Cefodizime (HR221) versus norfloxacin for treatment of urinary tract infections

Cefodizime is a stable new beta-lactamase cephalosporin chemically related to cefotaxime and with a long half-life. Its clinical efficacy and tolerability were compared with those of norfloxacin in patients with intercurrent urinary tract infections plus chronic liver diseases. Cefodizime (2 g, once a day, i.v.) and norfloxacin (400 mg, twice a day, p.o.) were randomly given to two groups of 20 patients each with urinary tract infections caused by organisms sensitive in vitro to these drugs. Cultures of midstream bladder urine, urinalysis and blood biochemical tests were performed before and after each antibiotic treatment. Clinical resolution was observed in 100% of the patients at the end of the treatments, but bacteriological eradication was obtained in 90% of the patients treated with cefodizime and 85% of those treated with norfloxacin, because of the development in five patients of asymptomatic bacteriuria (superinfections).     

An inhibition of the hypothalamic somatostatinergic tone is not the cause of the enhanced growth hormone response to growth hormone-releasing hormone in patients with liver cirrhosis.

Animal models of liver cirrhosis (LC) display a reduced hypothalamic somatostatinergic tone. To test whether a similar mechanism could explain the enhanced Growth Hormone (GH) secretory response to GH-Releasing Hormone (GHRH), which is seen in human LC, we studied the effect of the cholinesterase inhibitor pyridostigmine (PD), which is able to reduce the release of hypothalamic somatostatin (SS), on the GHRH-stimulated GH secretion. We considered that if PD were unable to increase GH secretion, this would constitute evidence of an already inhibited endogenous somatostatinergic tone. If proved, this in turn could explain the enhanced GH response to GHRH seen in LC. Ten LC patients and nine controls were given GHRH (100 microg, intravenously), or PD (120 mg, orally) plus GHRH. After GHRH alone, the GH peak was four times higher in LC than in controls (40.85+/-15.7 ng/ml in LC and 9.35+/-2.5 ng/ml in controls). In LC, PD administration markedly increased the GH response to GHRH (GH peak: 98.0+/-19.7 ng/ml; +240% vs. GHRH alone). The ability of PD to increase the GH response in patients with LC suggests that in this condition the enhanced GH response to GHRH is not due to a completely inhibited endogenous somatostatinergic tone. SS appears instead to maintain its modulator role on GH secretion in human LC, in contrast with what observed in animal models.     

FDA Review of a Panitumumab (Vectibix™) Clinical Trial for First‐Line Treatment of Metastatic Colorectal Cancer

On September 27, 2006, the U.S. Food and Drug Administration granted accelerated approval to panitumumab (Vectibix?; Amgen, Inc., Thousand Oaks, CA) for the treatment of patients with epidermal growth factor receptor–expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine‐, oxaliplatin‐, and irinotecan‐containing chemotherapy regimens. Accelerated approval was based on demonstration of a beneficial effect on progression‐free survival (PFS). The present submission summarizes a second clinical trial, to be included in the panitumumab package insert in June 2008, of chemotherapy and bevacizumab with and without panitumumab in the first‐line treatment of patients with metastatic colorectal cancer. The study was closed when inferior PFS and greater toxicity were demonstrated at the time of the planned interim efficacy analysis. Patients receiving panitumumab in combination with bevacizumab and chemotherapy experienced a higher incidence of death (9% versus 4%) and a higher risk for grade 3 and 4 toxicities than patients receiving bevacizumab and chemotherapy alone. The incidences of any Common Terminology Criteria for Adverse Events grade 3 and 4 adverse events (AEs) were 87% and 72% in the panitumumab and control groups, respectively. Grade 3 and 4 AEs occurring more commonly in panitumumab‐treated patients included rash/acneiform dermatitis, diarrhea, dehydration, primarily resulting from diarrhea, hypokalemia, stomatitis/mucositis, and pulmonary embolism. The addition of panitumumab to bevacizumab and chemotherapy for the first‐line treatment of metastatic colorectal cancer was harmful when compared with bevacizumab and chemotherapy alone. The use of panitumumab in this setting cannot be recommended.     

Platelet function and thrombin activity in patients with recent cerebral transient ischemic attacks

Platelet function and thrombin activity were investigated in 12 hospitalized patients (7 men and 5 women, mean age 53 years) who had had transient cerebral ischemic attacks in the previous 2-12 weeks. Each patient was given an extensive clinical and instrumental evaluation, including Doppler sonography of the cervical and lower limb vessels, cerebral angiography, and head computed tomography scan, after which relevant atherosclerotic disease was excluded. The controls consisted of 12 subjects hospitalized for nonvascular neurologic problems and matched for age, sex, and risk factors to the transient ischemic attack patients. Collagen-induced platelet thromboxane B2 production, plasma beta-thromboglobulin, and fibrinopeptide A were significantly higher in the patients than the controls. Platelet aggregability by collagen was the same in the 2 groups. Platelet hyperfunction and enhanced thrombin activity are present in patients some weeks after the acute episode, suggesting that the hemostatic system has a primary pathogenetic role.     

Measurement of CO2 response with the breath-by-breath automatic acquisition of the breathing pattern and occlusion pressure

Objective. Our objective is to present a methodology for the automated acquisition and storage of BP and P_0.1 during a CO₂ rebreathing test.Methods. The system consists of a microcomputer with additional circuits and an automatic electronically controlled valve to occlude the inspiratory airway. Data collection and data processing are separate programs. Airway pressure and flow are digitized at a 100-Hz rate, whilePetCO₂ is determined and P_0.1 is measured on a breath-by-breath basis. Off-line processing calculates the BP variables, generates a correlation matrix (Ve/PetCO₂,Ttot/PetCO₂,Ti/PetCO₂,Te/PetCO₂, [Vt/Ti]/PetCO₂, [Ti/Ttot]/PetCO₂, P_0.1/PetCO₂), and edits graphic data. The accuracy of the volume and pressure measurements was tested by comparing known volumes provided by a syringe (n=100) and a series of pressures controlled by a water manometer (n=41) on the one hand, with volumes and pressures measured by the device. The accuracy of the time intervals and P_0.1 was assessed by comparing in 10 healthy subjects the values measured manually on a graphic recording with those provided by the device (n=170).Results. Volumes: V_measured=0.99×V_controlled,r=0.99,p<0.001. Pressures: P_measured=0.97×P_controlled+0.09,r=0.98,p<0.001. Inspiratory time:Ti _automatic=0.91×Ti _graphic+0.22,r=0.93,p<0.001. Expiratory time:Te _automatic=0.93×Te _graphic+0.34,r=0.95,p<0.001. Occlusion pressure: P_{0.1 automatic}=0.95×P_{0.1 graphic}+0.62,r=0.94,p<0.001. Reproducibility was assumed to be represented by the intraindividual coefficient of variation of the CO₂ response. The comparison of an automatic breath-to-breath method with a graphic manual recording revealed significantly less variability with the former (Ve/PetCO₂: 15.2±4.5% vs 22.5±6.3%,p<0.01; P_0.1/PetCO₂: 8.3±4.3% vs 19.7±7.2%,p<0.001; [Vt/Ti]/PetCO₂: 9.1±3.5% vs 14.5±5.3%,p<0.05).Conclusion. Our automated acquisition and storage of waveforms and breath-by-breath determination of BP and P_0.1 provide an easy and thorough analysis of the respiratory response to CO₂ and decrease the variability of the results.     

gamma-Aminobutyric acidA receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands.

The properties of [3H]clonazepam, [3H]diazepam and [3H]zolpidem (N,N,6[trimethyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-acetamide hemitratrate) binding to synaptic membranes of cerebellum, cortex, olfactory bulb, striatum and spinal cord of rat were compared to the binding properties of [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. In the cerebellar, cortical and olfactory bulb membranes, the density of high-affinity binding sites of all these tritiated benzodiazepine (BZ) ligands is almost identical. In contrast, in the striatum, the density of [3H]clonazepam and [3H]zolpidem binding sites is approximately 60 and 30%, respectively, of the density of [3H]diazepam, [3H]flunitrazepam or [3H]flumazenil sites. In spinal cord membranes, the number of high-affinity binding sites of [3H]clonazepam and [3H]zolpidem is less than 20% of the number of binding sites for [3H]diazepam, [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. Moreover, the displacement of [3H]flunitrazepam from spinal cord membranes by clonazepam and zolpidem was characterized by high IC50 values and Hill slopes significantly less than 1. Because [3H]BZ ligand binding in the spinal cord is enhanced by gamma-aminobutyric acid (GABA), these data suggest that different regions of the rat central nervous system may contain different GABA-BZ receptor subtypes. The different pharmacological properties of clonazepam, diazepam and zolpidem (i.e., regarding their ability to enhance bicuculline seizure threshold, to decrease locomotor activity, to induce ataxia or to elicit anticonflict action) further support the concept that in the rat central nervous system preferential occupancy of heterogeneous GABAA receptors by these drugs can be related to their effects on behavior.