A patient presenting nasal septum perforation during bevacizumab-containing chemotherapy for advanced breast cancer.

Nasal septum perforation is a rare but described complication of the anti-angiogenetic agent bevacizumab. This is the case of a 48-year-old female breast cancer patient, who developed a nasal septum perforation during treatment with paclitaxel and bevacizumab for advanced disease. After 2 cycles the patient developed nasal irritation and occasional epistaxis; after the 4th cycle with bevacizumab the symptoms worsened to include nasal congestion, major epistaxis and rhinorrhoea. Anterior rhinoscopy revealed a large perforation involving the antero-inferior portion of the cartilaginous nasal septum surrounded by necrotic mucosa. The upper septum and the columellar strut were intact. The patient denied use of cocaine or other intranasal irritants. Bevacizumab was discontinued and with only a topical intranasal vitamin application the symptoms improved. One month later anterior rhinoscopy showed that the lesion healed and normal mucosa surrounded the previous site of perforation. The patient continued successfully with other chemotherapy regimens (gemcitabine and then vinorelbine) until irreversible progressive disease led to her death in February 2010. Thus far 8 other cases of bevacizumab-related nasal septum perforation have been published: 5 patients with colorectal cancer, 2 patients with breast cancer and 1 with ovarian cancer. Nasal septum perforation is an emerging challenge with targeted therapies and in particular with antiangiogenetic or antivascular agents. A rapid diagnosis is important and hence we recommend that patients undergoing treatment with bevacizumab and presenting with nasal symptoms (epistaxis, crusting, rhinorrhoea, nasal congestion and local pain or irritation) should undergo anterior rhinoscopy immediately.

Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies.

The effects of chitosan concentrations, osmolarity, medium and absorption enhancers in the chitosan solution on nasal insulin delivery were studied in vitro and in vivo. The penetration of insulin through the mucosa of rabbit nasal septum was investigated by measuring the transmucosal flux in vitro, while the nasal absorption of insulin in vivo was assessed by the efficiency in lowering the blood glucose levels in normal rats. It was demonstrated that increasing concentrations of chitosan up to 1.5% (w/v) caused an increase in the permeability of insulin across the nasal mucosa. Insulin given intranasally in hypo- or hyperosmotic formulation showed a higher hypoglycemic effect than insulin delivered in isoosmotic formulation. Insulin formulation in chitosan solution prepared with deionized water brought to a higher relative pharmacological bioavailability (Fr) value than that prepared with 50 mM pH 7.4 phosphate buffer. A formulation containing both 1% chitosan and 0.1% ethylenediaminetetraacetic acid (EDTA), 5% polysorbate 80 (Tween 80) or 1.2% beta-cyclodextrin (beta-CD) did not lead to a higher Fr than insulin formulated with 1% chitosan alone. The formulation containing both 5% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and 1% chitosan was more effective at reducing blood glucose levels than the formulation containing 5% HP-beta-CD or 1% chitosan alone. The studies indicated that chitosan concentrations, osmolarity, medium and absorption enhancers in chitosan solution have significant effect on the insulin nasal delivery. The results of in vitro experiments were in good agreement with that of in vivo studies.

Dihydrocapsaicin treatment depletes peptidergic nerve fibers of substance P and alters mast cell density in the respiratory tract of neonatal sheep.

In the present study we administered dihydrocapsaicin (DHC) to neonatal lambs to deplete C-fibers of neuropeptides. We measured the density of substance P (SP)-fibers in nasal septum to assess the effectiveness of the treatment at 3, 9, and 21 days. The numbers of mast cells in the upper and lower respiratory tract were determined at the same time points and histamine content was determined from lung tissue. DHC treatment depleted SP-fibers for up to the 21 day time point. This depletion was estimated as 85% in comparison with controls. In vehicle-treated lambs, the density of SP-fibers decreased progressively with age, but not to the degree of DHC-treated lambs whose SP-fibers were depleted from the initial 3-day measurement. In both, vehicle- and DHC-treated lambs, numbers of mast cells increased progressively with time; however, the density of mast cells was augmented in the entire respiratory tract of DHC-treated animals. Apparently, DHC treatment exerts a single and initial effect in increasing mast cells whereas time maintains a continuous influence; both factors exert their influence independently. Despite large numbers of mast cells in DHC-treated animals, histamine content in the lung had similar levels as controls. Our study provides fundamental data for a better understanding of conditions that may influence defense mechanisms dependent on the mast cell-nerve axis in the respiratory tract.

Sex comparison of neuronal Fos immunoreactivity in the rat vomeronasal projection circuit after chemosensory stimulation.

In rodents, reproductively relevant pheromonal cues are detected by receptors in the vomeronasal organ, which in turn transmit this information centrally via the accessory olfactory bulb, the medial nucleus of the amygdala, the posterior medial bed nucleus of the stria terminalis and the medial preoptic area. In the rat, more neurons are present in males than in females at virtually every relay in this vomeronasal projection circuit. Using Fos immunoreactivity as a marker of neuronal activation, we compared the ability of pheromonal cues derived from the urine and feces of estrous or anestrous female rats to activate neurons in this vomeronasal projection circuit in sexually experienced, gonadectomized male and female rats which were chronically treated in adulthood with a high dose of testosterone propionate (5 mg/kg). When compared with rats killed after 2 h of exposure to clean bedding, male and female subjects exposed for 2 h to bedding from estrous females had similar and significant increments in the number of Fos-immunoreactive neurons at each level of the vomeronasal projection circuit, including the granular layer of the accessory olfactory bulb, the posterior dorsal portion of the medial amygdaloid nucleus, the posterior medial portion of the bed nucleus of the stria terminalis and the medial preoptic area. Exposure to bedding from anestrous females stimulated similar and significant increments in Fos immunoreactivity in most of these same brain regions. Chemosensory stimulation failed to augment Fos immunoreactivity in neurons located in the ventrolateral subregion of the ventromedial nucleus of the hypothalamus or in the midbrain central tegmental field, sites at which mating has previously been shown to augment Fos immunoreactivity in both sexes. Finally, chemosensory stimulation augmented Fos immunoreactivity in the nucleus accumbens shell and core, two regions receiving dopaminergic afferents which have been implicated in sexual reward. On two occasions all subjects were given simultaneous access to bowls containing bedding from estrous versus anestrous females. Both males and females spent significantly more time investigating the estrous bedding, although the total time spent investigating either type of bedding was significantly greater in males. The results suggest that the previously established sexual dimorphism in the morphology of the rat's vomeronasal projection circuit is not reflected in the functional responsiveness of neurons in this circuit to chemosensory cues emitted by female conspecifics.

Inhibitory effects of sho-seiryu-to on acetylcholine-induced responses in nasal gland acinar cells.

Sho-seiryu-to, a traditional Japanese herbal medicine, has been used extensively in the treatment of allergic rhinitis. The effects of Sho-seiryu-to on electrical responses induced by acetylcholine in dissociated nasal gland acinar cells were investigated using patch-clamp and microfluorimetric imaging techniques. The application of Sho-seiryu-to inhibited both K+ and Cl- currents augmented by acetylcholine. The elevation of intracellular Ca2+ and Na+ concentrations induced by acetylcholine was also inhibited by Sho-seriyu-to. These findings suggest that Sho-seiryu-to attenuated the secretion of water and electrolytes from the nasal glands through an anti-cholinergic effect.