Comparison of cizolirtine citrate and metamizol sodium in the treatment of adult acute renal colic: a randomized, double-blind, clinical pilot study

BACKGROUND: Renal colic causes excruciating pain that provides a good clinical model of acute pain for the development of new analgesics. OBJECTIVE: The purpose of the study was to compare the analgesic efficacy and tolerability of cizolirtine citrate and metamizol sodium in adult acute renal colic. METHODS: This Phase II, randomized, double-blind, clinical pilot study was conducted in the emergency departments of 6 general hospitals in the Czech Republic between October 2000 and February 2001. Male and female patients aged 18 to 65 years and presenting with hematuria and moderate to severe pain due to suspected renal colic starting within the 24 hours before presentation were eligible. Patients were randomized to receive a single IV dose of cizolirtine 350 mg or metamizol 2,500 mg, administered by slow infusion over 15 minutes. Both doses were maximal for the respective drugs to attain adequate analgesia. Use of rescue medication with butorphanol was allowed 30 minutes after study drug administration. Pain intensity was assessed at various time points during the following 360 minutes using a 100-mm visual analog scale (VAS) and a verbal categoric scale. In addition, a specific verbal categoric scale was used to rank pain relief. Physical examinations, laboratory tests, and questioning for adverse events addressed drug tolerability. RESULTS: Sixty-four patients (50 men, 14 women; mean [SD] age, 44.21 [12.29] years; mean [SD] body mass index, 25.97 [3.38] kg/m(2)) were enrolled. Physical examination findings and mean VAS pain intensity scores at baseline (mean [SD], 79.42 [7.89] mm and 82.59 [10.50] mm in the cizolirtine and metamizol groups, respectively) were similar in both groups. After 30 minutes, the mean (SD) scores were 33.84 (25.15) mm and 25.41 (24.51) mm, respectively. This difference was not statistically significant, and the noninferiority of cizolirtine with respect to the comparator could not be established. However, the proportion of patients that showed satisfactory pain relief (ie, decrease of > or = 50% in VAS pain intensity score compared with baseline) at 30 minutes in the cizolirtine group was fairly high (64.5%), which means relevant analgesic activity. Both treatments were well tolerated; 6 adverse events were reported in 5 patients (7.8%), and all were considered as not treatment related. CONCLUSIONS: Although this limited pilot study did not include an internal measure of sensitivity, relevant pain reduction was shown in the population of patients with suspected renal colic undergoing treatment with cizolirtine, suggesting the presence of analgesic activity. However, the efficacy of cizolirtine was found to be similar to that of metamizol. Treatments were well tolerated.     

Comparison of Doppler parameters of central versus intraparenchymal renal arteries in physiologically normal newborns

Background: Changes in renal arterial Doppler flow may identify parenchymal disease, but in newborns knowledge of normal physiological parameters is a prerequisite for correct interpretation. Objective: To evaluate renal blood flow in healthy newborns by means of Doppler US. Materials and methods: On the fourth day of life we examined 100 normal term newborn infants (200 kidneys). Blood flow in the central renal arteries was compared with that in the intraparenchymal arteries. Maximum systolic velocity (V_max), end-diastolic velocity (V_ed), mean flow velocity (V_mean), resistive index (RI) and pulsatility index (PI) were assessed. Results: All parameters were significantly higher in the central renal arteries than in the intraparenchymal arteries (RI 0.78±0.07 vs 0.62±0.05, P<0.0001; PI 1.84±0.52 vs 1.09±0.18, P<0.0001). Conclusions: Physiological data are presented that are necessary for the correct interpretation of neonatal Doppler US.     

Effective antitumoral immune responses are not induced by cytosine deaminase suicide gene transfer in a syngeneic rat pancreatic carcinoma model

BACKGROUND: Experimental gene transfer can make tumors more immunogenic, leading to local regression and inducing immunological memory sufficient to permit resistance to a tumor rechallenge. However, this rarely had any significant impact on large established tumors. METHODS: To analyze potential immunological effects, we used weakly immunogenic pancreatic carcinomas in syngeneic, immunocompetent Lewis rats and performed in situ adenoviral mediated cytosine deaminase (CD) gene transfer followed by administration of the prodrug, 5-fluorocytosine (5FC). In order to reflect the clinical situation, such treated tumors were surgically resected and animals were rechallenged with parental DSL6A pancreatic tumor cells. Tumor growth and cytotoxic activity of immune cells were determined. RESULTS: CD/5FC treatment of the DSL6A cells revealed significant induction of apoptosis in vitro and slowed down tumor progression in syngeneic hosts. Furthermore, we observed neither significant change in tumor growth nor protective immunity in the rechallenged animals. Analysis of T lymphocytes showed no specific cytotoxic activity against DSL6A cells. There was only a trend towards a minor NK cell activation. CONCLUSIONS: Albeit the present study failed to induce protective antitumor immunity, the initial finding of reduced tumor growth argues for the development of multimodal therapeutic options to overcome negative impacts of advanced malignant disease or chemotherapy-related anergy and immunosuppression.     

Renal effects of HMG-CoA reductase inhibition in a rat model of chronic inhibition of nitric oxide synthesis

BACKGROUND/AIMS: In addition to their lipid-lowering effects, HMG-CoA reductase inhibitors (statins) induce a variety of pleiotropic actions that have been recently studied in the area of cardiovascular and renal protection. In the present studies we sought to determine whether statins retain beneficial effects in the experimental model of NO deficiency achieved by chronic administration of a pressor dose of L-arginine analogue N-nitro-L-arginine-methyl ester (L-NAME). METHODS: To address this issue, blood pressure (BP), renal function (GFR), and albuminuria were determined in rats treated for 4 weeks with L-NAME, L-NAME + atorvastatin (ATO), and in untreated controls. In addition, renal cortical protein expression of caveolin 1 (CAV1), vascular endothelial growth factor (VEGF), and activity of RhoA were also determined. RESULTS: L-NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria as compared to control animals. Co-administration of ATO with L-NAME normalized albuminuria and prevented decreases in GFR in L-NAME rats without having an impact on pressor effects of L-NAME. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L-NAME-treated animals, and normalized with co-administration of ATO. CONCLUSION: Treatment with ATO exerts early nephroprotective effects in the NO-deficient model of hypertension. These effects could be mediated by amelioration of VEGF expression and reduction of RhoA activity.     

Totally laparoscopic versus conventional ileoanal pouch procedure – design of a single-centre, expertise based randomised controlled trial to compare the laparoscopic and conventional surgical approach in patients undergoing primary elective restorative proctocolectomy- LapConPouch-Trial

Background  

Restorative proctocolectomy is increasingly being performed minimal invasively but a totally laparoscopic technique has not yet been compared to the standard open technique in a randomized study.     

Respiratory burst in alveolar macrophages exposed to urban particles is not a predictor of cytotoxicity

We examined the utility of respiratory burst measurements in alveolar macrophages to assess adverse cellular changes following exposure to urban particles. Cells were obtained by bronchioalveolar lavage of Fisher 344 rats and exposed (0–100 μg/well) to urban particles (EHC-93, SRM-1648, SRM-1649, PM2.5), the soluble (EHC-93sol) and insoluble (EHC-93insol) fractions of EHC-93 (EHC-93tot), mineral particles (TiO₂, SiO₂) and metal oxides (iron III oxide, iron II/III oxide, copper II oxide, nickel II oxide). The particle-induced respiratory burst was measured by chemiluminescence for 2 h after the addition of particles. The cells were then stimulated with phorbol 12-myristate 13-acetate (PMA), yeast Zymosan fragments (Zymosan), or lipopolysaccharide plus interferon-gamma (LPS/IFN-γ) and the stimulant-induced respiratory burst was measured. Independently of the potential of particles to induce directly a respiratory burst, exposure to most particles attenuated the subsequent stimulant-induced burst.The notable exception was SiO₂, which produced a strong respiratory burst upon contact with the macrophages and enhanced the subsequent response to PMA or LPS/IFN-γ. Based on the degree of inhibition of the stimulant-dependent respiratory burst, particles were clustered into groups of high (SRM-1649, iron III oxide), intermediate (EHC-93tot, EHC-93insol, SRM-1648, VERP, iron II/III oxide, copper II oxide), and low (EHC-93sol, SiO₂, TiO₂ and nickel II oxide) potency. Across these clusters, the potency of the particles to inhibit the stimulant-dependent respiratory burst showed poor correlation with cytotoxicity determined by XTT reduction assay.