Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.

AIM: G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects. METHODS: This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes. RESULTS: JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline. CONCLUSIONS: These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

Aspiration cytology of papillary cystic neoplasm of the pancreas.

The authors present a case of papillary and cystic neoplasm of the pancreas (PCN) in which fine-needle aspiration was performed intraoperatively. Only a few reports of fine-needle aspiration of this rare tumor have been published. The features most helpful in reaching a diagnosis of PCN were a monotonous population of tumor cells, round to oval bland-appearing nuclei, scanty to moderate ill-defined cytoplasm, and the presence of numerous capillaries. Despite the lack of branching papillary clusters described in previous reports, it was possible to suggest the correct diagnosis by identifying these other characteristic features. In addition, estrogen and progesterone receptor levels were measured and found to be negligible. A review of the literature with emphasis on cytologic features also is presented.

Hydrothorax as a late complication of central venous indwelling catheters.

Two cases of delayed onset hydrothorax following central venous catheterization are reported. Both involved left internal jugular vein percutaneous insertion sites, and chest roentgenograms of both demonstrated that the catheter tips were juxtaposed against the superior vena cava wall. Although both catheters functioned well for several days, we believe that this left neck site allowed for catheter tip motion, resulting in delayed perforation of the vessel. To avoid this complication we recommend that central venous catheters be checked routinely for position, with the catheter tip being parallel to the vessel wall. The left neck approach should be avoided if possible because of anatomic and mobility problems. These cases emphasize the fact that hydrothorax can occur long after successful catheter insertion, and they demonstrate the need to have continued suspicion of the possibility of this occurrence.

Antiulcer effect of rioprostil, a prostaglandin E1 analog, in combination with antacid.

Rioprostil, a primary alcohol prostaglandin E1 analog, is currently undergoing clinical evaluation for use in the treatment of peptic ulcer disease. Since antacids are often used in conjunction with other antiulcer agents, studies were conducted to determine if concomitantly administered antacid modifies the antiulcer activity of rioprostil. This investigation showed that concomitant administration of antacid (0.25-1.0 ml Maalox) does not inhibit the ability of rioprostil (0.125-4.0 micrograms/kg, p.o.) to prevent ethanol-induced gastric lesions in rats. The antiulcer effect of the drug combination was additive, suggesting that each compound acts independently to prevent gastric bleeding. These results in animals suggest that clinically the use of antacid will not compromise the efficacy of rioprostil and that the combination may be a useful mode of therapy for the treatment of peptic ulcer disease.

Antigastrolesive, gastric antisecretory, diarrheagenic and mucus-stimulating effects in rats following topically applied rioprostil, a synthetic prostaglandin E1 analog.

Prostaglandins may have many biological actions including hypotensive and antipeptic ulcer activity. The purpose of this investigation was to determine if the primary alcohol prostaglandin E1 analog rioprostil1 prevents ethanol-induced gastric lesions (antigastrolesive activity), inhibits gastric acid secretion (antisecretory activity), or causes diarrhea in rats when administered topically, and to compare these responses to the effect of rioprostil following enteral (oral or intraduodenal) administration. Rioprostil exhibited antigastrolesive activity in rats when administered either orally or when applied topically. The topical antigastrolesive potency of rioprostil against ethanol-induced lesions [ED50 = 3.7 (0.5-12) micrograms/kg] was similar to its oral potency [ED50 = 1.9 (1.7-2.2) micrograms/kg]. In 4 hr pylorus-ligated rats, topically administered rioprostil inhibited total gastric acid output with a potency [ED50 = 5.1 (2.6-24) mg/kg] similar to intraduodenal administration [ED50 = 3.7 (2.8-5.3) mg/kg]. In addition, in these rats rioprostil increased mucin levels and did not cause dermal irritation. Finally, the incidence of diarrhea was lower when rioprostil was applied topically than when given orally with a 16-fold difference in potency between these two routes of administration. These data show that when rioprostil is applied via the skin it has antigastrolesive, gastric antisecretory and mucus stimulatory effects in rats equal to enteral administration, and a diarrheagenic potency lower than following oral administration. This profile suggests that topical administration of rioprostil may be a useful means of delivery for clinical treatment of peptic ulcer disease.

Surgical approach to occult gastrointestinal bleeding.

In 5% of patients with gastrointestinal bleeding, standard evaluation fails to reveal the source of the bleeding. We describe the management of 71 patients treated for obscure gastrointestinal bleeding at the Mount Sinai Medical Center, New York, New York, from 1985 to 1991. There were 38 men (54%) and 33 women (46%). The mean age was 60 years. The patients had bleeding episodes for a mean period of 26 months and required an average of 20 units of blood prior to surgical treatment. All had undergone an extensive diagnostic workup including barium contrast studies, endoscopies, and angiographies. Some had multiple bleeding scans, Meckel scans, and surgical explorations. Three patients were found to have "watermelon stomach" on endoscopy and had an antrectomy. Sixty-eight (96%) patients underwent a preoperative small bowel enteroscopy, which revealed the precise diagnosis in 50 (70%) of the patients. All patients underwent surgery. In 30 (42%) patients in whom the bleeding site was not apparent at exploration, intraoperative enteroscopy was performed. Two actively bleeding patients had intraoperative enteroscopy, which failed to localize the bleeding site, and intraoperative scintigraphy was utilized. The bleeding was found to originate in small bowel arteriovenous malformation (AVM) (28 patients), leiomyoma (8 patients), primary small bowel malignancies (11 patients), and other causes (24 patients). Fifty-six patients (80%) had no further bleeding; 9 with multiple small bowel AVM have experienced rebleeding and are alive. Six patients died of recurrent bleeding, and six died of metastatic cancer. An aggressive approach should be applied in patients in whom standard evaluation fails to localize the source of gastrointestinal bleeding. Enteroscopy, surgical exploration with additional intraoperative enteroscopy, and occasional intraoperative scintigraphy can achieve an excellent yield and allow resection and potential cure.

Adenocarcinoma of the urachus masquerading as a right lower quadrant mass: a case report.

We report a patient who presented initially with a right lower quadrant mass which was attached to the anterior abdominal wall. The final pathological diagnosis was adenocarcinoma of the urachus, an exceedingly rare bladder tumor.

Jejunal obstruction as a late result of neonatal jejunal atresia.

The authors report on two adults who had jejunal dilatation after having had resection for jejunal atresia in the neonatal period. Both patients presented 20 years after the initial procedure, with severe iron deficiency anemia, marked jejunal dilatation proximal to the old anastomotic site (which was not narrowed), and a bezoar within the dilated segment. Upper gastrointestinal series were used to evaluate both patients before surgical resection of the enlarged intestine, with subsequent correction of the anemia.

Liesegang rings in renal cyst fluid.

Peculiar ring-like structures identified as Liesegang rings (LRs) were found in renal cyst fluid from three patients with benign renal cysts. They ranged in size from 5 to 820 mu. Most had a double-layer outer wall with equally spaced radial cross-striations and an amorphous central nidus. Special stains were performed in one case, and the results are discussed. Reports of LRs in cystic or inflamed tissues have recently appeared in the literature. Some LRs have been mistaken for eggs or mature components of the giant kidney worm, Dioctophyma renale. We propose that cytologic assessment of renal cyst fluid in conjunction with histologic examination decreases the likelihood of misdiagnosis of LRs.

Gastric antisecretory and antigastrolesive pharmacology of rioprostil.

Rioprostil, a primary alcohol prostaglandin E1 analogue, inhibits gastric acid secretion, both in vivo and in vitro, and prevents the formation of experimentally-induced gastric lesions in rats and dogs. In vitro experimental evidence suggests that the mechanism of the gastric antisecretory activity of rioprostil involves inhibition of the membrane bound histamine-stimulated adenylate cyclase. In vivo, rioprostil inhibits gastric acid secretion in 4-h pylorus-ligated rats, in gastric fistula dogs stimulated by betazole, tetragastrin, bethanechol, or 2-deoxy-D-glucose, and in Heidenhain pouch dogs stimulated by food. Rioprostil can completely prevent macroscopically visible gastric lesions induced by a variety of noxious agents in rats, including 50% ethanol, aspirin, indomethacin, strong acid, strong base and hypertonic saline. In dogs, rioprostil, but not the H2-blockers cimetidine or ranitidine, totally prevents endoscopically visible gastric lesions induced by aspirin tablets or 60% ethanol, and accelerates the healing of established aspirin-induced gastric lesions from 20 days (vehicle control) to 6 days (33 micrograms/kg p.o., t.i.d.) or 11 days (3 micrograms/kg p.o., t.i.d.). The precise mechanism for the antigastrolesive activity of rioprostil is not known, but may involve increased mucus and bicarbonate secretion, maintaining or increasing gastric mucosal blood flow, increasing the rate of cellular restitution, or possibly antigastrin activity that has been demonstrated in dogs. In rats, rioprostil also prevents duodenal lesions induced by cysteamine, small intestinal lesions induced by indomethacin, and colonic lesions induced by ethanol. The antisecretory and antigastrolesive potency of rioprostil given transdermally to rats is similar to its potency when given systemically, although its diarrhoeagenic potential is lower when given topically compared to oral administration. When used in combination with several non-steroidal anti-inflammatory drugs (NSAIDs) in a model of arthritis in rats, rioprostil inhibits gastric lesion formation without interfering with the anti-inflammatory or analgesic potency of the NSAIDs. In addition, concomitant use of either antacid or cimetidine with rioprostil does not inhibit either the antisecretory or antigastrolesive potency of rioprostil, with the effect of the combination being additive. The doses required to inhibit formation of experimentally-induced gastric lesions in both rat and dog are lower than those required to inhibit gastric acid secretion. This separation of antigastrolesive from antisecretory activity distinguishes rioprostil from other non-prostanoid antisecretory agents, such as histamine H2- receptor antagonists, and establishes rioprostil as a 'selective antigastrolesive agent' (SAGA).(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

The role of surgery in occult gastrointestinal bleeding.

The surgeon is frequently involved in the management of patients with occult gastrointestinal bleeding. It is important to have a systematic approach to these patients to avoid the "looking for a needle in a haystack" approach to this problem. These are a group of patients who have undergone extensive standard gastroendoscopic evaluation and continue to bleed. Five percent of gastrointestinal bleeding occurs between the ligament of Treitz and the ileocecal valve. Therapeutic management may be guided by the age of the patient. Patients aged younger than 50 years will usually bleed from readily identifiable palpable lesions, such as leiomyoma, Meckel's diverticulum, or other small-bowel tumors, whereas the patients aged older than 50 years most commonly bleed from angiodysplasias or arteriovenous malformations that are not palpable, frequently multiple, and may be evanescent.

Rioprostil heals pre-existing aspirin-induced gastric lesions in dogs during daily aspirin administration without altering the anti-inflammatory or analgesic efficacy of aspirin.

Rioprostil (3-100 micrograms/kg/day p.o.), but not cimetidine (30 mg/kg/day p.o.), healed pre-existing aspirin (1950 mg)-induced gastric lesions in dogs despite daily aspirin (975 mg) administration. Gastric antisecretory doses of rioprostil (10 and 100 micrograms/kg/day) decreased lesion scores by 71 to 77 and 90 to 93% after 7 and 11 days, respectively. A nonantisecretory dose of rioprostil (3 micrograms/kg/day) decreased lesion scores by 80% after 14 days. In contrast, lesion scores in dogs receiving either vehicle or a maximal gastric antisecretory dose of cimetidine (30 mg/kg/day) remained unchanged during the 28-day course of treatment. In addition, rioprostil prevented the weight loss which accompanied daily administration of aspirin (975 mg) in vehicle- or cimetidine-treated dogs. When cimetidine-treated dogs were switched to daily rioprostil (100 micrograms/kg/day) and aspirin (975 mg/day) therapy, lesions healed within 6 days. In separate studies, rioprostil had no effect on the sensitivity of the gastric mucosa to subsequent aspirin administration. In addition, discontinuation of maintenance therapy during rioprostil treatment was of no increased benefit (i.e., lesions did not heal faster). Finally, in a model of urate-induced knee-joint synovitis, rioprostil treatment did not inhibit the anti-inflammatory or analgesic efficacy of aspirin, or have any proinflammatory effect of its own.

Slow release delivery of rioprostil by an osmotic pump inhibits the formation of acute aspirin-induced gastric lesions in dogs and accelerates the healing of chronic lesions without incidence of side effects.

Rioprostil, a primary alcohol prostaglandin E1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirin-induced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspiring. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED50 = 0.77 micrograms/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 micrograms/kg/24 hr) healed preexisting aspirin-induced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 micrograms/kg/24 hr (935-2805 times the gastroprotective ED50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 micrograms/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety.