Nasal Cavity Of Rabbits Research Articles

Some aspects of enisamium iodide nasal spray safety: pre-clinical study results

The aim. To substantiate the safety using of the new nasal spray with Enisamium Iodide via study results of acute local drug-induced irritant action of the test object single-dose to eyes and nasal cavity mucosa.Material and methods. Enisamium Iodide 10 mg/mL (nasal spray) was the test object. The reference drug was 0.9 % saline. Flemish Giant rabbits were used to induce the experiment (2 groups, 9 rabbits in each group). All study objects were administered in single-dose into the eye conjunctival sacs (0.01 mL) and nasal passages (0.1 mL) by instillation. The eye examination we performed in different time observation point (through 1, 24, 48 and 72 h after drug instillation). Nasal endoscopy was used for control of nasal cavity in all stages of study (15 minutes before, 1-hour and 24 hours after drug instillation) under general anesthesia. The scales of the assessment were used to the result objectivity.Results. The total score was 0 points in all groups at all-time points according to the relevant scale and the scale of the assessment of rabbit nasal cavity mucosa by nasal endoscopy results. This corresponds to the condition of a healthy eye and healthy nasal mucosa.Conclusions. Enisamium Iodide 10 mg/mL (nasal spray) in the single-dose instillation into the rabbit eye conjunctival sacs and rabbit nasal passages did not show local drug-induced irritant action on the eye conjunctiva and nasal cavity mucosa in the experimental animals. Nasal endoscopy could be used as an informative visual method in preclinical studies

Anatomy and Surgical Approaches to the Rabbit Nasal Septum

The rabbit is the primary animal model used to investigate aspects of nasal surgery. Although several studies have used this model, none has provided a comprehensive analysis of the surgical anatomy and techniques used to gain access to the rabbit nasal fossae and septum. To describe and optimize the surgical anatomy and approach to the rabbit nasal vault and septal cartilage. In an ex vivo animal study conducted at an academic medical center, preliminary cadaveric dissections were performed on rabbit head specimens to establish familiarity with relevant anatomy and rehearse various approaches. Live Pasteurella-free New Zealand white rabbits (3.5-4.0 kg) were used to further develop this surgical technique developed here. Access of the nasal vault was gained through a midline nasal dorsum incision and creation of an osteoplastic flap with a drill. Submucosal resection was performed with preservation of the mucoperichondrium. All rabbits were monitored daily for 4 weeks in the postoperative period for signs of infection, pain, and complications. The study was conducted from June 1, 2014, to December 1, 2014. Surgical anatomy and techniques used to gain access to the rabbit nasal vault and harvest septal cartilage. Four Pasteurella-free New Zealand white rabbits (Western Organ Rabbit Co), ranging in age from 9 to 12 months and weighing between 3.5 and 4.0 kg, were used in this study. Initial dissections demonstrated the feasibility of harvesting septal cartilage while preserving the mucoperichondrial envelope. Access to the nasal vault through this 3-osteotomy approach allowed for maximal exposure to the nasal cavity bilaterally while maintaining the integrity of the mucoperichondrium following septal cartilage harvest. The maximum amount of bulk, en bloc, cartilage harvested was 1.0 × 2.5 cm. Following surgical dissection, all animals maintained adequate airway patency and support to midface structures. Furthermore, all specimens preserved the integrity of the mucoperichondrium, septum, vascular anatomy, and airway dynamics. No operative complications, postoperative airway compromise, or infections were observed. Access to the rabbit nasal vault and septal cartilage is feasible through a variety of surgical approaches and techniques. To date, this is the first study to meticulously document and review the surgical approaches to the rabbit nasal cavity. This approach describes a novel, 3-osteotomy method of accessing the nasal cavity bilaterally and successfully harvesting rabbit septal cartilage in a submucoperichondrial plane. The ability to preserve native anatomy and function allows for improved outcomes in translational and animal guided clinical research. NA.

Natural mucoadhesive microspheres of Abelmoschus esculentus polysaccharide as a new carrier for nasal drug delivery

This work describes the preparation and evaluation of mucoadhesive microspheres, using Abelmoschus esculentus polysaccharide as a novel carrier for safe and effective delivery of rizatriptan benzoate into nasal cavity. The polysaccharide was extracted from the fruit of A. esculentus and mucoadhesive microspheres were prepared by emulsification, followed by crosslinking using epichlorohydrin. Prepared microspheres were evaluated for size, morphology, swelling properties, mucoadhesive strength, encapsulation efficiency and drug release. Microspheres were found to release 50% of drug within 15 min and rest of the drug was released within 60 min. The drug release was found to decrease with increasing concentration of polysaccharide. To determine the retention time of the microspheres in the nasal cavity of rabbits, the microspheres were radiolabelled with 99mTc and subjected to gamma scintigraphy. The results showed a significant improvement in the nasal retention of the microspheres as compared to the aqueous solution of radiolabelled free-drug.

Stable Dry Powder Formulation for Nasal Delivery of Anthrax Vaccine

There is a current biodefense interest in protection against anthrax. Here, we developed a new generation of stable and effective anthrax vaccine. We studied the immune response elicited by recombinant protective antigen (rPA) delivered intranasally with a novel mucosal adjuvant, a mast cell activator compound 48/80 (C48/80). The vaccine formulation was prepared in a powder form by spray-freeze-drying (SFD) under optimized conditions to produce particles with a target size of D(50) = 25 μm, suitable for delivery to the rabbit nasal cavity. Physicochemical properties of the powder vaccines were characterized to assess their delivery and storage potential. Structural stability of rPA was confirmed by circular dichroism and attenuated total reflectance-Fourier transform infrared spectroscopy, whereas functional stability of rPA and C48/80 was monitored by cell-based assays. Animal study was performed using a unit-dose powder device for direct nasal application. Results showed that C48/80 provided effective mucosal adjuvant activity in rabbits. Freshly prepared SFD powder vaccine formulations or powders stored for over 2 years at room temperature elicited significantly elevated serum PA-specific and lethal toxin neutralization antibody titers that were comparable to that induced by intramuscular immunization with rPA. Nasal delivery of this vaccine formulation may be a viable alternative to the currently licensed vaccine or an attractive vaccine platform for other mucosally transmitted diseases.

In vivo evaluation of alginate microspheres of carvedilol for nasal delivery

Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid first pass metabolism and to improve bioavailability were prepared and evaluated. The microspheres were prepared by emulsification cross-linking method. Radiolabeling of CRV and its microspheres was performed by direct labeling with reduced technetium-99m ((99m) Tc). In vivo studies were performed on New Zealand white rabbits by administering the microspheres intranasally using monodose nasal insufflator. The radioactivity was measured in a well-type gamma scintillation counter. The noncompartmental pharmacokinetic analysis was performed. The pattern of deposition and clearance of the microspheres were evaluated using a radioactive tracer and the noninvasive technique of gamma scintigraphy. The clearance of alginate microsphere was compared with that of control lactose. The microspheres were nonaggregated, free flowing powders with spherical shape, and smooth surface. Pharmacokinetics study displayed an increase in area under the curve and hence in relative bioavailability when compared with intravenous administration of drug. The nasal bioavailability was 67.87% which indicates that nasal administration results in improved absorption of CRV. The results of gamma scintigraphy showed that the alginate microspheres had significantly reduced rates of clearance from the rabbit nasal cavity when compared with the control lactose.

Evaluation of the Rabbit Nasal Cavity in Inhalation Studies and a Comparison with Other Common Laboratory Species and Man

The rabbit is occasionally used for inhalation and intranasal safety assessment studies, but there are no detailed descriptions of the anatomy or histology of the rabbit nose. To address this deficit, the nasal cavities of thirty-two control adult rabbits were sectioned and examined to provide mapping of the main epithelial types and histological structures present within the cavity and turbinates. Four levels of the nasal cavity were prepared and examined using anatomic landmarks. Level I was sectioned immediately posterior to the incisors, Level II at the first palatal ridge, Level III immediately anterior to the first upper premolar teeth, and Level IV immediately anterior to the first upper molar. Level I was lined predominantly by squamous epithelium with small amounts of thick transitional epithelium, and examination is recommended only for studies involving test article administration via instillation. Level II was lined primarily with transitional and respiratory epithelia, whereas Levels III and IV were lined with respiratory and olfactory epithelia and often contained nasal-associated lymphoid tissue. The vomeronasal organs were evident only in Level II. The similarities and differences of these features are compared with those of other common laboratory species (rat, mouse, dog, and cynomolgus monkey) and man.

Evaluation of ISCOM matrices clearance from rabbit nasal cavity by gamma scintigraphy

Immune stimulating complexes and/or ISCOM matrices (adjuvant nanoparticles without antigen as a structural component) found potential applications as nasal vaccine adjuvant/delivery system owing to virus like particulate structure and saponin as potent Th1 adjuvant. One of important limiting factor for nasal vaccine delivery is the limited time available for absorption within the nasal cavity due to mucociliary clearance. In this report the clearance rate of ISCOM matrices from nasal cavity of rabbit was determined by gamma scintigraphy. ISCOM matrices were radiolabelled with (99m)Tc by direct labelling method using stannous chloride as a reducing agent. (99m)Tc labelled ISCOM matrices were administered into the nostril of female New Zealand rabbits and 1 min static views were repeated each 15 min until 4h. Clearance rate of ISCOM matrices from nasal cavity was calculated after applying the physical decay corrections. The mean labelling efficiency for ISCOM matrices were calculated as approximately 58.4%. ISCOM matrices showed slower clearance rate compared to sodium pertechnetate control solution (p<0.005) from nasal cavity that may be due to particulate and hydrophobic characters of ISCOM particles even though it was also cleared within 4h from nasal cavity. Mucoadhesive ISCOM formulations that retain in nasal cavity for longer duration of time may reduce the dose/frequency of vaccine for nasal immunization.

Single- and repeated-dose local toxicity in the nasal cavity of rabbits after intranasal administration of different glycols for formulations containing benzodiazepines.

To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 L, the maximum volume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formulations containing benzodiazepines and to document the effects to support clinical trials in man. After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single-dose studies with examinations 5 or 10min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)-glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14-day repeated-dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)-glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four-week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)-glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150-microL doses daily, but no abnormalities after one or three 100-microL doses daily. It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non-irritating drugs for short-term use in man.

NALT (nasal cavity-associated lymphoid tissue) in the rabbit

Due to its many advantages, interest in intranasal vaccination of domestic mammals and humans is currently increasing. Successful stimulation of the immune system by intranasal vaccines requires, however, the presence of lymphoid tissue in the nasal cavity. This nasal cavity-associated lymphoid tissue (NALT) has already been described in humans and many laboratory rodents, but data about rabbits are very scarce. For this purpose, histological sections of the nasal cavities of 10 female adult New Zealand White rabbits were examined for the presence of lymphoid tissue. Primary (I) and secondary (II) lymphoid follicles divided by interfollicular regions were mainly present at the bottom of the ventral nasal meatus and the nasopharyngeal meatus from 1 to 3.3 cm from the tip of the nose. In this region intraepithelial and lamina propria lymphocytes, and isolated lymphoid follicles (ILF's) were additionally seen at the dorsal and dorsolateral sides of the nasopharyngeal meatus and within the mucosae of the nasal conchae and the lateral nasal walls. Intraepithelial and lamina propria lymphocytes, and ILF's were, just like in humans, randomly distributed along the entire nasal mucosa. The rabbit NALT is more voluminous compared to rodents in which lymphoid tissue is only present at the bottom of the nasopharyngeal meatus. Since the relative volume of the rabbit nasal cavity is also similar to that of humans, the rabbit could be a valuable research model not only for animal but also for human intranasal vaccine development.

Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy

To develop a novel, in situ gel system for nasal delivery of scopolamine hydrobromide (SCOP) and study its efficacy on motion sickness. SCOP in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of viscosity, in vitro release, and nasal ciliotoxicity. Single photon emission computing tomography technique was used to evaluate the nasal residence time of gel containing (99m)Tc tracer. The antimotion sickness efficacy produced by the in situ gel formulation was investigated in rats and compared with those achieved after subcutaneous and oral administration. The viscosity of the gellan gum formulations either in solution or in gel increased with increasing concentrations of gellan gum. Its release in vitro was moderate in artificial nasal fluid. The micrographic results showed that in situ gels were safe, without nasal ciliotoxicity. In comparison with phosphate buffer saline, a prolonged radioactivity of (99m)Tc in the rabbit nasal cavity was observed after administration of the gellan gum formulation. Intranasal SCOP in situ gel at a dose of 100 microg/kg decreased symptoms of motion sickness significantly in comparison with subcutaneous and oral administration (P<0.01). SCOP nasal in situ gel is a safe and promising therapeutic alternative to existing medications for motion sickness.

Influence of deposition and spray pattern of nasal powders on insulin bioavailability

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol ® 974P (90/10, w/w) or a spray-dried mixture of Amioca ® starch/Carbopol ® 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability. To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.

Enhanced Delivery of Octreotide to the Brain via Transnasal Iontophoretic Administration

Transnasal drug delivery affords an opportunity to circumvent the blood–brain barrier and gain direct access to the brain. To date, this approach has used a relatively passive process relying on drug instillation high into the nasal cavity, formulation and gravity for drug delivery. The present study examined the use of an applied electrical field (transnasal iontophoresis or electrotransport) to actively drive a charged peptide, octreotide, into the rabbit brain. A simply designed electrode containing a reservoir of octreotide was placed deep into the nasal cavity on both sides. A return electrode was applied to the back of the head and a current strength of 3.0 mA was applied for 60 min. In control rabbits, electrodes were placed into the nasal cavity, but no current was applied (passive delivery). Additional control animals were given a bolus intra-arterial injection of octreotide. At the conclusion of drug delivery, animals were sacrificed and samples of brain, spinal cord, cerebrospinal fluid (CSF) and plasma were taken for measurement of octreotide levels by radioimmunoassay (RIA). In a second experiment, rabbits were exsanguinated prior to drug delivery to measure the ability of iontophoresis to transport octreotide into the brain in the absence of blood or CSF circulation. In both experiments, transnasal iontophoresis resulted in significantly elevated levels of octreotide in the brain, although results varied considerably due to electrode and tissue damage related to problems with electrode insertion into the rabbit's nasal cavity. Octreotide was present in samples extending from the olfactory bulb to the cerebellum with 2- to 13-fold increases in active compared to control/passive animals. High and sustained levels of octreotide were also present in the blood following transnasal delivery, but there were negligible amounts of octreotide in the brain following systemic administration indicating that the blood was not a significant route for drug redistribution. The results demonstrate that transnasal electrotransport is a unique, minimally invasive approach for enhancing drug delivery to the brain.

Scintigraphic evaluation in rabbits of nasal drug delivery systems based on carbopol 971p ® and carboxymethylcellulose

The residence time of apomorphine mucoadhesive preparations incorporating 99mTc labeled colloidal albumin in rabbit nasal cavity was evaluated by gamma scintigraphy. This technique was used to compare the nasal clearance of preparations based either on Carbopol 971P ® or lactose (control), each with and without apomorphine, or carboxymethylcellulose with apomorphine. The planar 1-min images showed an excipient-dependent progressive migration of radioactivity with time from the nasal cavity to the stomach and intestine. Thirty minutes post insufflation, the percentages of the formulations cleared from the nasal cavity were 47% for lactose, 26% for lactose/apomorphine, 10% for Carbopol 971P ®, and 3% for both Carbopol 971P ®/apomorphine and carboxymethylcellulose/apomorphine. Three hours post insufflation, the percentages of the formulations cleared from the nasal cavity were 70% for lactose, 58% for lactose/apomorphine, 24% for Carbopol 971P ®, 12% for Carbopol 971P ®/apomorphine, and 27% for carboxymethylcellulose/apomorphine. Apomorphine inhibited nasal mucociliary clearance since migration of the radioactivity administered with apomorphine containing preparations was in all cases slower than that of the corresponding powder without apomorphine. The peak plasma concentration of apomorphine was attained while all the formulations were still within the nasal cavity. The use of mucoadhesive polymers such as Carbopol 971P ® or carboxymethylcellulose in nasal dosage forms increases their residence time within the nasal cavity and provides the opportunity for sustained nasal drug delivery.

Development and Evaluation of Nasal Formulations of Ketorolac

Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 θ m to 63 θ m did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.

High absorbency and subchronic morphologic effects on the nasal epithelium of a nasal insulin powder dosage form with a soybean-derived sterylglucoside mixture in rabbits.

A soybean-derived sterylglucoside mixture (SG) is a potential enhancer of the nasal absorption of insulin. The aim of the study was to examine the absorption of insulin given as the powder dosage form with SG and excipient and to determine the subchronic effects of SG on the morphology of rabbit nasal epithelium. The insulin powder dosage form with SG was administered to the rabbit nasal cavity for five successive days. The average bioavailability and the average pharmacological bioavailability of insulin were about 25.0 and 61.6%, respectively. The nasal mucosa was taken from the nasal cavity and side-effects were investigated using an optiphoto light microscope. The insulin powder dosage form with SG produced no signs of inflammation, erosion or squamous metaplasia. These findings indicate that SG can be considered as a safe and effective enhancer and excipient in the nasal insulin powder dosage form.

Reversibility and clinical relevance of morphological changes after nasal application of ephedrine nasal drops 1%

To predict the toxicity of nasal formulations, various in vitro and in vivo techniques have been used. Many of these techniques are very sensitive and it is a general problem to extrapolate the results to the clinical situation. The aim of the present study was to establish a clinically well known nasal formulation, Ephedrine Nasal Drops 1%, DAK 63 (EBE), as a relevant reference for other nasal formulations with respect to histological changes to and reversibility of the nasal mucosa after repeated short-term nasal application to rabbits. This ephedrine formulation also contains the well known local irritants, benzalkonium chloride and EDTA, which is why it is abbreviated to EBE. Seventy five μ1 was applied in one nasal cavity of rabbits ( n = 3) four times per day for 1 week, while the other cavity served as a control. Twelve rabbits were divided into four groups and were sacrificed at 4 h and 1, 7 and 21 days after last nasal application, respectively. The macro- and microscopical changes of the nasal mucosa were recorded. Except for minor greyish exudates seen at 4 h, and a slight congestion of the mucosa seen at 4 and 24 h after application, there were no gross changes of the nasal mucosa. The microscopical examination, however, showed an extended infiltration of the mucosa by eosinophils, a general inflammatory reaction and a pronounced atrophy and disorganisation of the epithelium, which was furthermore void of goblet cells and cilia. These microscopical changes were seen after 4 h and, to a minor extent, 24 h after application. After 7 days, no changes could be found, indicating that they were reversible in less than 1 week. It is concluded that EBE may be a good reference in the predictive testing of local toxicity, with respect to a cost/benefit evaluation of nasal formulations, meant for acute or short-term treatment.

Establishment of a rabbit model for bovine herpesvirus type 5 neurological acute infection

This study was conducted to evaluate the suitability of the rabbit as a model for bovine herpesvirus 5 (BHV-5) acute infection. In a preliminary experiment, a total of 24 one-month old New Zealand white rabbits were inoculated with BHV-5 or bovine herpesvirus 1 (BHV-1) by the intraconjunctival, intracerebral or intranasal routes. BHV-5 or BHV-1 inoculated in the conjunctiva induced virus proliferation in the eye mucosae and the nasal cavity of rabbits without meningo-encephalitis. On the other hand, only BHV-5 infection by intranasal or intracerebral routes produced a fatal meningo-encephalitis. The intranasal route was used in a further experiment for the establishment of a rabbit model for BHV-5 infection. A total of 45 rabbits were inoculated intranasally with BHV-5 or BHV-1. The results showed that intranasal inoculation of BHV-5 strain N569 in rabbits was followed by the development of a lethal meningo-encephalitis for 66% of rabbits while all BHV-1 infected rabbits remained healthy throughout this experiment (28 days). Analysis between the mortalities of rabbits infected with BHV-5 and BHV-1 were highly significant ( p < 0.001). The presence of BHV-5 in the central nervous system (CNS) was confirmed by virus isolation (essentially the cerebrum, midbrain and pons) and by immunohistochemical staining of BHV-5 antigen (essentially in the neurons of the cerebrum) only in BHV-5 infected rabbits showing clinical signs of meningo-encephalitis. The findings obtained confirmed the suitability of a rabbit model for the establishment of BHV-5 neurological acute infection and also as a valuable tool for the comparative study of BHV-5 and BHV-1 neuropathogenicity.

Pharmacokinetics and Pharmacodynamics of Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) following Intranasal Administration in Rabbits

The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of G-CSF as well as their relationship following intranasal (i.n.) administration of aqueous rhG-CSF preparations with or without additives. In order to achieve a better understanding of the dosage regimen and the effectiveness of intranasally administered rhG-CSF in inducing leukopoiesis, we investigated rhG-CSF absorption and blood leukocyte dynamics with respect to dose in rabbits. RhG-CSF could be absorbed through the nasal cavity of rabbits when rhG-CSF aqueous preparations, especially those containing alpha-cyclodextrin (alpha-CyD) were intranasally administered. We found that serum G-CSF levels and the total count of leukocytes in peripheral blood (total blood leukocyte count) showed a dose-dependent increase with rhG-CSF. The area under the serum G-CSF concentration-time curve (AUC, a pharmacokinetic parameter) and the area under the increased total blood leukocyte count-time curve (AUL, a pharmacodynamic parameter) increased with increase of dose of rhG-CSF administered intranasally. Good agreement was observed between log AUC and AUL; thus, it is concluded that an increase of AUC leads to an increase in effectiveness of rhG-CSF in inducing leukopoiesis in rabbits. A novel rhG-CSF delivery system in the form of i.n. administration of rhG-CSF was thus achieved.

STUDIES ON SO2, NO2 AND NH3: EFFECT ON CILIARY ACTIVITY IN RABBIT TRACHEA OF SINGLE IN VITRO EXPOSURE AND RESORPTION IN RABBIT NASAL CAVITY.

AbstractDalhamn, T. and J. Sjöholm. Studies on SO2, NO2 and NH3: effect on ciliary activity in rabbit trachea of single in vitro exposure and resorption in rabbit nasal cavity. Acta physiol. scand. 1963. 58. 287—291. — One of the factors which determine the toxicity of pulmonary irritant gases, etc., presumably is their action on the ciliated epithelium of the respiratory tract. The degree to which such gases are resorbed in the mucous layer of the respiratory passages must also be taken into ac‐count when hygienic limits and allied questions are discussed. The present paper illustrates these two factors, viz., ciliostatic action and resorption, by experiments with three common respiratory irritant gases — sulphur dioxide, nitrogen dioxide and ammonia. As regards concentration required to arrest tracheal ciliary activity in vitro, the three gases varied considerably. The degree of resorption in the upper respiratory tract also showed wide variations. It seems probable that a gas which even in low concentration rapidly impairs ciliary activity and which is resorbed to a relatively slight degree can penetrate deeper into the bronchial tree and thus, on the stated assumptions, be more toxic than gases with the reverse characteristics.