoxin, methamphetamine (MA), within male mice. In the present report, we examined the effects of a combined infusion of TMX and MA within superfused striatal tissue fragments of male mice as an approach to understand some of the bases for TMX to function as a NSDA neuroprotectant within male mice. In Experiment 1, a coinfusion of TMX at 1, 10, or 100 pg/ml were all equally effective in increasing MA-evoked dopamine (DA) output as compared with a 0 pg/ml (control) dose. In Experiment 2, we tested whether this effect of TMX was specific for MA-evoked DA output by coinfusing TMX with a depolarizing concentration of potassium chloride (K +—30 mM). No statistically significant differences were obtained between superfusions of striatal tissue fragments stimulated with K + in the presence or absence of TMX (100 pg/ml). In Experiment 3, we assessed whether these effects of TMX may be exerted upon the dopamine transporter (DAT) by coinfusing DA (1 μM) in the presence or absence of TMX (100 pg/ml). No differences in DA recovery rates were obtained between superfusions performed in the presence or absence of TMX. Taken together, these results show that the striatum of male mice is very sensitive to the modulatory effects of TMX upon MA-evoked DA output. These effects of TMX appear to be relatively specific for MA-evoked DA output, as K +-stimulated DA was not altered by TMX, and do not appear to exert these effects by altering dopamine transporter function.

Superselective docetaxel–nedaplatin combined infusion concurrent with radiation therapy in advanced oral cancers

Cisplatin-based superselective intra-arterial chemotherapy concurrent with radiotherapy (SIART) has been reported to be effective in advanced head and neck carcinomas (HNC). However, the ideal regimen has not been established. We combined nedaplatin (CDGP) with docetaxel (DOC) as a new combination in SIART for treatment of advanced oral squamous cell carcinomas (OSCC). Two patients with stage IV advanced OSCC were treated and complete response (CR) were attained, although a residual metastatic lymph node remained in one case. Thirteen and 10 months post-treatment, no recurrence or metastatic spread was observed. This result indicated that CDGP and DOC combination in SIART is effective in advanced OSCC treatment.

Impact of combined NO and PG blockade on rapid vasodilation in a forearm mild-to-moderate exercise transition in humans.

We tested the hypothesis that nitric oxide (NO) and prostaglandins (PGs) contribute to the rapid vasodilation that accompanies a transition from mild to moderate exercise. Nine healthy volunteers (2 women and 7 men) lay supine with forearm at heart level. Subjects were instrumented for continuous brachial artery infusion of saline (control condition) or combined infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) and ketorolac (drug condition) to inhibit NO synthase and cyclooxygenase, respectively. A step increase from 5 min of steady-state mild (5.4 kg) rhythmic, dynamic forearm handgrip exercise (1 s of contraction followed by 2 s of relaxation) to moderate (10.9 kg) exercise for 30 s was performed. Steady-state forearm blood flow (FBF; Doppler ultrasound) and forearm vascular conductance (FVC) were attenuated in drug compared with saline (control) treatment: FBF = 196.8 +/- 30.8 vs. 281.4 +/- 34.3 ml/min and FVC = 179.3 +/- 29.4 vs. 277.8 +/- 34.8 ml.min(-1).100 mmHg(-1) (both P < 0.01). FBF and FVC increased from steady state after release of the initial contraction at the higher workload in saline and drug conditions: DeltaFBF = 72.4 +/- 8.7 and 52.9 +/- 7.8 ml/min, respectively, and DeltaFVC = 66.3 +/- 7.3 and 44.1 +/- 7.0 ml.min(-1).100 mmHg(-1), respectively (all P < 0.05). The percent DeltaFBF and DeltaFVC were not different during saline infusion or combined inhibition of NO and PGs: DeltaFBF = 27.2 +/- 3.1 and 28.1 +/- 3.8%, respectively (P = 0.78) and DeltaFVC = 25.7 +/- 3.2 and 26.0 +/- 4.0%, respectively (P = 0.94). The data suggest that NO and vasodilatory PGs are not obligatory for rapid vasodilation at the onset of a step increase from mild- to moderate-intensity forearm exercise. Additional vasodilatory mechanisms not dependent on NO and PG release contribute to the immediate and early increase in blood flow in an exercise-to-exercise transition.

Combined modality therapy of resectable rectal cancer: current approaches.

There are two conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is in stage T3 or N1-2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is classified at ultrasound as uT3-4 or N+. A number of new chemotherapeutic agents have been developed for the treatment of patients with colorectal cancer. Ongoing phase I and II trials are examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting; early results suggest that the complete response rates are higher. Based on results from phase I and II trials, the standard regimen for patients who receive combined modality therapy is continuous infusion 5-fluorouracil (5-FU) and pelvic radiation. Regimens using CPT-11 or oxaliplatin-based combined modality therapy plus either continuous infusion 5-FU or capecitibine are under active development.

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904)

4011 Background: In the treatment of advanced pancreatic cancer, chemotherapy regimens utilizing prolonged infusions of gemcitabine or combinations of gemcitabine and other agents have been associated with higher objective tumor response rates and, in some cases, improvements in progression-free survival when compared with gemcitabine administered as a standard 30-minute infusion. Comparisons between these novel regimens have been limited. We therefore performed a randomized phase II study of four investigational chemotherapy regimens in pts with documented metastatic pancreatic cancer. Methods: Pts were randomized to receive one of the following four treatments: gem 1000 mg/m2 d 1, 8, 15 with cisplatin 50 mg/m2 d1, 15 q 28d (Arm A); gem 1500 mg/m2 at a fixed dose rate of 10 mg/m2/minute d1, 8, 15 q 28d (Arm B); gem 1000 mg/m2 d1, 8 with docetaxel 40 mg/m2 d1, 8 q 21d (Arm C); or gem 1000 mg/m2 d1, 8 with irinotecan 100 mg/m2 d1, 8 q 21d (Arm D). Planned follow up per pt is 6 months. Results: Two hundred and fifty-one pts (61–65 per arm) were enrolled, with the following characteristics: median age 60.7 (range (31–84); M/F = 157/94; ECOG PS 0/1/2 = 49/86/18. Median follow-up time is 4.8 months. Pts were followed for overall survival, tumor response, time to tumor progression, and toxicity. The major toxicities experienced by 198 enrolled pts for whom data is currently available are shown in Table 1. Three pts experienced treatment related deaths: 1 (2%) in Arm A and 2 (4%) in Arm B. Conclusions: While the specific toxicities differ to some degree between regimens, all four regimens have acceptable toxicity profiles. Accrual to the trial has been completed. Updated toxicity data, as well as preliminary data for survival, response, and time to tumor progression will be presented at the annual meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceuticals

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904)

4011 Background: In the treatment of advanced pancreatic cancer, chemotherapy regimens utilizing prolonged infusions of gemcitabine or combinations of gemcitabine and other agents have been associated with higher objective tumor response rates and, in some cases, improvements in progression-free survival when compared with gemcitabine administered as a standard 30-minute infusion. Comparisons between these novel regimens have been limited. We therefore performed a randomized phase II study of four investigational chemotherapy regimens in pts with documented metastatic pancreatic cancer. Methods: Pts were randomized to receive one of the following four treatments: gem 1000 mg/m2 d 1, 8, 15 with cisplatin 50 mg/m2 d1, 15 q 28d (Arm A); gem 1500 mg/m2 at a fixed dose rate of 10 mg/m2/minute d1, 8, 15 q 28d (Arm B); gem 1000 mg/m2 d1, 8 with docetaxel 40 mg/m2 d1, 8 q 21d (Arm C); or gem 1000 mg/m2 d1, 8 with irinotecan 100 mg/m2 d1, 8 q 21d (Arm D). Planned follow up per pt is 6 months. Results: Two hundred ...

Prevention of Postischemic Spinal Cord Injury by Means of Regional Infusion of Adenosine and l-carnitine Dissolved in Normothermic Saline

Spinal cord ischemia still remains an unsolved problem in modern aortic surgery. In this study, we investigated the effectiveness of combined agents such as adenosine and L-carnitine infused to the isolated segment of abdominal aorta in a rabbit model. Twenty-eight rabbits divided into four groups underwent 40 min of isolated infrarenal aortic occlusion. Group I animals received no medication. Group II received an infusion of 100 mg/kg L-carnitine in normothermic saline over the first 10 min of ischemia. Group III received 50 mg adenosine, and group IV received a combination of the two agents in the same fashion. Spinal cord function was evaluated at 24 and 72 hr after operation on the basis of Tarlov scale and similar results were obtained. After a second evaluation, spinal cords were harvested for histological examination. Group I animals were all paraplegics. Spinal cord function was partially intact in two of the group II animals with Tarlov scores of 5 in two and 4 in two whereas one of the rabbits could not hop with a score of 3, and the remaining two could not sit with scores of 1 and 0. The spinal cord function of group III animals was intact with Tarlov scores of 5 in three, 4 in two, and 3 and 1 in remaining ones. In the group IV animals, it was fully intact with Tarlov scores of 5. Histological examination in group I revealed marked enlargement of the vacuoles of glial cells in the white matter of spinal cord. Glial cells were deteriorated in some locations in group II whereas they were mostly protected in the third group. In group IV, histological examination revealed no evidence of spinal cord injury. In conclusion, combined infusion of adenosine and L-carnitine provided better protection against postischemic spinal cord injury than individual infusion of these agents.

The effectiveness of continuous epidural infusion of low-dose fentanyl and mepivacaine in perioperative analgesia and hemodynamic control in mastectomy patients

Study objectives To investigate, in mastectomy patients, the effectiveness of continuous cervical epidural block using a low-dose fentanyl infusion in combination with local anesthetics. Design Prospective, observational study. Setting 450-bed, university-affiliated hospital. Patients 21 ASA physical status I and II female patients undergoing modified radical mastectomy. Interventions An epidural catheter was inserted at the C 7 -Th 1 interspace before the induction of anesthesia. Anesthesia was maintained using a low concentration of sevoflurane with nitrous oxide-oxygen (N 2 O-O 2). A mixture of 100 μg fentanyl and 49 mL of 1% mepivacaine was prepared, and 7 mL of this solution was epidurally injected before the initial incision. This same solution was continuously infused at a rate of 7 mL/hr (fentanyl 17.5 μg/hr) throughout the anesthesia, and at 2 mL/hr (fentanyl 5 μg/hr) postoperatively. Measurements and main results Intraoperative mean arterial pressure (MAP) and heart rate (HR), postoperative pain and analgesic use, and the frequency of postoperative side effects of anesthesia, including nausea, dizziness, and respiratory depression, were recorded. The protocol described provided stable intraoperative hemodynamic control with no or low-dose nicardipine infusion. Sufficient postoperative analgesia was achieved in 18 of 21 patients. One patient reported postoperative nausea, and no other side effects were reported. Conclusions Continuous epidural infusion of the low-dose fentanyl mixture described above provides adequate intraoperative hemodynamic control and postoperative pain relief, with a low rate of side effects in mastectomy patients.

切迫早産治療中の妊産婦くも膜下出血の治験例―脳血管れん縮に対し塩酸ファスジルとミルリノンの併用動注療法が有効であった１例―

Subarachnoid hemorrhage from an intracranial aneurysm during pregnancy is a rare complication but with high maternal and fetal mortality. We report a 37-year-old woman during the 25th gestational week who was under treatment of preterm labor when she suffered from subarachnoid hemorrhage due to a ruptured cerebral aneurysm. Emergent surgical clipping of the aneurysm was performed and the following severe vasospasm was successfully treated by intra-arterial infusions in combination with Fasudil Hydrochloride and Milrinone. The patient had a good outcome and delivered a healthy female by cesarean section. Milrinone is a direct vasodilator with noncatecholamine, nonglycosidicinotropic activity. Although its potency is known to be 10-30 times higher than that of the parent compound Amrinone, fewer adverse effects like hypotension are reported. Intra-arterial combined use of Fasudil Hydrochloride and Milrinone is an effective and safe treatment of choice in a pregnant patient with severe vasospasm after subarachnoid hemorrhage, because both maternal and fetal hypotension can be avoided.

Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma in the rat.

Cytokines play a major role in the regulation of the immune system. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate dendritic cells to present tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies have shown that each of these cytokines alone can induce the regression of tumor cells. In the present study we postulated that peripheral infusion of GM-CSF along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased survival from 9L brain tumors. 9L gliosarcoma cells (10(6)) were implanted in the brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12. Irradiated 9L cells were injected subcutaneously at various time points during treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis were used to further characterize the anti-tumor response. Treatment with GM-CSF and irradiated tumor cells led to an increase in survival rate in rats with intracranial 9L tumors when compared to untreated animals. The addition of IL-2 or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These results suggest that the combined infusion of GM-CSF and other cytokines may be effective adjuvants in treating brain tumors.

Arginine Vasopressin in Vasodilatory Shock

To the Editor: Dunser et al1 concluded that the combined infusion of vasopressin and norepinephrine is superior to infusion of norepinephrine alone in the treatment of shock resistant to catecholamine. We believe that this study is flawed and do not support such a conclusion. First of all, the design included two interventions in parallel, one of arginine vasopressin (and its control group in the other arm, without such treatment) and the other with two different doses of norepinephrine. They concluded that the combination group required a lower dose of norepinephrine, which was a consequence of the experimental protocol. The major shortcoming of this study, however, is an evident mistake in the statistical interpretation of their main results. The authors concluded that patients treated with the combination had improved cardiac performance, an effect that did not occur at all. Table 2 of …

Effects of Casein and Glucose on Responses of Cows Fed Diets Based on Restrictively Fermented Grass Silage

This study was conducted to investigate whether well fed dairy cows given restrictively fermented grass silage diet will respond to incremental glucose and amino acid supply at early stage of lactation. Four rumen-cannulated Finnish Ayrshire cows were used in a 4×4 Latin square experiment with 14-d periods. The cows were fed good quality restrictively fermented grass silage ensiled with a formic acid additive for ad libitum intake. A concentrate mixture consisting of barley (85%) and solvent extracted rapeseed meal (11.4%) was given at a rate of 9 kg/d. The four treatments were continuous abomasal infusions of water (control), casein 300g/d, glucose 300g/d, and casein 300g/d + glucose 300g/d. The infusions had only minor effects on feed intake, diet digestibility, or rumen fermentation pattern. Both casein and glucose infusions increased milk, protein and lactose yields the effects being partly additive on the combined infusion. Infused casein increased milk protein and urea as well as plasma urea concentrations. Both casein and glucose tended to increase plasma glucose concentration. Casein increased arterial plasma concentrations of essential amino acids (EAA), branched-chain AA (BCAA), and total AA (TAA). Both casein and glucose, although glucose usually less than casein, increased arteriovenous differences of EAA, nonessential AA, BCAA, and TAA. Extraction efficiencies of AA were higher for glucose than for casein. Mammary plasma flow was at highest on the control diet, but reduced owing to infused nutrients, the reduction being less with combined rather than separate infusions of casein and glucose. Based on the partly additive increases in milk production parameters and changes in plasma metabolites, it is suggested that glucose alone increased milk protein yield by sparing AA from hepatic utilization, while casein increased both supply of AA and glucose. It was concluded that cows at early stage of lactation fed diets comprising of restrictively fermented grass silage and a cereal-based concentrate suffer from both limited AA and glucose supplies.

Superiority of combined chemo-embolization and portal infusion with 5-fluorouracil over locoregional infusion concepts in Novikoff hepatoma-bearing rats

The aim of this study was to investigate experimentally whether there is a superior effect of the combination of hepatic artery chemo-embolization with portal vein infusion over either of the two treatment modalities alone. Novikoff hepatoma cells transplanted under the liver capsule of Sprague Dawley rats were used as a model. Tumor growth was assessed at 7 and 21 days after tumor inoculation. The prolamine solution Ethibloc was employed for embolization, and 5-fluorouracil was used as a chemotherapeutic agent for both infusion and chemo-embolization. All arterial treatment modalities were administered in a super-selective manner. There was no intolerable toxicity after dosages of 55 to 125 mg 5-fluorouracil/kg body weight. With regard to therapeutic efficacy the results show that embolization is an effective therapeutic means for inducing tumor necrosis in selected liver areas. As a consequence, the ranking of all treatment modalities was based on the combined evaluation of tumor size and extent of tumor necrosis. According to this evaluation, hepatic artery chemo-embolization was superior to the respective type of infusion (P<0.01). In addition, the combination of both modalities in the form of hepatic artery chemo-embolization and portal vein infusion was effective in destroying more than 97% of vital tumor tissue (P<0.01). These results suggest the need for a comparative clinical study.