Nasal Cavity Of Rat Research Articles

The effect of surgical procedure in the nasal cavity in rats on the passive avoidance conditioning and the level of monoamines in the hypothalamus

In a biological model of septoplasty in rats, the effect of the operation on the passive avoidance conditioning (PAC) was studied. It has been shown that septoplasty increases anxiety and reduces exploratory activity in rodents under PAC. Neurochemical analysis of the hypothalamus carried out immediately after the end of the experiment revealed an increase in norepinephrine metabolism in rats after septoplasty, which may be associated with activation of the hypothalamic-pituitary-adrenal axis.

Preparation and Evaluation of the In situ Gel-forming Chitosan Hydrogels for Nasal Delivery of Morphine in a Single Unit dose in Rats to Enhance the Analgesic Responses.

In this study, an in situ gel-forming chitosan hydrogel was prepared with the use of glutamate salt of chitosan (Ch-Ga), β-glycerophosphate (Gp), and morphine (Mor). The paper is focused on in vitro physicochemical properties and in-vivo analgesic effects of the prepared chitosan hydrogel. The thermosensitive properties of prepared chitosan hydrogel were evaluated during the different temperatures and times. The physicochemical properties of chitosan hydrogel were investigated by infrared (IR) spectroscopy and X-ray diffraction analysis (XRD). Also, its cell cytotoxicity effects were evaluated in murine NIH/3T3 normal cells. Subsequently, the distribution of chitosan hydrogel in the nasal cavity of rats and its analgesic responses were evaluated. The prepared chitosan hydrogel showed that it could be gelled at the temperature of 34 °C before leaving the nose in the shortest possible time of 30 s. The analgesic responses of the intranasal (IN) injection of chitosan hydrogel (IN-chitosan hydrogel, 10 mg Mor/kg) in a single unit dose in rat relative to the placebo and intranasal or intraperitoneal (IP) injection of free morphine solution (IN-Free Mor or IP-Free Mor, 10 mg Mor/kg) via the hot plate test, reveal that the IN-chitosan hydrogel could induce fast analgesic effects of morphine with maximum possible effect (MPE) of 93% after 5 min compare to the IN-Free Mor and IP-Free Mor with MPE of 80% after 15 min and 66% after 30 min, respectively. Also, prolonged analgesic effects with MPE of 78 % after 6 h of injection were only seen in the IN-chitosan hydrogel injected group. The obtained fluorescent images of rat's brain injected with IN-chitosan hydrogel containing doxorubicine (Dox) as a fluorescent agent showed that the mucosal adhesive and absorption enhancer properties of IN-chitosan hydrogel resulting in longer presence of them in the nasal cavity of rats followed by more absorption of Dox from the blood vessels of olfactory bulbs with a 74% color intensity compared to the IN-Free Mor and IN-Free Dox with 15%. These data reveal that the IN-chitosan hydrogel could induce fast and prolonged analgesic effects of morphine compare to the IN/IP-Free Mor, which could be considered as an in situ gel-forming thermosensitive chitosan hydrogel for nasal delivery of wide ranges of therapeutic agents.

Expression of the P53 Protein and Morphological Changes in Neurons in the Pyramidal Layer of the Hippocampus After Simulation of Surgical Interventions in the Nasal Cavity in Rats

To determine the role of surgical stress on the formation of p53-positive and dark neurons (DN) in the hippocampus, and to examine the parallelism of their formation in the pyramidal layer of the hippocampus. Simulated septoplasty was performed on 20 Wistar rats. The hippocampus and dentate gyrus (DG) were examined, in which the number of DN and p53-positive neurons was determined at 2, 4 and 6 days after surgery. In each rat, 10 brain slices were stained with antibodies to p53 protein with Meyer's haematoxylin and 10 slices were stained with Nissl toluidine blue. Hippocampal subfields CA1, CA2, CA3 and DG were studied. In the pyramidal subfield layer, the absolute number of neurons that were nuclear antibody-positive to p53 protein was counted, as well as the number of dark neurons. The counting area in each subfield was 20934±1260 µm2. Neurons are counted using the Aperio ImageScope program. For the histological specimen analysis, the ImageJ software was used. The data obtained using cell counting methods were presented as mean ± SE. Then, they were compared between both groups using a t-test SPSS 21software. Compared with the control group (n = 5), the number of DN and p53-positive neurons increased in experimental animals at all periods. A direct relationship was obtained between the increase in the number of DN and p53-positive neurons in the hippocampal formation. Septoplasty simulation in rats results in the pathogenetic cascades onset, which, in its turn, changes the morpho-functional properties of neurons of the pyramidal layer of the hippocampus and contributes to their neuroplasticity. Activation of NMDS receptors of neurons during stress apparently, initiates two ways of neuron life - the beginning of p53 protein expression and the DN formation. Both ways can finally lead to apoptosis. The formation of dark neurons and the expression of the p53 protein in them are most likely to be interconnected and can probably provide neuroprotective mechanisms.

Association of Intranasal and Neurogenic Dural Inflammation in Experimental Acute Rhinosinusitis.

BackgroundNasal cavity and sinus disorders, such as allergic rhinitis, rhinosinusitis, or certain anatomical defects, are often associated with transient or ongoing headaches. On the other hand, migraine headache patients often exhibit pain referral over the area of nasal sinuses and typical nasal autonomic symptoms involving congestion and rhinorrhea. Mechanism for convergence of nasal or sinus disorders and headaches is unknown. Herein, we examined the association of sino-nasal inflammatory pain with common preclinical indicators of trigeminovascular system activation such as dural neurogenic inflammation (DNI) and neuronal activation in brainstem nociceptive nuclei.MethodsNasal and paranasal cavity inflammation and pain was induced by formalin (2.5%/10 μl) or capsaicin (0.1%/10 μl) instillation at the border of maxillary sinus and nasal cavity in rats. Quantification of inflammation of nasal mucosa and DNI was performed by spectrophotometric measurement of Evans blue - plasma protein complex extravasation. Pain behavior was quantified by rat grimace scale (RGS). Nociceptive neuronal activation in caudal part of spinal trigeminal nucleus (TNC) was assessed by c-Fos protein immunohistochemistry.ResultsCapsaicin and formalin administered into rat nasal cavity increased plasma protein extravasation in the nasal mucosa and dura mater. Intensity of plasma protein extravasation in nasal mucosa correlated with extravasation in dura. Similarly, facial pain intensity correlated with nociceptive neuronal c-Fos activation in the TNC.ConclusionPresent data show that inflammatory stimuli in deep nasal and paranasal structures provoke distant intracranial changes related to trigeminovascular system activation. We hypothesize that this phenomenon could explain overlapping symptoms and comorbidity of nasal/paranasal inflammatory disorders with migraine.

Study on nasal absorption of Cistanche deserticola phenylethanol glycosides nanoemulsion in vivo

To investigate the transnasal absorption characteristics of Cistanche deserticola phenylethanol glycosides nanoemulsion and its influencing factors. With the use of the classic in vivo nasal circulation perfusion model in rats, the absorption rate constant was used as the index to compare the nasal absorption characteristics of C. deserticola phenylethanol glycosides nanoemulsion and its aqueous solution in different concentrations, and to explore the effects of pH value of the preparation and absorption accelerator Azone on the nasal absorption of C. deserticola phenylethanol glycosides nanoemulsion. The results showed that, as compared with the aqueous solution group, the absorption rate constant was significantly higher in C. deserticola phenylethanol glycosides nanoemulsion with the same concentration(P<0.05), and C. deserticola phenylethanol glycosides nanoemulsion was more easily absorbed by the nasal cavity of rats; with the increase of the concentration of C. deserticola phenylethanol glycosides, the transnasal absorption amount of nanoemulsion was also increased in a dose-dependent manner. When the pH value of nanoemulsion was 6.0 and the ratio of Azone was 2%, the absorption rate constant was highest and the effect of promoting infiltration was the best.

PECILARITIES OF MORPHOGENESIS OF NASAL REGION STRUCTURES IN RATTUS NORVEGICUS

With the purpose to clarify general patterns and species characteristics of prenatal morphogenesis of nasal region structures in rattus norvegicus 21 series of consecutive histological sections preparations of 4,0-36,0 mm parietal-coccygeal length of rattus norvegicus were examined. It has been established that development of nasal cavity in rats begins with nasal placodes with ectodermal origin. The formation of nasal cavity in rats passes five sequential stages: olfactory placode, nasal fossa, nasal sacks, primary nasal cavity and definitive nasal cavity. Formation of nasal cavity includes obligatory process of physiological atresia of nostrils, nasal-palatine channels and ducts of vomeronasal organ. Physiological atresia of these structures proceeds the time when palatine processes become horizontal. Regularities of nasal glands morphogenesis have a certain sequence of development: first lateral nasal gland is laid, then maxillary sinus, respiratory and olfactory glands. In general, development of nasal glands in rats occurs on earlier stages of development, as compared to human.

Intranasal infusion of nanostructured lipid carriers (NLC) containing CNS acting drug and estimation in brain and blood

The present study was aimed to evaluate the nanostrucured lipid carriers (NLC) containing duloxetine (DLX-NLC) for intranasal infusion through the nasal cavity of rat. The in vivo nasal infusion studies were performed using Wistar rats and the amount of DLX permeated and its amount in brain and blood was estimated. The effects on absorption rate and type of drug delivery systems (nanocarriers and drug solution) for nose to brain/blood permeation were assessed. DLX was found to be permeated from the nasal cavity into the body of rat and the permeated amount was found to be more in case of DLX-NLC. Approximately 2.5-times better permeation was exhibited by DLX-NLC than DLX-solution. Appreciable amount of DLX was estimated in blood and brain and the estimated amount was higher in case of DLX-NLC. Thus the administration of NLC containing DLX through intranasal route was found to be potential method for the delivery of DLX for the treatment of depression.

Construction of recombinant house dust mite group 1 allergen vaccine and study on immune response induced by nasal immunization

To study the preparation of recombinant house dust mite group 1 allergen vaccine (chitosan-pVAX1-Derp1 nanoparticles, pVAX1-Derp1/CS) and to investigate the efficacy and mechanism of intranasally given chitosan-pVAX1-Derp1 nanoparticles on mouse model with allergic rhinitis (AR). The chitosan-pVAX1-Derp1 nanoparticles was prepared by complex coacervation, and its nature was identified and analysed. A total of 40 BALB/c rats were randomly divided into 5 groups: the normal group (group A), the AR model group (group B), the chitosan (CS) prevention group (group C), the pVAX1-Derp1 prevention group (group D), and the pVAX1-Derp1/CS prevention group (group E). The nasal cavity of rats in the group B, C, D and E were dripped with phosphate buffered saline (20 µl), CS (20 µl), pVAX1-Der p1 (20 µl), pVAX1-Derp1/CS nanoparticles (20 µl) on the first day and day 8, once daily. Rats in the latter 4 group were sensitized with Der p1 and Al(OH)3 in day 15 and day 22, and challenged with Der p1 to establish AR model from day 36 to day 43, while rats in group A were treated with PBS. Then the level of cytokines in serum was assayed by ELISA, inflammatory reactions in nasal mucosa were analyzed by haematoxylin and eosin staining. pVAX1-Derp1/CS nanoparticles was successfully constructed, the mean grain size of pVAX1-Derp1/CS was (205.3 ± 12.8) nm, and the zeta potential was (30.5 ± 5.6) mV. In nasal mucosa tissue, group B and C showed significant allergic inflammation, while group D and E showed lighter allergic inflammation. Compared with the group B, the group D and E could effectively reduced serum IgE level and IL-4 level [group B: (120.0 ± 8.8) ng/ml, (248.7 ± 10.6) pg/ml; group D: (109.6 ± 14.5) ng/ml, (192.5 ± 10.2) pg/ml; group E: (88.1 ± 8.3) ng/ml, (165.7 ± 9.7) pg/ml; IgE: t value were 3.5, 6.9, all P < 0.01; IL-4: t value were 10.0, 15.2, all P < 0.01], and increased IFN-γ level [group B: (709.0 ± 26.5) pg/ml; group D: (856.3 ± 37.4) pg/ml; group E: (904.8 ± 37.7) pg/ml; t value were 8.2, 10.8, all P < 0.01)]. IL-10 level of group D [(129.9 ± 16.1) pg/ml] and E [(107.1 ± 11.8) pg/ml] was lower than IL-10 level of group B [(160.6 ± 24.2) pg/ml]. The difference were significantly (t value were 2.9, 5.5, all P < 0.05). Chitosan can effectively encapsulate pVAX1-Derp 1 and inhibit nuclease degradation of the plasmid, the DNA vaccine has some preventive effect on AR animal model by nasal immunization.

Nasal and Pulmonary Toxicity of Titanium Dioxide Nanoparticles in Rats

In recent decades, titanium dioxide (TiO2) nanoparticles have been used in various applications, including paints, coatings, and food. However, data are lacking on the toxicological aspects associated with their use. The aim of this study was to assess the inhalation toxicity of TiO2 nanoparticles in rats by using inhalation exposure. Male Wistar rats were exposed to TiO2 nanoparticles for 2 weeks (6 hr/day, 5 days/week) at a mean mass concentration of 11.39 ± 0.31 mg/m3. We performed time-course necropsies at 1, 7, and 15 days after exposure. Lung inflammation and injury were assessed on the basis of the total and individual cell counts in bronchoalveolar lavage fluid (BALF), and by biochemical assays, including an assay for lactate dehydrogenase (LDH). Furthermore, histopathological examination was performed to investigate the lungs and nasal cavity of rats. There were no statistically significant changes in the number of BALF cells, results of biochemical assays of BALF and serum, and results of cytokine analysis. However, we did observe histopathological changes in the nasal cavity tissue. Lesions were observed at post-exposure days 1 and 7, which resolved at post-exposure day 15. We also calculated the actual amounts of TiO2 nanoparticles inhaled by the rats. The results showed that the degree of toxicity induced by TiO2 nanoparticles correlated with the delivered quantities. In particular, exposure to small particles with a size of approximately 20 nm resulted in toxicity, even if the total particle number was relatively low.

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = -3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

Transport and subcellular distribution of intranasally administered zinc in the olfactory system of rats and pikes.

Zinc is an essential element, which can act as a neuromodulator and also is bound in zinc proteins in the brain. The olfactory bulb contains high concentrations of zinc. In the present study, 65Zn(2+) was applied on the olfactory epithelium of rats and pikes and the transport of the metal in the olfactory system was then examined. Administration of 65Zn(2+) in the nasal cavity of rats or the olfactory chambers in pikes resulted in an uptake of the metal in the olfactory epithelium and a transport of the metal along the primary olfactory neurons to their terminations in the olfactory bulbs. Low levels of 65Zn(2+) passed these terminals and continued into the interior of the bulbs. In the rats 65Zn(2+) was also detected in the anterior parts of the olfactory cortex. Subcellular fractionations of the olfactory mucosa and olfactory bulb of rats given 65Zn(2+) intranasally showed that the metal is bound both to particulate cellular constituents and to cytosolic components in these tissues. Gel chromatography indicated that some of the zinc in the cytosol is bound to metallothionein in the olfactory mucosa and bulb. Inhalation of zinc-containing dusts or fumes occurs in some work-places and may imply high exposure of the nasal tissues. It is not known whether neurotoxicity may be related to uptake of zinc in the olfactory system. However, this is an issue which deserves attention, since zinc dysregulation has been implied to play a role in Alzheimer's disease. In addition, impairment of the sense of smell and degenerative changes of the olfactory tissues have been seen in early stages of some neurodegenerative disorders.

Inhibition of experimental allergic rhinitis by the n-butanol fraction from the anomalous fruits of Gleditsia sinensis.

This study was conducted to clarify the effect of the n-butanol fraction from the anomalous fruits of Gleditsia sinensis LAM. (NBGS) on experimental allergic rhinitis. NBGS (100, 200, 400 mg/kg, p.o.) dose-dependently inhibited nasal symptoms (sneezing and nasal rubbing) and dye leakage induced by antigen challenge into the nasal cavity of actively sensitized rats. Significant effects were observed at doses of 200 and 400 mg/kg. NBGS (200, 400 mg/kg) also showed a clear inhibition of sneezing and an inhibitory tendency on nasal rubbing induced by histamine in normal rats. At 400 mg/kg, it significantly reduced dye leakage induced by histamine into the nasal cavity of rats. Terfenadine (10 mg/kg, p.o.), an antihistaminic drug, clearly inhibited the nasal symptoms and the amount of dye leakage induced by antigen or histamine. Furthermore, NBGS significantly reduced in vitro histamine release from rat peritoneal mast cells triggered by compound 48/80 at concentrations of 30 and 100 microg/ml. These results suggest that NBGS may be clinically effective in alleviating the nasal symptoms of allergic rhinitis, probably by inhibiting both histamine release from mast cells and nasal vascular permeability.

Lack of Modifying Effects of 2,6-Dimethylaniline on Lung Carcinogenesis in Transgenic Mice Carrying Human Prototype c-Ha-&lt;i&gt;ras&lt;/i&gt; Gene Initiated with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

2,6-Dimethylaniline (DMA) is known as a major metabolite of xylazine, α2-adrenergic agonist used as a tranquilizer for domestic animals, and has been reported to have a carcinogenic potential to the nasal cavity in rats as well as a nasal tumor pomoting effect in rats. In order to examine whether DMA has any tumor modifying effect in the other respiratory organs, transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) that are highly susceptible to genotoxic carcinogens were given diet containing 0 or 3000 ppm DMA for 26 weeks or 0 or 2000 ppm DMA for 53 weeks after initiation with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. No significant difference in the incidence/multiplicity of pulmonary proliferative lesions was observed between the groups treated with NNK alone and NNK plus DMA. These results suggest that DMA has no tumor modifying effect in pulmonary proliferative lesions induced in rasH2 and non-Tg mice.

CHLOROFORM: EXPOSURE ESTIMATION, HAZARD CHARACTERIZATION, AND EXPOSURE-RESPONSE ANALYSIS

Chloroform has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to chloroform principally through inhalation of indoor air, particularly during showering, and through ingestion of tap water. Data on concentrations of chloroform in various media were sufficient to serve as the basis for development of deterministic and probabilistic estimates of exposure for the general population in Canada. On the basis of data acquired principally in studies in experimental animals, chloroform causes hepatic and renal tumors in mice and renal tumors in rats. The weight of evidence indicates that chloroform is likely carcinogenic only at concentrations that induce the obligatory precursor lesions of cytotoxicity and proliferative regenerative response. Since this cytotoxicity is primarily related to rates of formation of reactive, oxidative metabolites, dose response has been characterized in the context of rates of formation of reactive metabolites in the target tissue. Results presented here are from a "hybrid" physiologically based pharmacokinetic (PBPK) animal model that was revised to permit its extension to humans. The relevant measure of exposure response, namely, the mean rate of metabolism in humans associated with a 5% increase in tumor risk (TC05), was estimated on the basis of this PBPK model and compared with tissue dose measures resulting from 24-h multimedia exposure scenarios for Canadians based on midpoint and 95th percentiles for concentrations in outdoor air, indoor air, air in the shower compartment, air in the bathroom after showering, tap water, and food. Nonneoplastic effects observed most consistently at lowest concentrations or doses following repeated exposures of rats and mice to chloroform are cytotoxicity and regenerative proliferation. As for cancer, target organs are the liver and kidney. In addition, chloroform has induced nasal lesions in rats and mice exposed by both inhalation and ingestion at lowest concentrations or doses. The mean rate of metabolism associated with a 5% increase in fatty cysts estimated on the basis of the PBPK model was compared with tissue dose measures resulting from the scenarios already described, and lowest concentrations reported to induce cellular proliferation in the nasal cavities of rats and mice were compared directly with midpoint and 95th percentile estimates of concentrations of chloroform in indoor air in Canada. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.

Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture.

This is an overview of the cellular biology of upper nasal mucosal cells that have special characteristics that enable them to be used to diagnose and study congenital neurological diseases and to aid neural repair. After mapping the distribution of neural cells in the upper nose, the authors' investigations moved to the use of olfactory neurones to diagnose neurological diseases of development, especially schizophrenia. Olfactory-ensheathing glial cells (OEGs) from the cranial cavity promote axonal penetration of the central nervous system and aid spinal cord repair in rodents. The authors sought to isolate these cells from the more accessible upper nasal cavity in rats and in humans and prove they could likewise promote neural regeneration, making these cells suitable for human spinal repair investigations. The schizophrenia-diagnosis aspect of the study entailed the biopsy of the olfactory areas of 10 schizophrenic patients and 10 control subjects. The tissue samples were sliced and grown in culture medium. The ease of cell attachment to fibronectin (artificial epithelial basement membrane), as well as the mitotic and apoptotic indices, was studied in the presence and absence of dopamine in those cell cultures. The neural repair part of the study entailed a harvesting and insertion of first rat olfactory lamina propria rich in OEGs between cut ends of the spinal cords and then later the microinjection of an OEG-rich suspension into rat spinal cords previously transected by open laminectomy. Further studies were done in which OEG insertion was performed up to 1 month after rat cord transection and also in monkeys. Schizophrenic patients' olfactory tissues do not easily attach to basement membrane compared with control subjects, adding evidence to the theory that cell wall anomalies are part of the schizophrenic "lesion" of neurones. Schizophrenic patient cell cultures had higher mitotic and apoptotic indices compared with control subjects. The addition of dopamine altered these indices enough to allow accurate differentiation of schizophrenics from control patients, leading to, possibly for the first time, an early objective diagnosis of schizophrenia and possible assessment of preventive strategies. OEGs from the nose were shown to be as effective as those from the olfactory bulb in promoting axonal growth across transected spinal cords even when added 1 month after injury in the rat. These otherwise paraplegic rats grew motor and proprioceptive and fine touch fibers with corresponding behavioral improvement. The tissues of the olfactory mucosa are readily available to the otolaryngologist. Being surface cells, they must regenerate (called "neurogenesis"). Biopsy of this area and amplification of cells in culture gives the scientist a "window to the developing brain," including early diagnosis of schizophrenia. The "Holy Grail" of neurological disease is the cure of traumatic paraplegia and OEGs from the nose promote that repair. The otolaryngologist may become the necessary partner of the neurophysiologist and spinal surgeon to take the laboratory potential of paraplegic cure into the day-to-day realm of clinical reality.

Intranasal absorption of sumatriptan and naratriptan: no evidence of local transfer from the nasal cavities to the brain arterial blood in male rats.

Nasal administration to rats of small molecules (tritiated water, tyrosine, and propanol) results in a higher concentration in the brain arterial blood than in other arteries. The preferential distribution is based on a counter current transfer, which takes place between nasal vein blood and brain arterial blood in the cavernous sinus-carotid artery complex. This model was used to investigate whether the antimigraine 5HT(1B/1D) receptor agonists sumatriptan and naratriptan may also be transferred by the system. The ratio of 'head':'heart' plasma concentrations obtained from two carotid catheters after intranasal administration was not different from 1.00 for either compound, and thus, there was no experimental evidence of a preferential local transfer of drug from the nose to the carotid artery circulation. However, plasma concentrations increased from the first minute after intranasal dosing suggesting that sumatriptan and naratriptan are absorbed into the general systemic circulation from the nasal cavity in rats in a first-order fashion with no lag time. This is consistent with the clinical onset of efficacy of sumatriptan after an intranasal dose which occurs as early as 15 min post dose.

ACETALDEHYDE: HAZARD CHARACTERIZATION AND EXPOSURE–RESPONSE ANALYSIS

Acetaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Based on short-term and long-term inhalation studies conducted in experimental animals, the target tissue has consistently been the site of entry, with non-neoplastic and neoplastic effects occurring principally in the upper respiratory tract at lowest concentrations. It is likely that both the genotoxicity and irritancy of acetaldehyde play a role in its carcinogenicity. A tolerable concentration of 390 μg/m3 has been derived based upon the benchmark dose associated with a 5% adverse effect for non-neoplastic lesions in the nasal cavities of rats in a short-term inhalation assay. Also, a tumorigenic concentration of 28 mg/m3 has been derived, based on the concentration associated with a 5% increase in the incidence of nasal adenocarcinomas and squamous cell carcinomas (combined) in rats exposed by inhalation.

A HYBRID COMPUTATIONAL FLUID DYNAMICS AND PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR COMPARISON OF PREDICTED TISSUE CONCENTRATIONS OF ACRYLIC ACID AND OTHER VAPORS IN THE RAT AND HUMAN NASAL CAVITIES FOLLOWING INHALATION EXPOSURE

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of inhaled vapors in the rat and human nasal cavity. Application to a specific vapor would involve the incorporation of the chemical-specific reactivity, metabolism, partition coefficients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application to a representative acidic vapor, acrylic acid, for interspecies tissue concentration comparisons to assist in risk assessment. By using the results from a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tissue doses between species were conducted. To make these comparisons, the assumption was made that the susceptibilities of human and rat olfactory epithelium to the cytotoxic effects of organic acids were similar, based on similar histological structure and common mode of action considerations. Interspecies differences in response were therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The results of simulations with the seven-compartment CFD-PBPK model suggested that the olfactory epithelium of the human nasal cavity would be exposed to tissue concentrations of acrylic acid similar to that of the rat nasal cavity when the exposure conditions are the same. Similar analysis of CFD data and CFD-PBPK model simulations with a simpler one-compartment model of the whole nasal cavities of rats and humans provides comparable results to averaging over the compartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose comparisons for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not involve significant histopathological damage to the nasal cavity.

INHALATION TOXICITY STUDIES OF THE a,ß-UNSATURATED KETONES:2-Cyclohexene-1-One

2-Cyclohexene-1-one (CHX) is a cyclic alpha,beta-unsaturated ketone with broad human exposure. CHX is an environmental pollutant and is present in tobacco smoke and in soft drinks sweetened with cyclamate. Interest in the toxicity of this class of compounds is due to their structural similarity to the cytotoxin acrolein. In a pilot study, rats and mice were exposed to 0, 20, 40, or 80 ppm CHX for 6 h/day. The study was terminated after 4 days due to acute toxicity in the high-dose groups. In a subsequent 14-day study, mice and rats were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day. All animals survived exposure until terminal sacrifice. Body weights were not significantly different from controls after 14 days of exposure. Liver/body weights were increased in male and female mice exposed to 5 and 10 ppm, and in male and female rats exposed to 10 ppm CHX. Ninety-day toxicity studies were conducted to provide data required to design chronic toxicity and carcinogenicity studies of CHX if it is determined such studies are necessary. Groups of 10 male and female F-344 rats and B6C3F1 mice were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day for 13 wk. All animals survived until sacrifice. Body weights were not significantly different from controls after 13 wk of exposure. Liver weights were increased in male and female mice exposed to 5 and 10 ppm and in male and female rats exposed to 10 ppm CHX. No adverse effects on bone-marrow micronuclei, sperm motility, or vaginal cytology were observed. Microscopic lesions included hyperplasia, and squamous metaplasia in the nasal cavity in rats and mice of both sexes at all doses. Nasal-cavity erosion and suppurative inflammation also occurred in high-dose mice. Larynx and lung were not affected in either sex or species. Dose-related hepatic centrilobular cytoplasmic vacuolation was seen in male rats only. These data suggest that CHX acts as an alkylating agent primarily producing toxicity at the exposure site.

Lipid emulsions as vehicles for enhanced nasal delivery of insulin

The objective of this work is to explore lipid emulsion based formulations of insulin as an enhancer of nasal absorption. Insulin was incorporated into the aqueous phases of water-in-oil (w/o) and oil-in-water (o/w) emulsions. The formulations were perfused through the nasal cavity of rats in situ. Enhancement of insulin absorption was observed when insulin was incorporated into the continuous aqueous phase of an o/w emulsion. The presence of a small fraction of oil droplets along with insulin in the aqueous phase appeared to favor insulin absorption. When the oil phase constitutes the external phase, as in w/o emulsion, no insulin absorption was noted. Inhibition of insulin absorption might arise from a rate limiting barrier effect of the membrane completely covered by a stagnant oil layer. The in situ model was validated by in vivo experiments, which also revealed an increase in insulin absorption with o/w emulsions. However at lower insulin doses there was no statistically significant enhancing effect. In situ perfusion experiments across rat nasal pathway appear to be an appropriate model to study the enhancement effect of nasal formulations.