Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study.

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.

Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity.

Bisphosphonates have become an important addition to the pharmacological armamentarium against postmenopausal osteoporosis. One of the major side effects of oral therapy with some nitrogen-containing bisphosphonates appears to be gastrointestinal (GI) intolerability, particularly esophageal irritation and ulceration. Because nitrogen-containing bisphosphonates can cause apoptosis in a variety of cell types in vitro, by inhibiting the mevalonate pathway, we hypothesized that the effect of these agents on the GI tract may be due to apoptosis or inhibition of growth of gut epithelial cells. A comparison between clodronate, etidronate, pamidronate, alendronate, and risedronate demonstrated that only the nitrogen-containing bisphosphonates were effective at inducing apoptosis or inhibiting proliferation of Caco-2 human epithelial cells in vitro, at concentrations of between 10 and 1000 micromol/L. The ability of nitrogen-containing bisphosphonates to cause apoptosis and inhibit Caco-2 cell proliferation was due to inhibition of the mevalonate pathway, because the addition of farnesol, oxidized low-density lipoprotein (LDL) cholesterol, or especially geranylgeraniol suppressed the effects. Furthermore, pamidronate, alendronate, and risedronate inhibited protein prenylation in Caco-2 cells, as determined by analysis of the processing of Rap1A, a prenylated small GTPase. These studies suggest that the effects of nitrogen-containing bisphosphonates observed in the GI tract may be due to inhibition of proliferation or apoptosis of gut epithelial cells, following loss of prenylated proteins and sterols.

Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women.

BACKGROUND: Bisphosphonates are effective treatments for osteoporosis. Since some primary amino bisphosphonates are associated with oesophageal injury, we conducted a study of the upper gastrointestinal effects of risedronate, a pyridinyl bisphosphonate. METHODS: Healthy, postmenopausal women received risedronate 5 mg (n=26), aspirin 2600 mg (n=27), or placebo (n=27) daily for 14 days and underwent endoscopy at baseline, Day 8 and Day 15. RESULTS: Oesophageal erosions were noted in one subject in the aspirin group, two in the placebo group, and none in the risedronate group, and an ulcer in one aspirin-treated subject. Gastric erosions and ulcers were observed most frequently in the aspirin group. Gastric ulcers were noted in eight subjects in the aspirin group, one in the placebo group, and none in the risedronate group (P=0.010, placebo vs. aspirin; P=0.002, risedronate vs. aspirin). Duodenal erosions and ulcers were observed in the aspirin group only. Gastroduodenal erosion scores of three or more occurred more frequently in the aspirin than in the risedronate and placebo groups (P < 0.001). CONCLUSIONS: Risedronate 5 mg was not associated with oesophageal or gastroduodenal ulcers in healthy, postmenopausal women, a population representative of patients who will receive risedronate in the clinical setting.

Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women.

BACKGROUND & AIMS: Bisphosphonates are effective treatment for osteoporosis, but upper gastrointestinal injury associated with some compounds has caused concern. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, and alendronate, a primary amino bisphosphonate. Esophageal and gastroduodenal injury assessed by endoscopy scores was a secondary endpoint. METHODS: Healthy, postmenopausal women (n = 515) received 5 mg risedronate (n = 255) or 10 mg alendronate (n = 260) for 2 weeks. At baseline and on days 8 and 15, subjects underwent endoscopy and evaluator-blinded assessment of the esophageal, gastric, and duodenal mucosa. RESULTS: Gastric ulcers were observed during the treatment period in 9 of 221 (4.1%) evaluable subjects in the risedronate group compared with 30 of 227 (13.2%) in the alendronate group (P < 0.001). Mean gastric endoscopy scores for the risedronate group were lower than those for the alendronate group at days 8 and 15 (P

X-irradiation chronosensitivity and circadian rhythmic proliferation in healthy and sarcoma-carrying rats' bone marrow.

Mitotic activity of bone marrow and tumor of sarcoma-bearing rats and of bone marrow of healthy controls is circadian periodic. Whereas the circadian rhythm in mitotic activity of bone marrow is similar for intact and tumor-bearing rats, with a peak occurring shortly after the onset of the dark (activity) span, the circadian rhythm in mitotic activity of tumor has a much smaller amplitude and a different acrophase occurring late in the dark span. This difference in acrophase of mitotic activity of bone marrow and tumor has important implications for scheduling the administration of oncotherapy. For the tumor model examined herein, it suggests the possibility to achieve concomitantly near maximal efficacy and near minimal myelotoxicity, a result awaiting further investigation in humans with different kinds of malignancies.

[Individual variability in the number of stem cells in mammalian tissues]. / Individual'naia variabel'nost' chisla stvolovykh kletok nekotorykh tkanei mlekopitaiushchikh.

The distribution of animal groups (3--4 control or gamma-irradiated mice per group) were obtained when analysing published data on the mean number of the CFUs in the femoral bone marrow or stem cells of small intestinal crypt. Almost 50% of such groups have the mean number less than the geometric mean. The mean value for the group of animals deviation from the expected geometric mean for all animal population for more than 2.5 times, both for the larger values and for the smaller, was about 5% in such groups for the marrow CFUs and 20% for intestinal stem cells. The percentage of mice, that died from acute radiation sickness after acute irradiation, was related with the parameter D(0), that characterized the CFUs survivability on the exponential part of the survivability curve. The negative correlation (r = -0.83) was determined between the mean value of the small intestine crypt stem cells and the ability of intestinal stem cells to the radiation damage reparation, evaluated through the parameter D(q) of the stem enterocyte survival curve for this animal groups.

[Monotonous and wave-form changes in the myelogram of rats over a 24-hour period]. / Monotonnye i volnoobraznye izmeneniia mielogrammy krys v techenie sutok.

Circadian changes of the mean value of each component of rat myelogram and of the proliferative pool of bone marrow cells were obtained. These changes were imposed on a monotonous decrease in the case of subpopulations of granulocytes or on a monotonous increase in the case of subpopulations of the erythroid cells and lymphocytes (from 12.00 to 09.00 next day). This process was not influenced by the elimination of the lymphocytes from the individual myelograms. These myelogram changes appeared to be due to the circadian mature cell production rhythm and flows of the lymphocytes and of mature granulocytes between the bone marrow and the peripheral blood. These changes also suggest the antiphase monotonous correction of the erythrocytic and granulocytic precursors production during several days.

The peptide VIP is a neurotransmitter in rat adrenal medulla: physiological role in controlling catecholamine secretion.

1. The perfused adrenal gland of the rat was used to establish the identity of a non-cholinergic substance involved in splanchnic nerve-mediated secretion of catecholamines. 2. The perfused adrenal medulla was rich in vasoactive intestinal polypeptide (VIP) content (28 pmol g-1 of wet tissue). VIP-immunoreactive nerve fibres were present in the adrenal medulla and the adrenal cortex. 3. Field stimulation (10 Hz for 15 min plus 1 Hz for 15 min) caused a large increase in the output of VIP in the perfusate over the spontaneous release of VIP. Secretion of catecholamines was also greatly elevated by field stimulation. Field stimulation-evoked output of VIP and catecholamines was abolished after chronic denervation of the adrenal glands. 4. Infusion of acetylcholine (ACh) did not increase the output of VIP but caused a robust secretion of catecholamines. 5. The VIP output declined when the stimulation frequency was increased (8.6 x 10(-3) fmol pulse-1 at 1 Hz and 4.0 x 10(-3) fmol pulse-1 at 10 Hz). 6. In contrast, the output of 3H-acetylcholine (3H-ACh, expressed as a fraction of tissue 3H-ACh content) increased from 7.0 x 10(-2) pulse-1 at 1 Hz to 16.3 x 10(-2) pulse-1 at 10 Hz. 7. Secretion of catecholamines evoked by low-frequency stimulation (1 Hz) was reduced by 40% in the presence of cholinergic receptor antagonists (atropine plus hexamethonium). Inclusion of a VIP receptor antagonist ([Ac-Tyr1, D-Phe2]-GRF 1-29 amide) caused about 75% inhibition. 8. The VIP receptor antagonist inhibited VIP-evoked secretion of catecholamines without affecting ACh-evoked secretion. 9. In conclusion, VIP satisfies all the essential criteria to assume the role of a neurotransmitter in the rat adrenal medulla. The contribution of VIP to the secretion of adrenal medullary hormones is more prominent at low rates of neuronal activity whereas ACh is the major contributor at higher activity.

Differential neuropeptide expression after visceral and somatic nerve injury in the cat and rat.

The expression of neuropeptides galanin, vasoactive intestinal polypeptide (VIP) and substance P was compared after injury to somatic (sciatic, pudendal) and visceral (pelvic) nerves. Studies in normal rats and the mutant rat 'mutilated foot' suggested that galanin increases in sensory but not sympathetic fibres after sciatic nerve injury, while VIP appears to increase in both sensory and sympathetic fibres, and substance P to decrease in sensory fibres. A direct comparison of neuropeptide changes after somatic and visceral nerve injury was made in the cat dorsal sacral spinal cord, where both pudenal (somatic) and pelvic (visceral) afferents terminate. Four weeks after pudendal nerve transection in the cat there was an increase of VIP and galanin but decrease of substance P in the dorsal sacral cord, similar to the changes in lumbar dorsal cord after sciatic nerve section in the rat. In contrast, 4 weeks after pelvic nerve transection in the cat, galanin was unchanged in the ipsilateral dorsal sacral spinal cord, whereas VIP is known to decrease markedly and substance P to remain unchanged. There is thus differential peptide expression before and after injury in somatic and visceral systems, which may be regulated in part by the target organ. We have proposed that the neuropeptide changes occur in neurons that regulate development, maintenance and repair after injury, processes that may differ in somatic and visceral systems.

Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis.

The neuropeptides vasoactive intestinal polypeptide (VIP), substance P and somatostatin were studied in skin biopsies from patients with eczema, psoriasis and axillary hyperhidrosis. VIP concentrations were elevated in skin affected by eczema and psoriasis, whereas substance P and somatostatin levels did not differ from controls. There was a higher concentration of VIP, but not of substance P or somatostatin, in normal axillary skin when compared to adjacent trunk skin, with abundant VIP-containing fibres surrounding eccrine sweat glands. The VIP concentration was unchanged in skin affected by axillary hyperhidrosis. VIP may increase local blood flow in eczema and psoriasis, but does not appear to play a role in axillary hyperhidrosis.

Effect of endothelin-1 and vasoactive intestinal contractor on blood flow and output of vasoactive intestinal polypeptide in the feline colon.

Injection of the structurally related peptides, endothelin-1 and vasoactive intestinal contractor (VIC), into a branch of the superior mesenteric artery in anesthetized cats caused dose-dependent reductions in blood flow in the portal vein and inferior mesenteric artery. The maximum effect occurred after 1 minute and was more prolonged in the portal vein. The effects of the two peptides were not significantly different. The colonic output of vasoactive intestinal polypeptide (VIP) into portal venous blood was decreased significantly by endothelin-1 and VIC, returning to baseline more rapidly than blood flow. When norepinephrine was injected to produce comparable reductions in blood flow, the output of VIP into portal venous blood was not altered significantly. These results suggest that inhibition of output of the vasodilator VIP contributes to the vasoconstrictor effects of endothelin-1 and VIC in the feline colonic vascular bed.

[The mechanism of the formation of a circadian rhythm of bone marrow proliferation in rats]. / O mekhanizme formirovaniia sutochnogo ritma proliferatsii kostnogo mozga u krys.

Flow cytofluorimetry and statmokinetic method were used to study the circadian rhythm of bone marrow proliferation in Pliss' lymphosarcoma-bearing and intact rats. These data were compared to those obtained in the study of the mitotic activity of the bone marrow in cancer patients. It was found that, already at early stage, tumor affected the circadian rhythm of bone marrow proliferation, reducing the amplitude of oscillations. A model simulating formation of the circadian rhythm of the bone marrow was suggested basing on the possibility to arrest cells at the end of G1 phase. The rate of transition of G1 cells to S phase was determined not only by endogenous "set-points" of the rhythm which formed the basic wave of proliferation but also by conditions of animal upkeep.

Studies of vasoactive intestinal polypeptide expression in injured peripheral neurons using capsaicin, sympathectomy and mf mutant rats.

The increased expression of vasoactive intestinal polypeptide (VIP) in injured peripheral neurons was studied. In contrast to substance P, there was a marked increase, and maintained fast axonal transport, of VIP in rat sciatic nerve after peripheral axotomy. Local capsaicin application to the nerve trunk failed to inhibit the injury-induced VIP increase, and capsaicin even increased VIP levels when applied locally to uninjured nerves. Pharmacological sympathectomy showed that some of the peripheral VIP increase may occur in post-ganglionic sympathetic fibres. The VIP increase after injury appeared unaffected in the mf mutant rat, in spite of its loss of lumbar dorsal root ganglion cells. VIP-staining fibres in the epi- and peri-neurium and perivascular plexuses of sciatic nerve showed an increase in number in parallel with the changes of the nerve VIP content. These findings suggest that sensory and sympathetic nerve fibres expressing VIP after injury play a role in the regulation of blood flow to nerves, and in the pathophysiological processes in nerve and dorsal spinal cord which follow peripheral nerve injury.

VIP antagonist [N-Ac-Tyr1,D-Phe2]-GRF-(1-29)-NH2: an inhibitor of vasodilation in the feline colon.

The effect of the vasoactive intestinal polypeptide (VIP) antagonist [N-Ac-Tyr1,D-Phe2]-GRF-(1-29)-NH2 on pelvic nerve-induced colonic vasodilation and VIP release was investigated in chloralose-anesthetized cats. VIP antagonist (10 and 50 nmol/kg in saline) or saline alone was injected into a branch of the superior mesenteric artery immediately before bilateral pelvic nerve stimulation. The increase in conductance in the inferior mesenteric artery during pelvic nerve stimulation was reduced in an apparently dose-dependent fashion by the VIP antagonist (by 35 +/- 10 and 42 +/- 9%, respectively) compared with the pelvic nerve-induced increase in conductance after injection of saline alone. Injection of the VIP antagonist (50 nmol/kg) did not alter conductance in the absence of pelvic nerve stimulation. VIP was released into portal venous blood during pelvic nerve stimulation in the presence of the antagonist (from 103 +/- 29 to 165 +/- 45 pmol/l). This was not significantly different from release in the presence of saline. The effect of the VIP antagonist (10 nmol.kg-1.min-1) on inferior mesenteric arterial vasodilation induced by exogenous VIP was also quantitated. The increase in conductance after VIP injection (0.2 nmol/kg) was significantly reduced when accompanied by simultaneous infusion of the VIP antagonist (by 54 +/- 6%) compared with the increase in conductance during simultaneous infusion of saline. We conclude that [N-Ac-Tyr1,D-Phe2]-GRF-(1-29)-NH2 is an inhibitor of pelvic nerve-induced vasodilation in the feline colon and does not act by modulating VIP release.(ABSTRACT TRUNCATED AT 250 WORDS)