Rupture of Cystic Artery Pseudoaneurysm: a Rare Complication of Acute Cholecystitis.

Pseudoaneurysm (PA) of the cystic artery is rare. Most of the reported cases are iatrogenic and develop secondary to liver biopsy, laparoscopic cholecystectomy, ERCP, and liver transplant. Other reported causes include trauma, malignancy, arteriovenous malformations, and inflammation in the hepatobiliary and pancreatic system. Cystic artery psuedoaneurysm is usually asymptomatic but may also present as vague abdominal pain, intra-abdominal mass, and hemobilia. In the event of rupture, it may present as a catastrophic intra-peritoneal bleeding with hemorrhagic shock. Doppler ultrasound and contrast-enhanced CT scan are useful tools for the diagnosis of this condition. However, selective visceral angiography is confirmatory and offers the opportunity for therapeutic embolization. We report a case which presented with upper right quadrant abdominal pain, vomiting, and hypotension. Abdominal ultrasonography revealed subhepatic hematoma and pericholecystic fluid collection along with acute calculus cholecystitis and sludge in the bile duct. Subsequent contrast-enhanced CT and CT angiography confirmed the presence of ruptured cystic artery psuedoaneurysm with subhepatic hematoma. The patient after resuscitation underwent selective visceral angiography and successful coil embolization of the cystic artery pseudoaneurysm. During the same admission, ERCP and biliary stenting were also performed followed by laparoscopic cholecystectomy. This case reports a rare entity which was successfully treated using a multimodality strategy.

Ilaprazole: Is this a superior proton pump inhibitor for duodenal ulcer?

BACKGROUND: Preclinical studies have found ilaprazole to be significantly effective in preventing the development of reflux oesophagitis and gastric secretion in a dose-dependent manner; the drug also has a broad dose range and safety feature. Till date only one clinical study on patients with gastro-oesophageal reflux disease has shown its potency in suppressing gastric acid secretion. OBJECTIVES: To review the published randomized controlled trials (RCTs) assessing the efficacy of ilaprazole in duodenal ulcer (DU) compared to other available proton pump inhibitors (PPI). METHODS: RCTs comparing ilaprazole with other PPIs in DU were searched in the PubMed and Cochrane Library database using the term 'ilaprazole and duodenal ulcer'. All clinical studies showing effectiveness of ilaprazole in patients with DU, either full texts or scientific abstracts and found to be potentially eligible for the systematic review, were included and evaluated. RESULTS: Four RCTs having follow-up data were included. A total of 1077 patients with DU were assessed. All the trials had included omeprazole as a comparator PPI. The majority of patients (80%) became asymptomatic after treatment in both the groups. None of the trials data predict ilaprazole to be superior to omeprazole in terms of efficacy in patients with DU. CONCLUSION: The trials conducted were limited in numbers and all the trial data indicated the efficacy of ilaprazole to be similar to that of omeprazole. None of the trials indicated superiority of ilaprazole over the existing PPIs.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force.

AIMS: To study the profile of irritable bowel syndrome (IBS), and the frequency of such symptoms among the general population, in India. METHODS: In this prospective, multi-center study, data were obtained from 2785 patients with chronic lower gastrointestinal symptoms (complainants) with no alarm feature and negative investigations for organic causes visiting physicians at 30 centers, and from 4500 community subjects (non-complainants), using separate questionnaires. RESULTS: Most complainants were middle-aged (mean age 39.4 years) and male (1891; 68%). The common symptoms were: abdominal pain or discomfort (1958; 70%), abdominal fullness (1951; 70%); subjective feeling of constipation (1404 of 2656; 53%), or diarrhea (1252 of 2656, 47%), incomplete evacuation (2134; 77%), mucus with stools (1506; 54%), straining at stools (1271; 46%), epigastric pain (1364; 49%) and milk intolerance (906; 32%). Median stool frequency was similar in patients who felt they had constipation or those who felt they had diarrhea. Information to subtype symptoms using standard criteria was available in 1301 patients; of these, 507 (39%) had constipation-predominant IBS ( 3 3 stools/day) and 744 (57%) had indeterminate symptoms. Among non-complainants, most subjects reported daily defecation frequency of one (2520 [56%]) or two (1535 [34%]). Among non-complainants, 567 (12.6%) reported abdominal pain, 503 (11%) irregular bowel, 1030 (23%) incomplete evacuation, 167 (4%) mucus and 846 (18%) straining at stools; a combination of abdominal pain or discomfort relieved by defecation, and incomplete evacuation was present in 189/4500 (4.2%) community subjects. CONCLUSIONS: Most patients with IBS in India are middle-aged men, and have a sense of incomplete evacuation and mucus with stools. Abdominal pain or discomfort is frequent but not universal. Importantly, stool frequency was similar irrespective of whether the patients felt having constipation or diarrhea. Most (90%) non-complainant subjects had 1 or 2 stools per day; symptoms complex suggestive of IBS was present in 4.2% of community subjects.

Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial.

BACKGROUND: Chronic low back pain (LBP) is a growing health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat this condition, but have not demonstrated efficacy beyond 2 weeks, and no studies have shown that NSAIDs produce durable improvements in disability. METHODS: To evaluate the efficacy and durability of effect of etoricoxib for chronic LBP, a randomized, double blind, placebo-controlled trial was conducted at 46 centres. Three hundred and twenty-five patients with chronic LBP requiring treatment with an NSAID or paracetamol were randomized 1:1:1 to etoricoxib 60 mg (n=109), 90 mg (n=106), or placebo (n=110), daily for 3 months. Pre-specified endpoints over 3 months included LBP intensity scale (visual analog scale 0-100 mm) time-weighted average change from baseline, the Roland-Morris Disability Questionnaire (RMDQ), the LBP bothersomeness scale, patient and investigator global assessments, and measures of quality of life. RESULTS: Both etoricoxib groups experienced significant reductions in LBP intensity at 4 weeks versus placebo [-15.15 mm and -13.03 mm for 60 and 90 mg, respectively, probability (p)<0.001 for each], which was maintained over 3 months. Treatment resulted in significant improvement from baseline compared to placebo in RMDQ scores (etoricoxib 60 mg, -2.82 and 90 mg, -2.38, p<0.001 for each) over 12 weeks and most other efficacy endpoints. There were no significant differences between treatments in incidence of adverse events (AEs) or discontinuations due to AEs. CONCLUSION: Etoricoxib provided significant relief of symptoms and disability associated with chronic LBP detected at 1 week, confirmed at 4 weeks, and maintained over 3 months. Reductions in chronic LBP severity corresponded to improvements in physical functioning and quality of life. All treatments were generally well tolerated.

Incidence, etiology, and impact of Fever in patients with acute pancreatitis.

BACKGROUND/AIM: Fever, as a significant event, has not been studied systematically in patients with acute pancreatitis. We studied prospectively incidence, etiology, and impact of fever on the management and outcome in patients with acute pancreatitis. METHODS: All consecutive patients with acute pancreatitis were studied for the development of fever, its etiology, and its influence on the management and outcome of acute pancreatitis. Fever was considered to be significant, if the temperature was >38 degrees C and persisted for >2 days. RESULTS: A total of 75 patients (51 males; mean age 41 years) with acute pancreatitis were included between January 1997 and June 1998. The causes of pancreatitis were gallstones in 48%, alcohol in 28%, and others in 24% of the patients. 20 patients had pancreatic necrosis, and 45 (60%) developed fever during the course of pancreatitis. The etiology of fever was infected pancreatic necrosis in 8 (18%), pancreatitis per se in 10 (22%), cholangitis in 4 (9%), nonpancreatic infections in 17 (38%), and an undetermined one in 6 (13%) patients. Of the 45 patients with fever, 17 had pancreatic necrosis as compared with only 3 of 30 patients who did not develop fever (p < 0.05). Patients with fever had a higher pancreatitis-related mortality than those without fever (p = 0.03). CONCLUSIONS: 60% of the patients with acute pancreatitis developed fever. Infected pancreatic necrosis was the cause of fever in 18% of the patients and not in the majority, i.e., 82% of the patients. The mortality rate was higher in patients who developed fever than in those who did not.

Incidence, spectrum and antibiotic sensitivity pattern of bacterial infections among patients with acute pancreatitis.

BACKGROUND AND AIM: Secondary infection of pancreatic necrotic tissue and peripancreatic fluid is a serious complication of acute pancreatitis resulting in significant morbidity and mortality. The aim of this study was to find out the spectrum of bacterial infections, and their antibiotic sensitivity pattern in patients with acute pancreatitis. METHODS: All consecutive patients with acute pancreatitis were studied prospectively. Detailed investigations were carried out to identify bacterial infections and their antibiotic sensitivities in patients with suspected infection. These investigations included cultures of various body fluids, throat swabs, indwelling cannula and catheter tips. Pancreatic tissue was obtained by using needle aspiration or at surgery for Gram's stain, culture and sensitivity. All cultures were repeated until the presence of infection was confirmed or excluded. RESULTS: A total of 169 patients with acute pancreatitis were studied during the period between January 1997 and June 2000 (mean age 41.3 years; 116 males and 53 females). Of the 169 patients, 63 had infections at various sites. A total of 80 cultures were positive, and 12 different bacterial isolates were cultured from samples taken from these 63 patients. Polymicrobial infection was seen in 32% of patients. Twenty-four patients had a confirmed pancreatic infection. Blood cultures had a growth of organisms in 19 patients, with evidence of ongoing or worsening pancreatitis, thus raising a strong suspicion of infected necrosis in them. The commonest organisms were Escherichia coli from 20 cultures and Pseudomonas aeruginosa from 18 cultures. The antibiotic sensitivity pattern showed that most bacteria were sensitive to third generation cephalosporins and quinolones; notably among them were cefotaxime, ceftazidime, and ciprofloxacin. CONCLUSION: Bacterial infections were seen in 37% of patients with acute pancreatitis. The commonest organisms were Pseudomonas aeruginosa and Escherichia coli. Most bacterial isolates were sensitive to third generation cephalosporins and quinolones.

Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.

BACKGROUND: In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. OBJECTIVE: The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. RESULTS: A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). CONCLUSION: In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.

Preference comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg tablet in migraine.

OBJECTIVE: To compare the proportion of patients who prefer rizatriptan orally disintegrating tablet (ODT) 10-mg to sumatriptan 50-mg tablet. BACKGROUND: Migraineurs express treatment preference based on a variety of attributes including the speed of pain relief and medication formulation. Rizatriptan ODT is an orally disintegrating formulation of rizatriptan, a selective 5-HT1B/1D receptor agonist. This study was conducted to determine patient preference between rizatriptan ODT 10-mg and sumatriptan 50-mg tablet for the acute treatment of migraine. METHODS: This was a multicenter, randomized, open-label, two-period crossover study conducted in the United States with 524 enrolled patients. Patients treated a single moderate or severe headache in each treatment period. Patients treated one migraine with either rizatriptan ODT 10-mg or sumatriptan 50-mg tablet, then treated a second migraine with the alternate therapy. Patients completed diary assessments at baseline, and 30, 45, 60, 90, and 120 minutes postdose and rated headache severity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). At the final study visit following treatment of their second migraine, patients expressed preference for one of the two study medications by completing an interviewer-administered Global Preference Question and then responded to a self-administered series of questions to capture their most important reason for preferring one study medication over the other. Safety measurements were recorded through standard adverse experience reporting. RESULTS: Three hundred eighty-six patients treated two migraine attacks. For those patients who expressed a preference for either rizatriptan ODT or sumatriptan (n = 374), the percentage of patients who preferred rizatriptan ODT 10-mg (57%, n = 213) was significantly greater than those who preferred sumatriptan 50-mg tablet (43%, n = 161) (P<.01). For those patients who treated two migraine attacks and had drug severity measures for both attacks (n = 384), a significantly greater percentage of patients reported pain relief after taking rizatriptan ODT than sumatriptan at the 45- and 60-minute time points (38% versus 29% and 58% versus 49%, respectively) (P<.01). In addition, a significantly greater percentage of patients taking rizatriptan ODT reported a pain-free status at the 60- and 120-minute time points (23% versus 17% [P<.05] and 60% versus 52% [P<.01], respectively). Both rizatriptan ODT and sumatriptan were well tolerated. CONCLUSIONS: A significantly greater proportion of patients preferred rizatriptan ODT 10-mg to sumatriptan 50-mg tablet for the acute treatment of migraine. Efficacy and safety data are consistent with the preference findings.

A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine and pneumococcal polysaccharide vaccine in toddlers.

Children who had been randomized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PCV) or 23-valent pneumococcal polysaccharide vaccine (PN23) at 12, 15, or 18 months of age were subsequently randomized to receive a booster injection of either PCV or PN23 12 months later. For those children who received a priming dose of PCV (N=75) compared to PN23 (N=48) at 12, 15, or 18 months of age, higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested (p<0.001). Within the group of children receiving a priming dose of PCV, those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B, yet more frequent erythema (p=0.030) and pain or soreness (p=0.024) at the injection site compared to those boosted with PCV. In conclusion, a single dose of PCV at 12-18 months of age primed for responses to booster doses of either PCV or PN23 12 months later. For those children who received a priming dose of PCV, boosting with PN23 resulted in more frequent injection site pain and erythema than boosting with PCV, yet higher antibody concentrations for most of the serotypes tested.

Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine.

Children 12-18 months old were randomized to receive one dose of a conjugate heptavalent pneumococcal vaccine, two doses of the same vaccine, or one dose of a 23-valent native polysaccharide vaccine. Before immunization, pneumococci included in the conjugate vaccine were isolated from 24% of the children, and an antibiotic-resistant pneumococcus was isolated from 22% of the children. The vaccines had no effect on carriage of non-vaccine-type pneumococci. In contrast, there was a significant reduction in carriage of vaccine-type pneumococci 3 months after one dose and 1 month after a second dose of conjugate vaccine (from 25% to 9% and 7%, respectively; P < .001). No effect was seen after vaccination with the nonconjugate vaccine. One year after immunization, carriage of antibiotic-resistant vaccine-type pneumococci in children receiving conjugate vaccine was lower than that in children receiving the nonconjugate vaccine (4% vs. 14%, P = .042). Conjugate pneumococcal vaccines may reduce spread of pneumococci in the community.

Duration of protection from clinical hepatitis A disease after vaccination with VAQTA.

Recent papers examining the expected persistence of anti-hepatitis A virus antibody following vaccination with inactivated hepatitis A vaccine have estimated that geometric mean antibody levels will remain above cut-off levels for 10-30 years. However, the methodology used in these papers did not take into account any estimates of variability between subjects. In this paper data from the persistence of antibody after the administration of another vaccine, VAQTA (hepatitis A vaccine, inactivated; MSD), were used to develop further models of antibody decay. Using individual subject estimates instead of group means allowed the estimation of time to negativity for various percentiles of the population (including the median), and the construction of confidence intervals on estimates of time to negativity. Data from studies of subjects who seroreverted to negativity, and subsequently received a booster dose, were also considered to show that subjects who lose detectable antibody are likely to remain protected from hepatitis A disease by persistent immune memory and rapid anamnestic response soon after exposure to hepatitis A virus. The estimates of duration of protection suggest that VAQTA will provide protection for many years, first through presence of antibody and further through an anamnestic response based on persistent immune memory.

Medicament release from suppository bases I: Physicochemical characteristics and bioavailability of indomethacin in rabbits.

This investigation was designed to determine the in vitro release of indomethacin from suppository bases and the in vivo bioavailability in rabbits. Suppositories containing 25 mg of indomethacin were made by the fusion method with theobroma oil, esterified fatty acids (C10-C18), and polyethylene glycol 1000. To produce an exact dosage form, a formula for the determination of the displacement value was derived, and it was found that theobroma oil greater than esterified fatty acids (C10-C18) greater than polyethylene glycol 1000. The suppository hardness was determined by using appropriate apparatus and it was found that the esterified fatty acids (C10-C18) allowed the formation of more brittle suppositories. The release rates were determined with the USP dissolution apparatus, with or without cellophane membrane, and it was found that polyethylene glycol 1000 greater than esterified fatty acids (C10-C18) greater than theobroma oil. The bioavailability of indomethacin after rectal administration was greater with polyethylene glycol base. Significant correlation was obtained during the first 45 min between the in vitro release (dialyzing tubing) and the in vivo bioavailability.

Studies on interaction of timolol, hydrochlorothiazide and amiloride in the rat.

1. The acute effects of hydrochlorothiazide, amiloride, timolol and their combinations on diuresis and arterial pressure were studied in rats. 2. Timolol did not modify the diuretic and saluretic effects of hydrochlorothiazide and/or amiloride and had no diuretic or antidiuretic effects alone. 3. At a single dose of 1.25 mg/kg, p.o., timolol alone had no antihypertensive effect in spontaneously hypertensive rats. 4. The antihypertensive effect of hydrochlorothiazide + amiloride + timolol was significantly greater than with any of the drugs alone.

Cardiotonic effects of anthopleurin-A, a polypeptide from a sea anemone.

The positive inotropic effect of anthopleurin-A (AP-A) was studied in vitro on isolated cat heart papillary muscles and in vivo in anesthetized and conscious dogs. In vitro, in low Ca2+ solution (1.27 mM), AP-A increased the force of contractions of isolated cat heart papillary muscles at concentrations from 0.2 x 10(-8) M and higher; on a molar basis, AP-A was more than 200 times as potent as digoxin and on a weight basis, 33 times as potent. In vivo in anesthetized dogs, AP-A at 0.2 microgram/kg/min i.v. increased myocardial contractile force; the geometric mean dose of AP-A required to increase the contractile force by 25% was 2.6 micrograms/kg; the corresponding dose of digoxin (infused at 2.8 micrograms/kg/min) was 107.4 micrograms/kg. The geometric mean lethal dose of AP-A for 8 dogs was 19.3 and that of digoxin 263.2 micrograms/kg i.v. The therapeutic index of AP-A was significantly higher than that of digoxin. All animals that received either AP-A or digoxin died in ventricular fibrillation. The reversal of t-wave was typical for AP-A. As measured by left ventricular pressure telemetry, AP-A, 2 micrograms/kg i.v. single dose, increased LV dp/dt max in conscious dogs for longer than 2 hr.

Diuretic and antihypertensive effects of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447).

2-Aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride or MK-447, is a chemically novel diuretic agent which produced diuretic and saluretic effects in rats, dogs and chimpanzees. At doses ranging from 0.1 to 10 mg/kg p.o. (0.32-32 mumol/kg) MK-447 was more effective then furosemide at the same or higher doses in increasing the excretion of Na+, K+ and Cl- in rats and dogs. At single oral doses, MK-447 had antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs. Other diuretics are known to lower arterial pressure in these models only by repeated administration. The antihypertensive and diuretic effects of MK-447 in spontaneously hypertensive rats were reduced by indomethacin.

Mantel-Haenszel analyses of litter-matched time-to-response data, with modifications for recovery of interlitter information.

The Mantel-Haenszel procedure for comparing sets of time-to-response data is adaptable to data that can be stratified on other variables. A particular adaptation, which we have used, is one in which animals from the same litter have been assigned to different treatment groups, e.g., some to a control group and some to a drug treatment group. The time to response used was that of tumor appearance; death from other causes was considered a loss to observation. The initial litter-adjusted analysis seemed to have only limited advantages compared to analysis that ignored litters and could be interpreted as suggesting that litter matchihg was not advantageous. Contributing to the difficulty was the fact that in the litter-matched analysis no further information was forthcoming from the remaining similarly treated animals in a litter when there were no remaining contrastingly treated littermates. Several devices for recovering interlitter information from such remnants and for combining it with intralitter information are examined and applied.

Some cardiovascular effects of ST-91 and clonidine.

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.