Single Large Dose Research Articles

Parenteral Aminoglycoside Therapy

Aminoglycosides are potent water-soluble antibiotics, with peak concentration-dependent bactericidal activity against many pathogenic aerobic Gram-negative bacilli and Staphylococcus aureus. For systemic therapy, they must be given parenterally (intravenously or intramuscularly). In the body they remain largely extracellular, but penetration into cerebrospinal fluid and other secretions is meagre. They display trough concentration-dependent reversible nephrotoxicity and The commonly irreversible ototoxicity, which may present after treatment ceases. Gentamicin is the usual all-purpose agent of choice, tobramycin is slightly more effective against Pseudomonas aeruginosa infections, amikacin is the least susceptible to degradation by bacterial enzymes and netilmicin is probably the least toxic. Clinical and drug concentration monitoring have a role in therapy. Aminoglycosides exhibit enduring antibacterial activity (especially against Gram-negative bacilli) many hours after tissue concentrations become negligible. Appreciation of this postantibiotic effect is leading to replacement of conventional multiple daily doses by large single daily doses. The latter regimens confer at least equivalent efficacy and less risk of toxicity (particularly renal). However, single daily dosage may be unsuitable for immunocompromised patients and in those with infective endocarditis, where there is insufficient experience. Cotreatment with beta-lactams is commonly used in order to exploit the synergism between these agents, particularly in enterococcal endocarditis and severe Gram-negative sepsis. Liposomal aminoglycosides are promising parenteral formulations. After being taken up by phagocytes they reach the liver, spleen and sites of inflammation; subsequently they are gradually released. To substantiate the applicability of these hitherto experimental formulations, findings from clinical studies are keenly awaited.

Enhancement of cyclophosphamide cytotoxicity in vivo by the benzamide analogue pyrazinamide.

The ability of pyrazinamide to enhance the in vivo cytotoxicity of cyclophosphamide in Lewis lung and RIF-1 tumours was investigated. Using an in vivo/in vitro excision assay a large single dose of pyrazinamide (500 mg kg-1 i.p.) was shown to enhance the tumour cell killing by cyclophosphamide. This enhancement was greatest when pyrazinamide was administered before the alkylating agent and had a dose-modifying effect on all cyclophosphamide doses tested, giving rise to a mean (+/- 1 s.e.) enhancement ratio (ER) of 1.54 (+/- 0.15) for the Lewis lung and 1.24 (+/- 0.08) for the RIF-1 tumour. Pyrazinamide also increased the cytotoxic action of cyclophosphamide in a normal tissue, namely white blood cell counts. However, the ER was only 1.14 (+/- 0.08), which although not significantly different from the value seen in RIF-1 was significantly less than the ER obtained with Lewis lung, suggesting the possibility of a therapeutic gain. This benzamide analogue did not appear to inhibit recovery from cyclophosphamide-induced potentially lethal damage in tumours, nor did it alter the bioactivation of cyclophosphamide or the subsequent clearance of the cytotoxic species from the plasma, so the mechanism for this chemosensitisation remains unclear.

High dose oral amiodarone loading exerts important hemodynamic actions in patients with congestive heart failure

Objective. The purpose of this study was to use invasive monitoring to analyze the hemodynamic effects of both a large single dose and a 48-h loading regimen of amiodarone in patients with severe heart failure.Background. Amiodarone is frequently used as an antiarrhythmic agent in patients with congestive heart failure, but the impact of this agent on cardiac function remains controversial. Recent successful experience with a rapid oral load of amiodarone makes invasive testing of the hemodynamic effects of oral amiodarone in such patients now feasible.Methods. After baseline hemodynamic assessment (using balloon-tipped pulmonary artery catheters) and electrocardiographic measurements, 16 patients received 12.5 mg/kg body weight of amiodarone orally. Hemodynamic measurements were obtained hourly for 4 h. Patients then received this dose an additional seven times over the next 2 days. Hemodynamic variables and QRS, QT and PR intervals were measured after 48 h of treatment.Results. Vasodilation was seen between 1 and 3 h after drug administration. Systemic vascular resistance decreased 326 ± 135 dynes·S·cm−5, cardiac index increased 0.24 ± 0.08 liters/mm per m2and mean arterial pressure decreased 6 ± 3 mm Hg (mean ±SEM, all p < 0.05). After 48 h of amiodarone administration, heart rate decreased 23 ± 3 beats/min (p < 0.005), stroke volume increased 9 ± 3 ml (p < 0.005), cardiac index decreased 0.23 ±0.09 ml/min per m2(p < 0.05), pulmonary capillary wedge pressure increased 4 ± 1 mm Hg (p < 0.01), right atrial pressure increased 3 ± 1 mm Hg (p < 0.005) and QT and PR intervals were markedly prolonged (p < 0.01).Conclusions. Although the first dose caused vasodilation, a complete loading regimen of amiodarone produced a decreased heart rate with elevated filling pressures and decreased cardiac index.

Flavonoid-Induced Acute Nephropathy

We report two cases of acute renal failure induced by sciadopitysin, a type of flavonoid, and review related papers of flavonoid-induced acute nephropathy in the literature. A total of eight patients were studied. The purpose of this report is to alert physicians to consider this cause of acute renal failure with hemolysis, because flavonoids are widely used in the world. All patients initially presented with fever and gastrointestinal upset after the ingestion of a single large dose or long-term small doses. Symptoms that followed were cola-colored urine and jaundice. Elevation of blood nitrogen and serum creatinine lasted for 2 to 9 weeks. Hemolysis (100%), cholestatic hepatitis (50%), and disseminated intravascular coagulopathy (50%) were also noted in flavonoid-induced oliguric acute renal failure patients. All of these patients required hemodialysis and all but one who died completely recovered within 2 to 9 weeks. Renal biopsy was performed and showed acute interstitial nephritis with acute tubular necrosis. Moreover, we first demonstrated multiple polymorphous inclusion bodies within tubular epithelial cells in electron microscopic examinations. The definite pathogenetic mechanism of flavonoid-induced acute nephropathy needs further elucidation.

Cure with cisplatin (II) or murine malaria infection and in vitro inhibition of a chloroquine-resistant Plasmodium falciparum isolate.

Antiplasmodium properties of cisplatin [cis-platinum (II) diamine dichloride], a neoplastic drug, have been assessed in in vivo and in vitro model systems of malarial parasite. A well-tolerated dose of 6 mg/kg body weight of the compound cured the mice infected with Plasmodium berghei and the amount of cisplatin required for in vitro inhibition (IC50) of a chloroquine-resistant Plasmodium falciparum isolate was smaller than either chloroquine or quinine. The minimum inhibitory concentration (MIC) needed to prevent the in vitro multiplication of asexual blood parasites was 30 ng/ml. Late ring and trophozoite stages of the erythrocytic cycle were the most susceptible, whereas schizont and early ring stages were the least sensitive to the toxic effect of cisplatin. Multiple smaller doses were more effective in curing malaria in mice than a single large dose. In a few of the mice treated with a single intraperitoneal large dose of 6 mg/kg body weight, there was a delay in appearance of parasitemia but most of them recovered completely but slowly. This compound exerts its toxicity mainly by randomly damaging and cross-linking DNA strands as shown by Southern hybridization with a synthetic oligonucleotide probe, which is a repeat sequence in the falciparum genome. The report clearly demonstrates the antimalarial potentials of this compound and suggests a closer evaluation of this and other related compounds, specially in combination with antimalarial drugs to probe their synergistic properties.

抗真菌剤ＨＯＣ‐１５５クリーム単回大量塗布時の薬物動態および安全性

抗真菌剤ＨＯＣ‐１５５クリーム単回大量塗布時の薬物動態および安全性

Tissue tolerance of normal and surgically manipulated canine liver to intraoperative radiation therapy (IORT)

Purpose : The purpose of the study is to obtain dose guidelines for the delivery of intraoperative radiotherapy to the liver of patients with colorectal liver metastases. Following partial resection of the liver, a single high dose of 10, 20, 25, and 30 Gy intraoperative radiotherapy was applied to both the resection plane as well as a nonsurgically manipulated part of the liver of 25 beagles. The temporal sequence of histological and ultrastructural changes of these irradiated parts of the liver tissue was investigated. Methods and Materials : The feasibility of delivering single large dose of intraoperative electron beam radiotherapy to the normal and partially hepatectomized liver was experimentally investigated in a canine study. Results : There were no postoperative complications, no morbidity or mortality with a minimal follow-up of 1 year. Autopsy performed 3 months following irradiation showed only mild histopathological changes. One year following intraoperative radiotherapy more distinct histopathological changes consisting of capsular thickening, diffuse parenchymal fibrosis and subcapsular hepatocellular atrophy were found. The liver function remained intact. Conclusion : This study demonstrated that intraoperative radiotherapy to part of the liver in the canine model can be safely applied and doses up to 30 Gy are well tolerated.

Long-term results of large-dose, single-session phenol injection sclerotherapy for hemorrhoids.

The aim of our study was to assess the medium to long-term outcome following single session large dose injection sclerotherapy for symptomatic hemorrhoids. One hundred eighty-nine patients (male = 106, female = 83, median age, 51; range, 20-85 years) were assessed following single-session, large-dose (3 x 5 ml) phenol injection therapy. The most frequent complaint was bleeding (100 percent). At four-year follow-up, 53 patients (28.0 percent) were cured, 26 (13.7 percent) were improved, 35 (18.5 percent) remained unchanged, 59 (31.2 percent) deteriorated, and 16 (8.5 percent) required surgical intervention. Among the patients who were not cured, symptoms were minimal in 50 percent. Sclerotherapy was associated with a reduced incidence of bleeding (P < 0.05) but an increase in difficulty in perineal cleaning was observed (P < 0.05). Large-dose, single-session sclerotherapy provides only short-term benefits in the majority of patients with symptomatic hemorrhoids.

Ablation of Remaining Functioning Thyroid Lobe With Radioiodine After Hemithyroidectomy for Carcinoma

Nineteen patients who had hemithyroidectomy as a surgical procedure for thyroid cancer were given radioiodine to ablate the residual hemithyroid. Two different protocols were used, with either a larger single dose or multiple smaller doses. Ablation was achieved in 28% with the single large dose approach and in 33% of patients given split doses of similar total amount. This response to the initial attempt at eradication of the residual normal hemithyroid is considerably lower than the accepted ablation rate with comparable doses administered to patients with small thyroid residues after total thyroidectomy. It is suggested that the effect of radioiodine treatment may relate inversely to the size of the thyroid remnant. Our findings also are in support of the surgical approach advocating total thyroidectomy for patients contemplating ablation of thyroid residues after surgery for thyroid carcinoma.

Travellers' diarrhoea. Which antimicrobial?

For those who venture from highly industrialised areas to developing tropical and semitropical areas, the chance of developing diarrhoea is about 40%. In most cases a bacterial pathogen is responsible for the illness. The antimicrobial agents with the greatest activity against these organisms are cotrimoxazole (trimethoprim/sulfamethoxazole) during the summer months in the interior of Mexico (a region where this agent has been studied extensively), and the fluoroquinolones for other places or other times, until data become available to indicate the appropriateness of cotrimoxazole here as well. Persons at risk should take along with them a drug to treat symptoms of travellers' diarrhoea, and an appropriate antimicrobial agent. At the passage of the third unformed stool, it is recommended that travellers treat themselves with fluids and salt (flavoured mineral water augmented with saltine crackers is sufficient in most cases), symptomatic treatment and antibacterial therapy. Of these, the antimicrobial is the most important component, which is given either as a single large dose or one or twice daily for 3 days. Perhaps optimal therapy for afebrile nondysenteric patients is loperamide in combination with the antibacterial drug. In the face of fever or dysentery, the antimicrobial should be used alone. In special situations where food and beverage restrictions cannot be followed and where the itinerary cannot tolerate even the slightest alterations because of illness, chemoprophylaxis can be considered. The most effective preventive medication in this case is the antimicrobial also used for therapy, taken in half the therapeutic dosage daily while in the area of risk. However, the majority of travellers should not use this approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscular fibrosis induced after pig skin irradiation with single doses of 192lr γ-rays

Localized irradiation of the skin and subcutaneous tissues with large single doses of gamma-rays can induce delayed effects characterized by fibrosis which invades the irradiated tissues. In this study the depth of penetration of muscle fibrosis was measured in the pig 30 weeks after irradiation of the skin surface with single doses of 192Ir gamma-rays of 16-256 Gy. Irradiation was directed either to the outer side of the thigh or to the back, close to the mid-dorsal line. Fibrosis only developed in irradiated muscle after doses that induced moist desquamation of the skin in the acute phase of the reaction, i.e. after skin surface doses of 48-64 Gy. In skeletal muscles, the limit of fibrotic expansion was reached at a depth dose of 14 +/- 4 Gy (+/- SD) for skin surface doses exceeding 48 Gy.

Estrogen-induced left ventricular chamber enlargement in ewes.

We studied the chronic effect of administration of a single large intramuscular dose of 17 beta-estradiol on left ventricular chamber size and output in the ewe. Fourteen oophorectomized ewes were successfully instrumented and studied, with measurements made of left ventricular, aortic, right and left atrial pressures, left ventricular stroke volume, and left ventricular minor axis dimension. Unanesthetized ewes were studied before and 1, 2, and 3 wk after intramuscular administration of 0.6 mg/kg 17 beta-estradiol (7 ewes) or 1.5 ml sesame oil placebo (7 ewes). Left ventricular end-diastolic pressure-end-diastolic dimension (LVEDP-EDD) and left ventricular end-diastolic pressure-stroke volume (LVEDP-SV) relationships were quantified during graded inferior vena caval occlusion and volume infusion. Left ventricular end-diastolic diameter was larger after estrogen but not after placebo administration. The LVEDP-EDD relationship shifted progressively rightward, indicating left ventricular chamber enlargement in the estrogen group but was unchanged in the placebo group. The plateau limb of the LVEDP-SV relationship in the estrogen group shifted up from a mean stroke volume of 77.1-89.5 ml/beat and did not change in the placebo group. We conclude that administration of a single large intramuscular dose of 17 beta-estradiol resulted in left ventricular chamber enlargement and increased stroke volume in the ewe.

Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs.

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

17 A single large dose of HPMPC is highly effective at inhibiting HCMV when administered in an in vitro drug delivery system : MR Moore, FM Hamzeh, FE-H Lee, and PS Lietman, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

The introduction of highly active antiretroviral therapy (HAART) for HIV has had a major impact on the treatment of CMV disease in HIV-infected individuals. There is mounting evidence that in patients with CMV retinitis who have a sustained response to HAART, CMV maintenance treatment can be discontinued without relapse of retinitis. In HAART-naı̈ve individuals with newly diagnosed CMV retinitis, the optimal timing for the initiation of HAART relative to the start of anti-CMV treatment is currently unknown. New local therapies for CMV retinitis (e.g. ganciclovir implant, the new antisense compound fomivirsen) provide treatment options in situations where high local drug delivery is warranted. A treatment algorithm for CMV disease in the HAART era is proposed. In the transplant setting, ganciclovir and foscarnet remain the major compounds used for treatment of CMV disease. In marrow and stem cell transplant recipients, CMV pneumonia still carries a high mortality. Ganciclovir in combination with CMV-specific immunoglobulin or regular intravenous IG remains the treatment of choice for CMV pneumonia; extended antiviral maintenance for several months is recommended in patients with continued immunosuppression. Preemptive treatment based on virologic markers (e.g. pp65 antigenemia, CMV DNA) has been very successful in reducing the incidence of early CMV disease in the transplant setting. The duration of preemptive treatment should be guided by the underlying immunosuppression and virologic markers. Late CMV disease is a challenge in marrow and stem cell transplant recipients, and occurs increasingly in highly immunosuppressed solid organ transplant recipients as well. Recent advances in prophylaxis strategies include oral ganciclovir for liver transplant recipients and valacyclovir for kidney transplant recipients.

Protective Effect of N-Acyl Amino Acids (NAAs) on Cephaloridine (CER) Nephrotoxicity in Rabbits

The protective effect of N-acyl amino acids (NAAs) against cephaloridine (CER)-induced nephrotoxicity was studied in rabbits. A large single intravenous dose of CER (more than 100 mg/kg) induced severe proximal tubular necrosis. Simultaneous treatment with several NAAs (at dosages of 100, 200 mg/kg, etc., i.v.), such as N-benzoyl-beta-alanine (NBBA), N-benzoyl-6-aminocaproic acid, and N alpha,epsilon-dibenzoyl-D,L-lysine, remarkably suppressed the histopathological damage in the kidney induced by CER. NAAs have generally low toxicity in laboratory animals (e.g., the LD50 of NBBA was more than 3,000 mg/kg, i.v. in rats), and NAAs were suggested to be good candidates for reducing the nephrotoxicity of CER and other beta-lactam antibiotics.

The Effect of Cyclophosphamide Treatment on Lymphocyte Subsets in the Nonobese Diabetic Mouse: A Comparison of Various Lymphoid organs

The nonobese diabetic (NOD) mouse is a model for human Type 1 diabetes mellitus. Pancreatic beta-cell destruction in NOD mice is mediated by an autoimmune process which can be accelerated by cyclophosphamide (CP). We studied the phenotype of lymphocytes from central, peripheral and regional lymphoid tissues in prediabetic NOD and C3H mice before and after a single large dose of CP. All lymphoid organs showed a greatly diminished cell number and most alterations appeared early after CP and were transient, but an aggressive insulitis was not seen in NOD mice until 14 d after injection. The pancreatic islets in C3H mice remained intact and were not infiltrated. NOD female mice, which are most prone to spontaneous and CP-induced diabetes, exhibited the most unusual lymphoid kinetics after treatment with CP. Their thymus and spleen showed the least relative drop in total cell number and the most rapid rate of recovery. The thymus of these mice was also found to have an increased proportion of CD3+ thymocytes while CD4/CD8 double positive thymocytes decreased 7 d after CP. At 14 d after CP the number of IL-2R+ thymocytes had surpassed that of normal levels. The most dramatic observation was the rapid recovery and overshoot in the number of pancreatic lymph node cells of female NOD mice which coincided with aggressive insulitis.

Effects of a Single Large Dose of Ethanol on Tissue Ascorbic Acid, Drug-Metabolizing Enzymes in the Liver, and Serum and Liver Lipids in Rats Fed with a PCB-containing Diet.

The effects of a single administration of ethanol after feeding a PCB-containing diet on tissue ascorbic acid, drug-metabolizing enzymes in the liver, and serum and liver lipids of rats were investigated. Male Donryu and Wistar rats that had been fed on a 20% casein diet with or without 0.03% PCB were given a 5g/kg of body weight ethanol solution (25%, w/v) via a stomach tube, and then killed 16h after the intubation. Intake of the PCB-containing diet accelerated the disappearance of blood ethanol. Dietary PCB and a single dose of ethanol independently affected the tissue levels of ascorbic acid. The combined effect on hepatic aniline hydroxylase activity was additive or synergistic. A single dose of ethanol did not significantly affect the hepatic aminopyrine N-demethylase activity. In Donryu rats, the effects from feeding on a PCB-containing diet and those from a single dose of ethanol on serum lipids were almost additive. In Wistar rats, the effects of ethanol alone on lipids were not necessarily apparent, but the effects of ethanol after feeding with the PCB-containing diet were strongly enhanced. Ethanol alone hardly affected the liver lipids. Most lipids that were increased by PCB alone were significantly decreased or tended to be decreased by a single dose of ethanol. The serum levels of GOT and GPT were markedly increased by a single large dose of ethanol concomitant with the PCB-containing diet in both strains of rats; however, PCB alone or ethanol alone hardly changed the serum levels of GOT and GPT. These results indicate that the effects of a single large dose of ethanol on drug and lipid metabolism, and on the liver function were markedly modified by the intake of a PCB-containing diet.

Role of gastric glutathione in smoke flavouring-induced gastric injury in rats

Some commercial liquid smoke flavourings have been shown to induce acute gastric mucosal injury in rats when given orally as a large single dose. The present study was carried out to examine the mechanism of action in rats of two selected smoke flavourings containing about 10% total acids as acetic acid. These flavourings and 10% acetic acid decreased the concentration of glutathione (GSH) in the glandular stomach. The decrease in gastric GSH was coupled with smoke flavouring-induced gastric injury. Pretreatment with N-ethylmaleimide, a GSH depletor, enhanced acetic acid-induced gastric injury. Pretreatment with cysteine, a sulphhydryl compound, protected rats against smoke flavouring-induced gastric injury. Aqueous fractions of the smoke flavourings, after removal of non-polar compounds and acidic organic compounds (including acetic acid) by diethyl ether extraction, decreased the gastric GSH concentration considerably and had a marked reactivity in vitro with GSH, but these fractions by themselves showed no ability to induce gastric injury. Addition of 10% acetic acid to these aqueous fractions caused greater gastric injury than 10% acetic acid alone, which suggests that these aqueous fractions contain the (unidentified) compound(s) that facilitate acetic acid-induced gastric injury. These findings indicate that gastric endogenous and exogenous sulphhydryls play an important part in gastric cytoprotection.

Dosimetry study of an accidental overexposure to 192Ir gamma rays.

Localized irradiation of the skin and subcutaneous tissues with large single doses of gamma rays can induce delayed effects characterized by fibrosis that invades the irradiated tissues. The skin surface dose and the depth of penetration of 192Ir gamma rays, measured in phantoms and in frozen thighs of sacrificed pigs after acute single doses of irradiation and different skin-to-source distances, are reported in this note. Correlations between the dosimetry and the evolution of the lesions are considered.

Large and prolonged in vivo response of pancreatic secretion to phenylethylamide and phenylethylester derivatives of Boc-[Nle 28-Nle 31]CCK(26–33) in the rat

Supramaximal doses of cholecystokinin (CCK) induce in vitro submaximal biological responses (i.e., smaller by 50% than the response to a maximal dose of CCK), desensitization and residual stimulation, and in vivo secretory inhibition and edematous pancreatitis. It has been reported previously that supramaximal doses of Boc-[Nle 28-Nle 31]CCK(27–32)/-phenylethylester (JMV180) do not produce these effects. The aim of this study was to analyze the in vivo response of pancreatic secretion of the rat to a wide dose range of Boc-[Nle 28-Nle 31]CCK(26–33) (JMV118), an analog of CCK8 with the same activity spectrum as CCK8, to JMV180 and to Boc-[Nle 28-Nle 31]CCK(27–32)-phenylethylamide (JMV170). The three peptides were administered as intravenous infusions and as bolus intravenous injections. In the case of infusions, the same maximal effect was observed with all three peptides. It was obtained with 22.5 pmol/kg · min of JMV118; JMV180 and JMV170 were about 700 times less potent. In the case of bolus injections, the maximal response to JMV118 was observed with 450 pmol/kg, and the response peaked 10–15 min after the injection. Higher doses of JMV118 induced a secretory peak that was smaller and delayed relative to the moment of injection. JMV180 and JMV170 were about 500 times less potent: the maximal response was observed with 218700 pmol/kg and peaked 10–15 min after the injection. Larger doses of JMV180 and JMV170 produced neither supramaximal inhibition nor a delayed peak response, but induced a sustained stimulation of pancreatic secretion that could last more than 3 h after the injection. These data indicate that single large doses of JMV180 and JMV170 can produce a large and long-lasting stimulation of pancreatic secretion in vivo, a goal that cannot be reached with JMV118 or CCK8.