Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat.

BACKGROUND: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. MATERIALS AND METHODS: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 µg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 µg/kg·h), were studied. Second, ROSE-010 (100, 200 µg/kg) Technosphere® powder was studied by inhalation. RESULTS: The baseline MMC cycle length was 17.5±0.8 min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 µg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7 min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39)amide. Insufflation of ROSE-010 (100, 200 µg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4 min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5 min, respectively. CONCLUSIONS: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment.

Influence of acarbose on post-prandial insulin requirements in patients with Type 1 diabetes.

The primary objective of this double-blind, placebo-controlled, randomised cross-over study was to investigate the influence of acarbose on insulin requirement in patients with Type 1 diabetes (T1DM) following a standardised meal. In addition, the study assessed the effects of acarbose on post-prandial triglyceride, glucagon and gastrointestinal peptide levels, gastric emptying, and oxidative glucose metabolism. Following normalisation of their blood glucose, 10 patients received a standardised meal together with acarbose (100 mg) or placebo. Each patient was evaluated twice (separated by 10+/-3 days), and the cross-over study design ensured that they received both acarbose and placebo. The insulin requirement for maintenance of normoglycaemia was assessed using a closed-loop insulin infusion system (artificial pancreas, Biostator). Acarbose produced a statistically significant reduction in mean insulin requirement over a 3-hr period following the meal compared with placebo (5171.7+/-2282.6 mU vs 8074.5+/-3045.4 mU; p=0.003). The level of blood glucose control over the same period was similar in the two groups. Gastric inhibitory polypeptide levels also showed a statistically significant decrease with acarbose treatment compared with placebo for AUC (area under the curve; p=0.006) and Cmax (maximum plasma concentration; p=0.022), but not tmax (time to reach Cmax from the start of the standardised meal; p>0.05). Analysis of the other efficacy parameters revealed no statistically significant differences between acarbose treatment and placebo (p>0.05). These results indicate that acarbose decreases insulin requirement in patients with T1DM without affecting gastric emptying.

Antibiotic prophylaxis in patients with urinary retention undergoing transurethral prostatectomy.

BACKGROUND AND AIMS: The risk of severe infection and complications in connection with transurethral resection of the prostate (TURP) has clearly increased in patients with urinary retention and an indwelling catheter. The aim of this study was to determine whether the antibiotics ciprofloxacin and ceftazidime are equally efficient in preventing infective complications in these patients. MATERIAL AND METHODS: An open randomized prospective study was carried out on 72 patients with urinary retention undergoing TURP, to compare of 500 mg of ciprofloxacin (CF) orally twice daily and 1 g of ceftazidime (CT) intravenously twice daily. RESULTS: The incidence of early complications was 26% in the CF group and 17% in the CT group. All the complications were minor. On removal of the indwelling catheter, a positive urinary culture was detected in 6% of the patients in the CF group and in 3% in the CT group. One month after TURP, a positive urinary culture was detected in 14% of the patients in the CF group and in 18% of the CT group. CONCLUSIONS: It is concluded that both of the antibiotics used in this trial were equally effective in the prevention of early urinary and other infections and also late complications, in patients with urinary retention undergoing TURP.

Prospective randomized open study between ciprofloxacin and a combination of sulfadiazine and trimethoprim in antibiotic prophylaxis in connection with transurethral prostatectomy.

A randomized open prospective study with antibodies was conducted on 398 cases of TURP to compare the efficacy of either 250 mg of ciprofloxacin twice daily (CF) or 500 mg/160mg of sulfadiazine-trimethroprim twice daily (ST) in the prevention of urinary and other infection complications. The medication was started on the evening preceding the operation and continued up to the day following the removal of an indwelling catheter. The preoperative risk factors were similar in both groups. The groups did not differ in terms of the duration of the operation, the volume of irrigation fluid or the weight of the resected chips. The incidence of immediate complications was 26% in the CF group and 20% in the ST group. All the complications were minor. There were three serious late complications, one intertervertebral discitis and one coxitis in the CF group and one endocarditis in the ST group. The patient with endocarditis died. One the removal of the indwelling catheter on the third postoperative day, bacteriuria was detected in 3% of the patients in the CF group and in 9% in the ST group. The difference was statistically significant (p < 0.05). One month after TURP, bacteriuria was detected in 7% in both study groups. It is concluded that ciprofloxacin may be more effective to preventing immediate urinary tract infections after TURP than a combination of sulfadiazine and trimethoprim. There were three serious late complications. As late as one month after TURP, bacteriuria was still diagnosed in about 7% of all patients, which is post-TURP monitoring of urinary values is important.

The effect of low level acoustic stimulation on susceptibility to noise in blue- and brown-eyed young human subjects.

OBJECTIVE: The aim of this study was to investigate the influence of pigmentation on the reduction in temporary noise-induced threshold shift (TTS) due to low level acoustic stimulation (LLAS). A pigmentation-dependent LLAS effect on TTS could be interpreted as a strial melanocyte involvement in LLAS. It could not be explained by cochlear sensorineural structure changes only. DESIGN: Teenagers were classified according to eye color (n = 6 + 6) and exposed to music at 70 dBA 6 h per day for 9 days (LLAS). TTS was measured before, during, and after the LLAS period. RESULTS: It was shown that LLAS reduced TTS significantly more in blue-eyed than in brown-eyed subjects. The difference in TTS remained for at least 1 wk after the cessation of LLAS. CONCLUSIONS: It is suggested that the observed difference in LLAS effect is due to strial melanocyte differences in free radical defense. It is also possible that other cochlear antioxidant enzyme systems, responsible for inactivation of harmful oxygen radicals and simultaneously involved in melanin synthesis such as the thioredoxin reductase/thioredoxin electron transfer system are activated.

The relationship between sound transfer functions and hearing levels.

The effects of individuals differences in sound transfer function (STF) from free sound field to the tympanic membrane on hearing levels was studied in the right and left ears of 55 young male and 45 young female subjects. Furthermore, canal volumes and lengths have been recorded. STFs were measured in 1/3-octave bands using a miniature microphone and an attached probe. STF measurements were performed in the 0.5-16 kHz frequency range. Audiograms were registered with linear frequency sweep from 0.25 to 8 kHz. Transfer function spectra and magnitudes as well as ear canal dimensions were compared to hearing levels. There was a significant relationship between the dimensions of the ear canal and hearing levels. Large, compared to small, ear canal volumes resulted in a shift of STFs towards lower frequencies. STF spectra and magnitudes had a significant effect on hearing levels. Subject with low-frequency-dominated STFs have higher hearing thresholds than subjects with lower magnitude STFs.

The relationship between sound transfer functions from free sound field to the eardrum and temporary threshold shift.

Three groups of 12 subjects were utilized for an experiment in which the temporary threshold shift due to a free-field exposure was measured and compared to the sound transfer functions from free-sound field to the subjects' eardrums. Subject selection was based upon their sound transfer functions and the requirement of normal hearing. The subjects were assigned to one of three groups depending on their dominantly sound transfer function frequency: Low, middle, or high. A probe tube with a miniature microphone was used for the measurement of the sound transfer functions in 1/3-oct bands. The measurements were performed in frequency bands from 0.2 to 20 kHz with one direction of sound incidence: 0 degree azimuth and 0 degree elevation. The subjects were exposed twice to a 2-kHz and twice to a 4-kHz narrow-band noise monotonically on four different occasions. Pre- and postexposure sweep Békésy audiograms were recorded and the temporary threshold shift calculated as the difference between the two. The averaged temporary threshold shifts differed significantly among groups.

Miniature microphone probe tube measurements in the external auditory canal.

The use of a miniature microphone probe tube for sound-pressure level measurements in the outer earcanal was studied in four experiments. The main reason was to evaluate this method for clinical applications and for measurements of hearing protector attenuation. All measurements were registered in 1/3-oct bands. The dynamic range, frequency response of the microphone system, the insertion loss of the probe tube walls, and the influence of the probe tube in the ear canal on the sound-pressure level were examined. The first experiment attempted to determine an optimal placement of the probe tube in the earcanal. Sound-pressure levels resulting from a known free-field sound stimulus were measured at 12 different positions in the earcanal of human subjects. The results indicated that the position which is least sensitive for small movements of the probe tube on the measure was within 1 to 3 mm of the tympanic membrane. In a second experiment the changes in sound transfer function to the tympanic membrane caused by the microphone itself, when positioned just outside the ear canal entrance, were studied for 72 angles of sound incidences in ten subjects. A few minor but significant changes were observed with the microphone in this position. In a third experiment, sound transfer functions were measured from free sound field to the tympanic membrane in 19 subjects. The measurements were performed in 1/3-oct frequency bands (0.2 to 20 kHz) with sound incidences from 24 azimuthal positions and for each of these, three different elevations. The inter- and intrasubject-variability are analyzed and discussed. Finally, the reliability of probe tube microphone measurements was evaluated by repeated measurements of the sound transfer function, five times in ten subjects with the sound incidence from one position. The results indicated very small variations between repeated measurements.

Effect of low level acoustic stimulation on temporary threshold shift in young humans.

To assess the effect of a low level acoustic stimulation on the susceptibility to noise, young human subjects were exposed to music at 70 dBA for 6 h per day during 9 days (training period). Noise sensitivity was assessed by measuring temporary threshold shift (TTS) induced by 105 dBSPL, 1/3 octave band noise at 2 kHz for 10 min. On the fifth day of the training period, a significant decrease of TTS was observed in the frequency range 3-3.5 kHz, in comparison with the baseline TTS obtained before being trained. As the training continued, the frequency range which showed a significant reduction of TTS expanded to 2-5 kHz.

Ischemic colitis of the cecum after renal transplantation masquerading as malignant disease.

Fourteen years after kidney transplantation and following protracted rejection of the transplant, a patient developed abdominal pain, fever, and leukocytosis. Ultrasound demonstrated a pericolic abscess, and barium enema a deformity of the ascending colon suggesting malignant growth. Colonoscopy showed ulcerative and necrotic lesions of the cecum, and colonic carcinoma was suspected. At surgery, a granulomatous inflammatory reaction with fibrosis involving the kidney transplant and cecum was found. Histological examination revealed ulcerations secondary to ischemic colitis, but no malignancy. Thus, ischemic colitis should be ruled out in cases with a presumptive diagnosis of colonic malignancy at x-ray or endoscopy.

Suppression of castor oil-induced diarrhoea by alpha 2-adrenoceptor agonists.

The effects of systemic administration of alpha 2-adrenoceptor agonists on migrating myoelectric complexes and castor oil-induced diarrhoea of the small intestine were studied in conscious rats. Castor oil (1 mg/kg, intraduodenally) disrupted the migrating myoelectric complexes and induced irregular spiking activity with sporadic bursts of myoelectric activity. This change of motility pattern was present concomitant with diarrhoea 1-2 h after instillation of castor oil and during the whole period of diarrhoea. Pre-treatment with clonidine (5-10 micrograms/kg i.v.) or oxymetazoline (5.6-11.2 micrograms/kg i.v.), a peripherally active alpha 2-agonist, inhibited the irregular spiking induced by castor oil and no diarrhoea occurred during the experimental period of 6 h. Thus, the antidiarrhoeal action of peripherally acting alpha 2-adrenoceptor agonists such as oxymetazoline, may be of clinical value in the treatment of diarrhoea.

Neuropeptide regulation of human thymocyte, guinea pig T lymphocyte and rat B lymphocyte mitogenesis.

The effect of 15 defined neuropeptides on the mitogenic activation of lymphocytes from human thymus, guinea pig lymph nodes and rat spleen was investigated. Lymphocytes were incubated in the absence or presence of polyclonal T and B cell activators together with increasing doses of the neuropeptides, and harvested at 48 h of culture after pulse-labeling with 3H-thymidine to assess the DNA synthesis. A dose-related stimulatory effect on the spontaneous 3H-thymidine incorporation of human thymocytes was obtained with methionine-enkephalin (met-enk), motilin and neurotensin. Vasoactive intestinal polypeptide (VIP) and peptide HI (PHI) were inhibitory. A similar responsiveness was observed in cultures of phytohemagglutinin P (PHA)-activated human thymocytes. The low level of basal DNA synthesis of guinea pig lymph node cells was stimulated by VIP and inhibited by neuropeptide Y (NPY) and PHI. PHA-activated lymph node T lymphocytes were stimulated by neurotensin, bombesin and motilin, whereas NPY inhibited the thymidine uptake. The low rate of spontaneous DNA synthesis of rat spleen cells was increased in the presence of VIP. Met-enk stimulated both basal and dextran sulfate-activated splenic B cell proliferation, whereas PHI was inhibitory in both cases. The following peptides were found to be inactive in all the above assays: substance P, cholecystokinin-octapeptide, somatostatin, galanin, oxytocin, pentagastrin and gastrin-releasing peptide 1-27 and 14-27. Although the responses were generally of low magnitude and observed at high peptide concentrations, present study contributes to the understanding of possible mechanisms involved in interactions between the nervous and the immune system.