Detrimental effects of complement activation in hemorrhagic shock.

The complement system has been implicated in early inflammatory events and a variety of shock states. In rats, we measured complement activation after hemorrhage and examined the hemodynamic and metabolic effects of complement depletion before injury and worsening of complement activation after hemorrhage and resuscitation [with a carboxypeptidase N inhibitor (CPNI), which blocks the clearance of C5a]. Rats were bled to a mean arterial pressure of 30 mmHg for 50 min and were then resuscitated for 2 h. Shock resulted in significant evidence of complement consumption, with serum hemolytic activity being reduced by 33% (P < 0.05). Complement depletion before injury did not affect hemorrhage volume (complement depleted = 28 +/- 1 ml/kg, complement intact = 29 +/- 1 ml/kg, P = 0.74) but improved postresuscitation mean arterial pressure by 37 mmHg (P < 0.05) and serum bicarbonate levels (complement depleted = 22 +/- 3 meq/ml, complement intact = 13 +/- 8 meq/ml, P < 0.05). Pretreatment with CPNI was lethal in 80% of treated animals vs. the untreated hemorrhaged group in which no deaths occurred (P < 0.05). In this model of hemorrhagic shock, complement activation appeared to contribute to progressive hypotension and metabolic acidosis seen after resuscitation. The lethality of CPNI during acute blood loss suggests that the anaphylatoxins are important in the pathophysiological events involved in hemorrhagic shock.     

Parallel changes in brain tissue blood flow and mitochondrial function during and after 30 minutes of bilateral forebrain ischemia in the gerbil

Forebrain ischemia was induced in Mongolian gerbils by bilateral occlusion of the common carotid arteries for 30 minutes. These animals do not have a complete circulus arteriosus Willisii. Mitochondria were prepared from the forebrain tissue at the end of the 30 minutes occlusion period as well as at different time points after the release of the occlusion. Tissue blood flow in the forebrain was also determined by measuring the brain tissue accumulation of 14C-iodoantipyrine. Tissue blood flow in the forebrain decreased from a control level of 1.43 +/- 0.03 ml/min/gr to 0.13 +/- 0.03 ml/min/gr by the 30th minute of ischemia, increased to 1.12 +/- 0.25 ml/min/gr after 5 minutes of reflow, but decreased again to 0.41 +/- 0.07 ml/min/gr after 1 1/2 hours of reflow. Oxygen consumption rate of mitochondria prepared from the forebrain (glutamate + malate as substrates in the presence of ADP) was 98 +/- 13 nmoles O2/min/mg protein in control animals, decreased to 61 +/- 9 nmoles O2/min/mg protein after 30 minutes of occlusion, recovered to 106 +/- 9 nmoles O2/min/mg protein during the first 30 minutes of reperfusion. During extended reperfusion, mitochondrial respiratory activity declined reaching 20 +/- 5 nmoles O2/min/mg protein after 5 1/2 hours of reperfusion. Respiratory control ratio of the mitochondria (relative increase of respiration upon addition of ADP) was 9.2 +/- 1.3 in control animals, 7.0 +/- 1.5 after 30 minutes of carotid occlusion, 9.0 +/- 1.2 after 30 minutes of reperfusion, and 5.8 +/- 0.8 after 5 1/2 hours of reperfusion. Superoxide dismutase activity of the forebrain mitochondria was 5.10 +/- 0.7 I.U./mg protein in control animals, decreased to 3.3 +/- 1.6 I.U./mg protein after 30 minutes of occlusion and remained at this level throughout the reperfusion period. These data confirm earlier reports that deterioration of mitochondrial function may contribute to the development of ischemic and post-ischemic brain tissue damage. It also appears possible that postischemic damage of mitochondrial function develops secondary to postischemic deterioration of tissue blood flow.     

20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat

This study examined the effects of blocking the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) on the acute fall in cerebral blood flow after subarachnoid hemorrhage (SAH) in the rat. In vehicle-treated rats, regional cerebral blood flow (rCBF) measured with laser-Doppler flowmetry fell by 30% 10 min after the injection of 0.3 ml of arterial blood into the cisterna magna, and it remained at this level for 2 h. Pretreatment with inhibitors of the formation of 20-HETE, 17-octadecynoic acid (17-ODYA; 1.5 nmol intrathecally) and N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 mg/kg iv), reduced the initial fall in rCBF by 40%, and rCBF fully recovered 1 h after induction of SAH. The concentration of 20-HETE in the cerebrospinal fluid rose from 12 +/- 2 to 199 +/- 17 ng/ml after SAH in vehicle-treated rats. 20-HETE levels averaged only 15 +/- 11 and 39 +/- 13 ng/ml in rats pretreated with 17-ODYA or HET0016, respectively. HET0016 selectively inhibited the formation of 20-HETE in rat renal microsomes with an IC(50) of <15 nM and human recombinant CYP4A11, CYP4F2, and CYP4F3 enzymes with an IC(50) of 42, 125, and 100 nM, respectively. These results indicate that 20-HETE contributes to the acute fall in rCBF after SAH in rats.     

Hemodynamic effects after partial exchange transfusion with pyridoxylated polyhemoglobin in chimpanzees.

Partial exchange transfusion with 8.5% pyridoxylated polyhemoglobin solution [PolyHb-PPa] was performed in five anesthetized spontaneously-breathing male chimpanzees weighing 22-30 kg. Mean exchange volume was 42.5 +/- 10.7 ml/kg BW (26.8-54.6 ml/kg), mean exchange rate 56.7 +/- 7.1% (48.2-67.4%). All animals survived long-term. The chimpanzee's hemodynamics remained stable for the 5 h observation period. Right and left ventricular filling pressures remained constant, mean arterial pressure and mean pulmonary arterial pressure increased by up to 40% after the exchange. Cardiac output remained unaffected by the partial exchange and stroke volume did not change substantially although oxygen capacity and oxygen transport capacity decreased by about a third. The failure of cardiac output to rise after partial exchange transfusion with PolyHb-PPa contrasts with results after isovolemic hemodilution using non-oxygen-carrying blood substitutes and is not adequately explained by the oxygen capacity of 8.5% PolyHb-PPa (9.3 ml O2/dl).     

ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: A comparative study to captopril effects in rats

To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a single dose of AE (1 g/kg, p.o.) or repeatedly (0.5 g/kg/bid, p.o.) for 60 days. Captopril (50 mg/kg, p.o.) was used as positive control on the same animals. The effects on the blood pressure were recorded directly from the femoral artery (single dose), or indirectly by the tail cuff method (repeated doses) in conscious rats. The plasma ACE activity was determined spectrofluorimetrically using Hypuril-Hystidine-Leucine as substrate. The arterial blood pressure, heart rate and plasma ACE activity were not significantly modified within 24 h after a single dose administration of AE. Comparatively, blood pressure in captopril treated rats was reduced by 7-16% and heart rate was increased by 10-20% from 30 min to 24 h after drug administration. ACE activity after captopril presented a dual response: an immediate inhibition peaking at 30 min and a slow reversal to 32% up-regulation after 24 h. To correlate the drug effects upon repeated administration of either compound, normotensive rats were separated in three groups: animals with high ACE (48.8+/-2.6 nmol/min/ml), intermediate ACE (39.4+/-1.4 nmol/min/ml) and low ACE (23.5+/-0.6 nmol/min/ml) activity, significantly different among them. Repeated treatment with AE reduced the mean systolic blood pressure (121.7+/-0.5 mm Hg) by 20 mm Hg after 14 days. The hypotension was reversed upon washout 60 days afterwards. Likely, repeated captopril administration decreased blood pressure by 20 mm Hg throughout treatment in all groups. After 30 days treatment with AE (0.5 g/kg/bid, p.o.) the plasma ACE activity was unchanged in any experimental group. After captopril (50 mg/kg/bid, p.o.) administration the plasma ACE activity was inhibited by 50% within 1 h treatment but it was up-regulated by 120% after 12 h in all groups. It is concluded that the hypotension produced by prolonged treatment with AE of C. glaziovii is unrelated to ACE inhibition.     

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.     

Effect of glibenclamide on thyroid hormone metabolism in rats

This study was undertaken to elucidate the effect of glibenclamide, one of sulfonylurea drugs, on thyroid hormone metabolism in vivo and on the conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) in the isolated perfused rat liver and kidney. Glibenclamide (0.2 mg/kg body weight) was intraperitoneally administered to normal and streptozotocin-induced (50 mg/kg) diabetic rats for 14 days. The liver and kidney of normal rats were perfused for 30 minutes with a synthetic medium containing 20 micrograms/dl T4 and glibenclamide (200 or 400 ng/ml), and production of T3 in the tissues was measured by radioimmunoassay. Serum T4 and T3 levels in control and streptozotocin-induced diabetic rats were not changed by daily intraperitoneal glibenclamide administration. The production of T3 (111 +/- 40 and 95 +/- 16 ng/g/30 min, mean +/- SD) and the conversion rate of T4 to T3 (11.1 +/- 2.9 and 10.2 +/- 2.3%) in the liver perfused with glibenclamide (200 and 400 ng/ml) were not significantly different from those in controls (109 +/- 41 ng/g/30 min and 12.8 +/- 5.4%). And those (120 +/- 33 and 99 +/- 19 ng/g/30 min, and 3.5 +/- 0.6 and 2.5 +/- 0.4%) in the kidney perfused with glibenclamide (200 and 400 ng/ml) were similar to those in controls (98 +/- 33 ng/g/30 min and 3.0 +/- 1.5%).     

Effect of hemorrhage on regional morphometric indexes of cerebral capillarity

This study was performed to determine whether the brain can increase the number of perfused capillaries and arterioles supplying it regionally during hemorrhage. This was done using a technique to simultaneously determine total and perfused regional arteriolar and capillary morphology. Conscious Long-Evans rats served as unbled controls or were bled 65 mmHg or to 40-45 mmHg and stabilized for 30 min. Regional cerebral blood flow was determined using [14C]iodoantipyrine in half of these animals and fluorescein isothiocyanate-dextran was injected in the other half for determination of perfused cerebral microvascular morphometric indexes. The total microvasculature was labeled postmortem via an alkaline phosphatase stain. Regional cerebral blood flow was significantly increased in animals bled to 65 mmHg. During hemorrhage to 40-45 mmHg, cerebral blood flow was reduced 50% (from 59 +/- 28 to 26 +/- 11 ml X min-1 X 100 g-1, mean +/- SD) with no regional redistribution. For all treatments, total capillary density ranged from 400 to 500 capillaries/mm2, and in controls 47% were perfused. Animals bled to 65 mmHg did not mobilize their unperfused microvascular reserve even though they showed a slight tendency to do so. During hemorrhage to 40-45 mmHg, this percent increased significantly to 57% with the largest increase occurring in the pons. Approximately 51% of arterioles were perfused in controls and this was not different compared with the percent perfused during hemorrhage. Despite the overall lack of mobilization of unperfused arterioles, some regions within the brain significantly mobilized their reserves with severe hemorrhage, e.g., hippocampus (78%), hypothalamus (67%), and medulla (73%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of temporary hypovolemia on the early central pooling of the blood circulation following resuscitation and the survival of animals experiencing clinical death

The experiments were conducted on cats under pentobarbitone sodium anesthesia (40 mg/kg). The effect of 30-min hypovolemia (Wiggerse's model, 13.3 kPa or 100 mm Hg) on the cardiac output, its main fractions and the survival of animals recovered after clinical death (5 min) were studied. Hypovolemia was induced after cardiac contractions were recovered. In experimental (19 cats) and control (23 cats) studies clinical death was caused by arterial blood loss. The animals had been previously subject to hemorrhagic hypotension (according to Wiggerse, 6.7 kPa or 50 mm Hg, for 30 minutes). Temporary exclusion of part of blood volume from the circulation was found to abolish the phase of cardiac output increase in the postresuscitation period, attenuate the reaction of blood circulation centralization, improve the course of reparative processes and increase the survival of animals recovered after clinical death.     

Visceral pain decreases tolerance to blood loss in conscious female but not male rabbits

Pain is a component of traumatic blood loss, yet little is known about how pain alters the response to blood loss in conscious animals. We evaluated the effects of colorectal distension on the cardiorespiratory response to blood loss in six male and six female conscious, chronically instrumented New Zealand White rabbits. The goal of these experiments was to test the hypotheses that 1) colorectal distension would increase tolerance to hemorrhage (i.e., increase the blood loss required to decrease mean arterial pressure 相似文献   

Hypotension caused by intravenous infusion of rifampicin and its relation to the administration schedule

It was shown in studies on animals that bolus administration of rifampicin induced hypotension whose severity depended on the rate of the antibiotic administration. When the antibiotic was administered in the 5-, 10- or 15-minute regimen in a dose of 10 mg/kg the maximum decrease in blood pressure was 44, 34 or 21% of the initial level and the maximum antibiotic concentration attained in the blood was 34.4, 27.2 or 22.6 micrograms/ml, respectively. With the infusion for 30 minutes, the maximum antibiotic concentration in the blood was 17.6 micrograms/ml and the blood pressure did not undergo any significant changes. When the rate of the antibiotic infusion was high there was pharmacokinetic heterogeneity of the blood serum and biophase which could lead to unpredictable results. After repeated administrations of rifampicin to the same animals pronounced tachyphylaxis to the antibiotic was noted, which manifested itself in decreasing of hypotension, though the serum antibiotic level was 1.5 to 2 times higher that the initial one. It was concluded that administration of rifampicin in the therapeutic dose equal to 10 mg/kg for 30 minutes was the most sparing regimen for the antibiotic bolus intravenous infusion. Gradual increase in the antibiotic dose and administration rate in patients is possible under careful control of blood pressure and pharmacokinetic studies.     

Calcium-dependent activation of human neutrophils by a synthetic ionophore

Synthetic block copolymers composed of polyoxyethylene and poly-oxypropylene have been demonstrated to possess ionophore activity selective for monovalent cations and to cause histamine release from mouse mast cells and human basophils. We now report calcium-dependent release of granule contents from human neutrophils by the most active of these agents, TI30R2. At a concentration of 100 micrograms/ml (12.5 microM), net lysozyme release ranged from 17-40% after 30 minutes incubation at 37 degrees. Lysozyme release was dose-dependent over stimulus concentrations of 5-50 micrograms/ml (0.625-6.25 microM). Release was dependent upon the presence of extracellular calcium. T130R2 did not induce the release of superoxide anions over 30 minutes of incubation. As T130R2 induces sodium influx into cells, it is likely that a depolarizing influx of sodium ions in the presence of extracellular calcium constitutes a sufficient signal for granule release but not superoxide production by human neutrophils.     

Fewer metabolites of dietary choline reach the blood of rats after treatment with lithium

Choline is an important precursor for the biosynthesis of acetylcholine, phosphatidylcholine and sphingomyelin. It is also a major source of labile methyl groups. Lithium is an important component of the treatment of bipolar affective illness, and it inhibits choline transport across membranes. We studied the effect of lithium treatment upon the appearance in blood, liver and intestine of metabolites formed from dietary choline. Rats were treated for 9 days with 2 mEq/kg lithium carbonate or water. Animals were fasted overnight, and on the 10th day were fed with a solution containing radiolabeled choline chloride. The lithium-treated groups also received 2.0 mEq/kg lithium as part of this solution. After an oral dose of 1 ml of a 1 mM choline solution, the lithium-treated animals had significantly lower levels of choline-derived radiolabel in blood than did controls at 30, 60, 120, and 180 minutes (47% (+/- 5%; SEM), 51% (+/- 7%), 59% (+/- 4%) and 74% (+/- 9%), respectively). We observed similar decreases of the accumulation in blood, at 180 minutes after the dose, of choline-derived radiolabel when choline was administered at lower or higher concentrations. After an oral treatment containing 0.1, 1 or 10 mM choline, lithium treated animals accumulated 69% (+/- 6%; SEM), 66% (+/- 11%) and 72% (+/- 7%) as much radiolabel in serum as did controls. Most of the radiolabel found in blood at 180 minutes was in metabolites of choline which are formed within liver (betaine and phosphatidylcholine). The diminished accumulation of radiolabel in serum after lithium treatment was not due to increased accumulation of label by erythrocytes, liver or gut wall. We suggest that lithium influences the release by liver of betaine and phosphatidylcholine.     

Effect of water load in human body systems upon tolerance to +Gz acceleration

A possible improvement of +Gz acceleration tolerance, obtained in human subjects through administering specific volumes of water, viz. 7, 14 and 21 ml/kg body weight, to be drunk immediately before centrifuge examination in order to increase the volume of plasma, thus increasing the circulating blood volume, was the starting-point for this work. Two hundred healthy male subjects, aged 19.9 +/- 0.9, were classified in 4 main groups and 2 supplementary groups for examination. It was found that the water intake in volumes of 14 ml/kg body weight produced a significant mean increase in the acceleration tolerance of 0.8 G, and that of 21 ml/kg body weight improved acceleration tolerance by 1.1 G on the average. The increase tolerance to acceleration was maintained throughout a period of about 30 minutes (for 14 ml/kg body weight) up to approximately 50 minutes (for 21 ml/kg body weight). The favourable effect of water load in the body systems upon +Gz acceleration tolerance was probably due to the increase of plasma volume (by 5.24% and 6.98% for 14 and 21 ml/kg body weight, respectively).     

Corticotropin-releasing factor inhibits the acute inflammatory response of rat pawskin to cold injury

The anti-inflammatory effects of human/rat corticotropin-releasing factor (CRF), a 41-residue peptide hormone, on an experimental model of cold injury were examined. Male albino rats were anesthetized with sodium pentobarbital 60 mg/kg ip and the paws immersed for 1 or 2 min in a 22% NaCl solution maintained at -20 +/- 0.5 degrees C. Swelling in response to cold was measured by changes in paw volume using the fluid displacement method, and protein leakages from blood vessels were measured using Evans blue and Monastral blue dyes. Thirty minutes after cold exposure the paw volume increased from 1.5 +/- 0.1 to 2.4 +/- 0.1 ml/paw and the Evans blue content increased from 4 +/- 1 to 178 +/- 9 micrograms/pawskin. These responses to cold were inhibited by 40 to 60% after CRF was injected 56 micrograms/kg sc 30 min before or 28 micrograms/kg iv 10 min before or 5 min after cold exposures. Microscopic studies of the skin showed that CRF reduced leakage of Monastral blue pigment from the vascular compartment into the walls of capillaries and venules. The anti-inflammatory effects of CRF were blocked by alpha-helical CRF(9-41), a CRF receptor antagonist, injected 92 micrograms/kg iv 5 min before and 15 min before cold exposure.     

Tachykinins mediate bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

We tested the hypothesis that tachykinins mediate hyperpnea-induced bronchoconstriction (HIB) in 28 guinea pigs. Stimulus-response curves to increasing minute ventilation with dry gas were generated in animals depleted of tachykinins by capsaicin pretreatment and in animals pretreated with phosphoramidon, a neutral metalloendopeptidase inhibitor. Sixteen anesthetized guinea pigs received capsaicin (50 mg/kg sc) after aminophylline (10 mg/kg ip) and terbutaline (0.1 mg/kg sc). An additional 12 animals received saline (1 ml sc) instead of capsaicin. One week later, all animals were anesthetized, given propranolol (1 mg/kg iv), and mechanically ventilated (6 ml/kg, 60 breaths/min, 50% O2 in air fully water saturated). Phosphoramidon (0.5 mg iv) was administered to five of the noncapsaicin-treated guinea pigs. Eucapnic dry gas (95% O2-5% CO2) hyperpnea "challenges" were performed by increasing the tidal volume (2-6 ml) and frequency (150 breaths/min) for 5 min. Capsaicin-pretreated animals showed marked attenuation in HIB, with a rightward shift of the stimulus-response curve compared with controls; the estimated tidal volume required to elicit a twofold increase in respiratory system resistance (ES200) was 5.0 ml for capsaicin-pretreated animals vs. 3.7 ml for controls (P less than 0.03). Phosphoramidon-treated animals were more reactive to dry gas hyperpnea compared with control (ES200 = 2.6 ml; P less than 0.0001). Methacholine dose-response curves (10(-11) to 10(-7) mol iv) obtained at the conclusion of the experiments were similar among capsaicin, phosphoramidon, and control groups. These findings implicate tachykinin release as an important mechanism of HIB in guinea pigs.     

Simulated acute hemorrhage through lower body negative pressure as an activator of the hypothalamic-pituitary-adrenal axis

While insulin induced hypoglycemia is the principle method of producing hypothalamic-pituitary-adrenal stress response, the mechanism by which this occurs may be different from that produced by other stressors. In a pilot study, we explored ways to standardize lower body negative pressure (LBNP), as a simulator of hemorrhage, to determine its utility for future studies of hypothalamic-pituitary-adrenal (HPA) axis function. Reduced atmospheric pressure of -40 mmHg applied at the level of the iliac crests during LBNP rapidly lowers blood pressure in most subjects, simulating acute hemorrhage. In 6 normal subjects, ACTH and cortisol values were measured before, during and after the application LBNP at 0800, 1600 and 2300 hours in the baseline state and at 1600 hours on the day following 1 mg of dexamethasone. Peak ACTH values of 60-250 pg/ml occurred 2 to 10 minutes after the cessation of the stimulus in subjects experiencing presyncope or having a systolic or diastolic blood pressure decrease of greater than 20 mmHg with a rise in pulse of 30 beats per minute or more. There was no significant difference between ACTH responses at different times of day. Peak cortisol values of 25-30 micrograms/dl occurred 15-20 minutes after cessation of the stimulus. In all subjects, administration of dexamethasone greatly attenuated the ACTH response and decreased but did not ablate the cortisol response. In conclusion, these data indicate that LBNP may be used to simulate hemorrhage as a stimulus of the HPA axis. HPA axis changes occur only when physiologic evidence of hypovolemic stress is present. Dexamethasone may be used to modulate the response to this stress paradigm.     

Protective effect of CR 1409 (cholecystokinin antagonist) on experimental pancreatitis in rats and mice

CR 1409, a glutaramic acid derivative with competitive cholecystokinin-antagonistic activity, was administered IP and evaluated in comparison with proglumide (the model CCK-receptor antagonist), gabexate (protease inhibitor) and PGE₂ (cytoprotective) on two different models of experimental pancreatitis. Acute pancreatitis was induced in mice by six IP injections of 50 μg/kg caerulein at hourly intervals. The drugs were administered 30 minutes before each caerulein administration. Blood samples and pancreata were collected 3 hours after the last caerulein injection. In the second experiment, pancreatitis was induced in rats by injecting 0.3 ml 6% sodium taurocholate interstitially into the pancreas. The drugs were administered twice, 30 minutes before and 3 hours after taurocholate. The animals were killed 6 hours after laparotomy and blood samples and pancreata were collected. CR 1409 exhibited on both pancreatitis models a protective effect in a dose range of 0.3–10 mg/kg. Proglumide exhibited a protective activity at higher doses (200–400 mg/kg). Gabexate and PGE₂ were effective only in pancreatitis induced by taurocholate in a dose range of 30–60 mg/kg and 60–130 μg/kg respectively. These results, showing a high protective effect of CR 1409 on different models of acute pancreatitis, suggest an important role of CCK in the pathogenesis of pancreatitis.     

An evaluation of ampicillin pharmacokinetics and toxicity in guinea pigs

Sodium ampicillin was administered subcutaneously to 350-550 g male Dunkin Hartley guinea pigs at doses of 6, 8 and 10 mg/kg tid for 5 days. Over a period of 12 days, the lowest ampicillin dose appeared to be tolerated well. However, significant body weight reduction and mortality occurred with the two higher dosage regimens. Cecal cultures of dead animals confirmed the presence of Clostridium difficile, an organism associated with antibiotic-induced enterotoxemia. Assay of serum collected from ampicillin-treated animals revealed ampicillin concentrations of approximately 10 micrograms/ml at 5 minutes post-dosing which fell precipitously to less than 0.2 micrograms/ml at 60 minutes. Determination of biliary ampicillin levels during the 60 minutes after administration of a single 10 mg/kg SQ dose revealed concentrations ranging from 18 micrograms/ml to 90 micrograms/ml. Estimates of total urinary ampicillin content after a single 10 mg/kg SQ dose were less than 500 micrograms/animal at 7.5 minutes, but increased to greater than 2000 micrograms/animal at 60 minutes after dosing. Results of this study indicated that due to its short serum half-life, sodium ampicillin probably has little systemic therapeutic efficacy in guinea pigs. Because high concentrations of ampicillin accumulated in the urine and bile, the antibiotic probably would have therapeutic efficacy for urinary and intestinal infections. However, its associated toxicity at large doses probably precludes its use. In view of the rapid clearance of ampicillin in guinea pigs in comparison to other species, the pharmacokinetics of other antibiotics, especially those reported to be less toxic for guinea pigs, should be considered.