Laparoscopic distal pancreatectomy with splenic preservation.

BACKGROUND: The technique of distal pancreatectomy has been well described, both with en bloc resection of the spleen and with splenic preservation. Splenic preservation during pancreatic tail resection is desirable when oncologically appropriate, yet it is technically challenging, particularly with laparoscopic approaches. Skeletonization of the splenic artery and vein is associated with longer operative times and greater potential for bleeding. The authors report their experience with splenic preservation during laparoscopic pancreatic resection using ligation of the splenic vessels and preservation of the short gastric vessels. METHODS: A retrospective chart review was performed for all patients who underwent attempted laparoscopic pancreatic resection at Duke University Medical Center from July 2002 to October 2005. Charts were analyzed for demographic information, length of hospital stay, conversion, splenic preservation, and postoperative complications. RESULTS: A total of 12 laparoscopic distal pancreatic resections were attempted for three men and nine women with a mean age was 55.8 years (range, 33-74 years). All 12 patients underwent distal pancreatectomy, 8 with splenic preservation. The spleen was removed from three patients using splenic hilar lesions that prevented splenic salvage. One patient required splenectomy secondary to more than 50% ischemia of the spleen. No patients with preoperatively diagnosed malignancy underwent splenic salvage. The final pathologic diagnosis included neuroendocrine tumors (n = 2), cystic serous (n = 4) and mucinous (n = 2) neoplasms, intraductal papillary mucinous neoplasm (IPMN) (n = 1), pancreatitis (n = 2), and adenocarcinoma (n = 1). Two patients underwent conversion to open surgery for thickened parenchyma secondary to chronic pancreatitis (17%). There were no other conversions. There were three chemical leaks (25%) diagnosed by elevated drain amylase and low volume output, which were managed with intraoperatively placed drains removed at the initial postoperative clinic visit. There were three higher volume leaks (25%) that required extended or percutaneous drainage, with eventual removal. The average blood loss was 215 ml (range, 50-700 ml). The average operative time was 3 h and 41 min (range, 2 h 15 min to 5 h 58 min). The average length of hospital stay was 4 days (range, 2-7 days). CONCLUSION: Splenic preservation should be performed when technically possible to decrease the morbidity of laparoscopic distal pancreatectomy. The choice to ligate the splenic vessels allows for shorter operative times with minimal perioperative morbidity and blood loss while maintaining the spleen.

Studies on cadmium-induced inhibition of hepatic microsomal drug biotransformation in the rat.

Cadmium is a potent inhibitor of hepatic microsomal drug biotransformation in the rat. Male rats receiving a single intraperitoneal dose of cadmium exhibit significant decreases in hepatic microsomal metabolism of a variety of substrates. The threshold cadmium dose is 0.84 mg Cd/kg, and the effect lasts at least 28 days. Mechanistically, the inhibitory effect results from decreased cytochrome P-450 content since cadmium does not alter NADPH cytochrome c reductase activity. This effect is also observed following acute oral administration of cadmium in doses greater than 80 mg Cd/kg but is not observed following chronic administration of the metal via drinking water in concentrations of 5-200 ppm for periods ranging from 2 to 50 weeks. A tolerance to the inhibitory cadmium effect is observed if male rats are pretreated with subthreshold doses of the metal prior to the challenge cadmium dose. The degree of tolerance can be overcome by increasing the challenge dose of cadmium. Characterization of the tolerance phenomenon in terms of onset, duration, and intensity reveals a good correlation with the kinetics of metallothionein production, suggesting that the underlying basis for the tolerance phenomenon is likely the induction of metallothionein. A sex-related difference in the inhibitory effect of cadmium was observed. Cadmium did not inhibit the metabolism of hexobarbital or ethylmorphine in female rats but did inhibit that of aniline or zoxazolamine. Cadmium did not lower cytochrome P-450 content in female rats.

Acute and subchronic toxicology of LY-195115 in rats and dogs.

LY-195115 is a new (investigational) inotropic agent. When given orally to either young adult rats or mice, single doses of 2500 or 5000 mg/kg were tolerated with minimal lethality. Clinical signs included muscle weakness, hypoactivity, and evidence of hemorrhage. Dogs and monkeys survived a single oral dose of 10 and 5 mg/kg, respectively; however, there was sinus tachycardia for 6-8 h post dose in both species. Rats (20/sex/group) were fed diets containing LY-195115 in concentrations of 0, 0.005, 0.025, or 0.1% for 3 months. The average daily intake of the compound was approximately 0, 3.5, 17, or 70 mg/kg in both sexes. Deaths occurred only in the high-dose group. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced in males in the 0.1% dose group and animals of both sexes in this group had changes in hematology, clinical chemistry, and urinalysis parameters indicative of renal damage. Crystals containing LY-195115 were present in the urine of animals from the 0.025% and 0.1% treatment groups. Secondary hydronephrosis due to kidney stone formation was observed on gross and microscopic pathologic evaluation in the males of the 0.025% group and animals of both sexes in the 0.1% group. In addition, periarteritis was present in the adventitia and muscularis of small and medium-sized arteries in the pancreas, lymph node, kidney, and stomach of some animals in all LY-195115 treatment groups. No overt signs of toxicity were produced in beagle dogs (4/sex/group) given daily oral doses of 0.03, 0.12, or 0.5 mg/kg of LY-195115 for 3 months. The only adverse effect was the occurrence of focal subendocardial fibroplasia in the heart in 2 high-dose male dogs. Thus, subchronic exposure of rats to doses of LY-195115 as high as 70 mg/kg produced minimal mortality, renal toxicity, and mild, limited vascular changes, while dogs tolerated doses up to 0.5 mg/kg with no evidence of any effect of treatment except minimal histological changes in the heart consequent to the expected cardiotonic action of the compound.

Laparoscopic hernia repair following iliac crest harvest.

The repair of hernias through iliac crest defects is challenging secondary to the inherent weakness of the abdominal musculature and the rigidity of the pelvis. The defect is surrounded by inadequate tissue to properly buttress the repair. Full-thickness tricortical bone harvested from the iliac may result in an incisional hernia through the bony defect. Options for repair include using the aponeurosis of the gluteus muscle, prosthetic material, or straightening the iliac crest. We report two patients who had their defects repaired laparoscopically using polytetrafluoroethylene (PTFE) mesh. Two patients with hernias following full-thickness iliac crest bone harvest presented secondary to increasing pain and size of their hernias. Both defects were repaired laparoscopically using spiral tacks laterally, medially, and superiorly, and with an intracorporeal stitch inferiorly at the iliac crest to secure the mesh. The two defects averaged 24.5 cm(2) in size and were repaired with PTFE mesh. For adequate visualization, the cecum was mobilized and the mesh repair overlapped the defects by a 4-cm margin. Both patients were discharged after 2.5 days. There were no infectious or neurologic complications, and neither patient has recurred. The laparoscopic approach to the repair of hernias resulting from tricortical iliac crest bone harvest is safe and may be preferable to open repair. Advantages include durable repair, better interoperative visualization, and reduced post-operative pain, morbidity, and hospital stay.

Interaction between cadmium and phenobarbital on the activity of the hepatic microsomal monooxygenase system in the male rat.

Pretreatment of male rats with phenobarbital markedly stimulates, while treatment with cadmium inhibits, the activity of the hepatic microsomal monooxygenase enzyme system. When both agents were administered concomitantly, the stimulatory effect of phenobarbital and the inhibitory effect of cadmium cancelled each other.

The effects of disopyramide phosphate on serum glucose and glucose counterregulation in the dog.

The effect of oral administration of the antiarrhythmic disopyramide phosphate (DPP) on serum glucose and glucose counterregulation was determined in beagle dogs. In addition, the hypoglycemic effect of DPP, a racemate, and its optical isomers was determined. DPP produced dose-dependent significant decreases in serum glucose concentrations. Maximum decreases in serum glucose concentrations were approximately 10% at 10 mg/kg, 15% at 30 mg/kg, and 30% at 100 mg/kg when DPP was given as single doses, and 30% at 100 mg/kg when DPP was given as three divided doses. In each case, serum glucose concentrations returned to control values within 24 to 30 hr. To evaluate the effect of DPP on glucose counterregulation the recovery from acute insulin-induced hypoglycemia was determined. No differences of any practical significance were observed between the insulin tolerance curves of control and 50-, and 100-mg/kg DPP groups. Thus, the overall glucose counterregulatory response following insulin challenge was unaffected by DPP. The hypoglycemic effects of DPP, (S)-(+)-DPP, and (R)-(-)-DPP were compared by examining the ratio of the areas under the curve of serum glucose concentration to serum drug concentration. The absolute ratio for the (S)-(+) isomer was significantly greater than that of the (R)-(-) isomer, indicating that the hypoglycemic effect of DPP is largely due to its (S)-(+) isomer.

Comparative cardiovascular toxicity in dogs given inotropic agents by continuous intravenous infusion.

A comparative study of the toxicity of the inotropic amines isoproterenol hydrochloride (IP), 1-norepinephrine bitartrate (NE), dopamine hydrochloride (DP), and dobutamine hydrochloride (DB) was conducted in beagle dogs (2/sex/dose group). All drugs were administered at doses that produced maximal contractile tension in dog myocardium. Doses, continuously infused for 96 hr, were 0.625, 1.25, and 2.5 micrograms/kg/min IP, 2.5 and 5 micrograms/kg/min NE, and 25, 50, and 100 micrograms/kg/min DP and DB. Three of 4 dogs that received 5 micrograms/kg/min NE and one of 4 given 100 micrograms/kg/min DP died. Pronounced tachycardia (mean peak rate increases from baseline of 88-104 beats/min) was observed at all doses of IP. DB produced a transient moderate tachycardia (mean peak rate increases from baseline of 25-27 beats/min) at 25 and 50 micrograms/kg/min and pronounced tachycardia (mean peak rate increases from baseline of 74 beats/min) at 100 micrograms/kg/min. Moderate bradycardia occurred at both doses of NE and at 25 and 50 micrograms/kg/min DP (mean peak rate decreases from baseline of 42-46 and 22-38 beats/min, respectively). At high doses the 4 inotropes produced focal to multifocal myocardial necrosis located mainly in left ventricle and segmental medial necrosis of the coronary arteries, mainly in small intramural muscular branches. Segmental medial hemorrhage was also seen following administration of high doses of NE and DP. An additional intramural coronary arterial lesion produced by all of the inotropes consisted of a mild periadventitial cellular infiltrate and fibroplasia. The results indicated that NE and DP produced the most severe cardiovascular lesions, followed by IP which produced lesions of more moderate severity. DB produced only slight lesions in comparison to the other 3 inotropic amines.

Acute, subchronic, and chronic toxicity of the cardiotonic isomazole in rats.

Acute, subchronic, and chronic toxicity studies were conducted with isomazole, a new (investigational) inotropic agent with significant vasodilator properties. When given acutely to either young adult rats or mice, the oral median lethal dose was approximately 135 or 525 mg/kg, respectively. Clinical signs of toxicity were leg weakness, hypoactivity, tremors, clonic convulsions, and ataxia. Fischer 344 rats (15/sex/group) were fed diets containing isomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 months with no resulting mortality or clinical signs of toxicity. The average daily intake of the compound was approximately 0, 20, 65, or 198 mg/kg in both sexes. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced only in males in the 198 mg/kg dose group. There were no changes of toxicological significance in any of the hematology, clinical chemistry, or urine parameters. Isomazole produced significant increases in hepatic p-nitroanisole O-demethylase activity and relative liver weight primarily at the 65 and 198 mg/kg treatment levels. These effects were consistent with induction of the hepatic drug-metabolizing enzyme system. Histopathologic findings consisted of centrilobular fat deposition in the livers of 9 of 15 males in the 198 mg/kg dose group, and periarteritis in the adventitia of small and medium-sized arteries in the mesentery in 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dose groups, respectively. The plasma levels of isomazole had a tendency to drop after 90 days compared to Day 2 in all dose groups and was more apparent in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicological evaluation of the cardiotonic isomazole in the dog.

Acute, subchronic, and chronic toxicity studies were conducted in dogs with the new vasodilator/cardiotonic drug isomazole (IMZ) to support, in part, clinical investigations of this agent in humans. Single oral doses of IMZ of 25, 50, or 100 mg/kg given to English pointer dogs (2/dose) caused a marked drop in systemic blood pressure and reflex-induced increases in heart rate to values well over 200 beats per minute. These responses were maintained for 12 to 22 hr depending on the dose given. One of the dogs receiving 100 mg/kg died at 4.5 hr postdose. Results of subchronic (3 months) and chronic (1 year) studies in beagle dogs (4/sex/dose group), in which measurable plasma levels of the drug and its metabolites were found, indicated that IMZ did not produce any discernible adverse findings when given in doses up to 16 mg/kg, other than expected cardiotoxic effects. The plasma t1/2 of IMZ at 16 mg/kg increased to between 4 and 8 hr from 2 hr noted at lower doses. In the 1-year study, at all doses and in both sexes, plasma levels of IMZ declined over the first month, stabilizing (at the 2 and 6 mg/kg doses) thereafter for the duration of the study. At the high dose of 16 mg/kg, after 1 year plasma levels of IMZ exceeded (females) or equaled (males) the 1-month values. At peak plasma levels of IMZ (2 hr postdose), plasma levels of parent drug increased linearly with the dose. The cardiotoxic effects consisted of substantial postdose increases in heart rate throughout the course of treatment (5 mg/kg and above), significant increases in heart weight (6 mg/kg and above), and multifocal myocardial fibrosis (6 mg/kg and above). There was a decline in basal heart rate at doses of 12.5 mg/kg and higher. The results of these studies demonstrated that repeated IMZ administration, as expected, was cardiotoxic to the dog, a species relatively sensitive to the pharmacological activity and hemodynamic changes induced by vasodilator/cardiotonic drugs. The no-effect dose level for cardiotoxicity in the repeated dose studies was considered to be 2 mg/kg, the lowest dose tested.

Coronary artery toxicity in beagle dogs given indolidan, a type III phosphodiesterase inhibitor.

The hemodynamic changes and cardiovascular lesions produced by a single iv dose of 2.0 mg/kg indolidan were evaluated in four beagle (two male, two female) dogs. Four additional dogs (two male, two female) served as vehicle controls. This was followed by a multidose study in which the same dose of indolidan or vehicle was given iv to dogs (4/group) on 4 consecutive days. Both studies were followed for 4 days postdose before termination. Clinical signs, mean arterial blood pressure, and heart rate were evaluated. Seven sections of the heart, approximately 25 sections of the coronary arteries, and 3 sections of the carotid, subclavian, spermatic or ovarian, renal, and femoral arteries were examined. Mean blood pressure was decreased 20 to 25% over a 24-hr period and heart rates were increased 40 to 50% after treatment and remained elevated for at least a 24-hr period in both single and multidose treated groups. The earliest lesions occurred in three of four treated dogs after a single intravenous dose of 2.0 mg/kg. The main lesion was sporadic in distribution and seen in the outer one-half of the smooth muscle media of the coronary arteries. Smooth muscle degeneration and necrosis were present, with little secondary inflammation. No lesions were observed in the peripheral arteries or the myocardium. The coronary arterial lesions observed after the multidose study were more extensive and severe. The lesions were seen in large extramural and large intramural coronary arteries. These were characterized by marked smooth muscle necrosis involving most of the media, destruction of the internal elastic membrane, and marked adventitial fibroplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Testicular toxicity induced by oral administration of SC-32855, A 1,4-benzodiazepine, in the dog.

A 1,4-benzodiazepine, SC-32855, was administered orally once daily at doses of 30, 100, and 300 mg/kg for two weeks to adult Beagle dogs (1/sex/dose). The 300 mg/kg animals were sacrificed in extremis on day three after showing extreme signs of CNS depression. At necropsy, the testes of the 100 mg/kg male weighed considerably less than those of the control. The testicular weights of the 30 and 300 mg/kg animals were comparable to the weight of the control testes. Histopathologic evaluation of the testes of the 100 mg/kg male revealed degenerative and necrotic changes in the seminiferous tubules and cytoplasmic vacuolation in Leydig cells. In the 30 and 300 mg/kg animals, degenerative and necrotic changes were restricted to the seminiferous tubules.

Protection by zinc against acetaminophen induced hepatotoxicity in mice.

The purpose of this investigation was to assess protection by zinc against acetaminophen induced hepatotoxicity and to evaluate possible mechanisms of protection. Mice were treated with zinc (3 mg/kg, ip) or saline (ip) 48 and 24 hr before and sacrificed 12 hr after acetaminophen administration (375, 500, or 750 mg/kg, po). Liver toxicity was then assessed by histological examination. The incidence of hepatotoxicity was significantly less at 375 and 500 mg/kg of acetaminophen in zinc treated animals. The same dosage of zinc was not hepatoprotective when given 1 hr after acetaminophen. Mice were also treated with 1 to 10 mg/kg of zinc (ip) 48 and 24 hr prior to sacrifice, and metallothionein, cytochrome P-450, glutathione, and UDP-glucuronosyl transferase (GT) were determined in the liver. Metallothionein and UDP-GT were increased and P-450 and glutathione decreased at the higher dosages of zinc; however, only metallothionein was significantly changed at the dosage of zinc (3 mg/kg) used in the hepatoprotection experiments. Further, mice were similarly treated with 3 mg/kg of zinc before administration of 375 mg/kg of [3H]acetaminophen (po) and the amount of acetaminophen and acetaminophen bound to metallothionein were determined in the liver for 0.5 to 24 hr. In addition, after 6 hr the subcellular distribution and covalent binding to protein of acetaminophen were also determined. Zinc treatment had no significant effect in any of the above determinations. These results indicate that zinc protects against acetaminophen induced hepatotoxicity and that the observed protection is probably due to an induced biochemical change, but it is apparently not the result of any of the commonly invoked mechanisms.

Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs.

Tilmicosin(TM), a macrolide antibiotic and active ingredient in formulated Micotil 300 (Eli Lilly and Co., Indianapolis, IN, USA), is the active ingredient in a formulated animal product used for the treatment of respiratory tract infections in cattle. Owing to the concern of governmental regulatory agencies over the possibility of an accidental injection of the antibiotic to a livestock handler, the cardiovascular effects of sub lethal doses of TM were evaluated in conscious mixed-breed dogs. Left ventricular function, systemic arterial blood pressure, and heart rate (HR) responses to TM alone and in combination with propranolol(P) or dobutamine HCl(DOB) were evaluated. Dogs were instrumented with indwelling micromanometers implanted in the left ventricular chamber and in the thoracic aorta. Cardiovascular variables were recorded, and the peak value of the first derivative of left ventricular pressure (dp/dt(max)) was used as an index of left ventricular inotropic state. Six treatments were randomly assigned to each of the six dogs using a Latin square design. The six treatments were vehicle, TM alone (2.5 mg/kg of body weight), TM immediately followed by P, and TM immediately followed by 1 of 3 dosages of DOB infused for approximately 45 min. Additionally, doses of TM alone (0.25, 1.0, 2.5, and 5.0 mg/kg) were administered to complete a dose-response curve. TM caused dose dependent decreases in (dp/dt(max)) and aortic pulse pressure. HR increased dose-dependently. Left ventricular end-diastolic pressure increased at the 2.5 and 5.0 mg/kg dosages. Left ventricular systolic pressure was reduced dose-dependently at the 2.5 and 5.0 mg/kg dosages. Treatment with P exacerbated the negative inotropic effect and the decrease in left ventricular systolic pressure, but did not attenuate the tachycardia associated with TM treatment. DOB attenuated the changes in ventricular inotropic state in a dose-dependent manner. DOB infusion also restored left ventricular systolic pressure at dosages of 3 or 10 micrograms/min/kg. Our data indicate that toxic doses of TM may have a negative inotropic effect in conscious dogs. HR increased in a dose-dependent manner and was not the result of beta 1-receptor stimulation. DOB reversed some, but not all, of the effects caused by TM administration.

Effect of acute and chronic cadmium treatment on hepatic drug metabolism in male rats.

The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (greater than 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbital hypnosis and inhibition of hepatic microsomal metabolism of hexobarbital and aniline. Administration of cadmium in the drinking water at levels of 100 or 200 ppm Cd for periods of 2--12 weeks or at levels of 5 or 20 ppm Cd for 50 weeks did not produce alterations in either drug response or hepatitic drug metabolism. Significant levels of metallothionein, a cadmium binding protein, found in the liver of the rats receiving cadmium chronically may offer an explanation for the observed differences in drug metabolism between the acute and chronic administration of cadmium. In additional studies, pretreatment of the rats with subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) intraperitoneally produced a tolerance to the alterations in drug metabolism induced by the previous cadmium dose (0.84 mg Cd/kg, i.p.). However, chronic cadmium treatment (5 or 20 ppm Cd for 50 weeks) did not impart any such tolerance to subsequently administered Cd (0.84 mg/kg) by the intraperitoneal route. The hepatic levels of metallothionein induced by the chronic cadmium treatment were only 30--60% of those induced by the subthreshold cadmium and thus may not have bound enough of the large challenge cadmium dose to produce the tolerance phenomenon.