Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

Nasal Dermoid Cyst with Sinus Tract Intranasal Bone: A Case Report

Dermoid cysts are benign tumors originating from germ cells, which can form in various locations, including the nasal area in rare cases. They are of unknown exact etiology, but it is suggested that it is due to abnormal tissue migration during early embryonic development. Nasal dermoid cysts albeit rare, can present in various forms such as sinuses, fistulas, or intracranially extending tracts. They can be asymptomatic and incidentally discovered or present with a visible external mass or sinus that is either painful, infected or cosmetically concerning. If nasal dermoid cysts with an intra-nasal bone sinus tract are left untreated, they can lead to life-threatening complications. This report describes the case of a 6-year-old girl with a nasal dermoid cyst connected to a superficial punctum by an intra-nasal tract. She had undergone surgical excision of a nasal swelling previously diagnosed as a dermoid cyst. One year later, she returned to our clinic with a recurrence of the nasal swelling. Imaging tests revealed a nasal dermoid cyst with a tract extending to the nasal tip, without intracranial expansion. The cyst, along with the entire tract, was successfully removed surgically, and the postoperative follow-up indicated no complications. Histopathology confirmed the diagnosis of a dermoid cyst. This case underscores the significance of considering the dermoid tract in nasal cyst cases and the necessity of its complete removal to prevent recurrence.

Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider

The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great challenges due to the blood brain barrier(BBB)and limited drug distribution in the AD nidus sites.Thus,in this study,using vinpocetine(VIN)as a model drug,the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider,borneol(BOR),using nanoemulsion(NE)as the carrier.First of all,the NE were prepared and characterized.In vivo behavior of the NE after intranasal administration was investigated.Influence of BOR dose,BOR administration route on drug brain targeting behavior was evaluated,and the influence of BOR addition on drug brain subregion distribution was probed.It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery.Compared to intravenous injection,improved brain targeting effect was observed by intranasal route,and drug targeting index(DTI)of the VIN–NE group was 154.1%,with the nose-to-brain direct transport percentage(DTP)35.1%.Especially,remarkably enhanced brain distribution was achieved after BOR addition in the NE,with the extent depending on BOR dose.VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg,with the DTI reaching 596.1%and the DTP increased to 83.1%.BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route.Notably,BOR can remarkably enhance drug distribution in both hippocampus and cortex,the nidus areas of AD.In conclusion,in combination with intranasal delivery and the intrinsic brain guiding effect of BOR,drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly,providing the perquisite for improved therapeutic efficacy of AD.

Intranasal nerve growth factor for prevention and recovery of the outcomes of traumatic brain injury

Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.

Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury

The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.

INTRANASAL DELIVERY OF NERVE GROWTH FACTOR TO PROTECT THE CENTRAL NERVOUS SYSTEM AGAINST ACUTE CEREBRAL INFARCTION

Objective To confirmed reliability and feasibility of intranasal nerve growth factor (NGF) bypassing the blood-brain barrier and its potential neuroprotective effects on acute cerebral ischemia. Methods (1) To assay NGF concentrations in different brain regions after middle cerebral artery occlusion (MCAO).Rats were randomly divided into intranasal (IN) NGF, intravenous (IV) NGF, and untreated group (n= 4). The concentra-tions of NGF of different brain regions in the three groups after MCAO were measured by ELISA. (2) To observe neuro-protective action of NGF on focal cerebral ischemic damage. Rats were randomly assigned to 4 groups: IN vehicle, IN NGF, IV vehicle, IV NGF (n= 8). Treatment was initiated 30 minutes after onset of MCAO and given again 24 hours later. Three neurologic behavioral tests were performed 24 and 48 hours following onset of MCAO. Corrected infarct volumes were determined 48 hours after onset of MCAO. Results The olfactory bulb in IN NGF group obtained the highest concentration (3252 pg/g) of NGF among all regions, followed by the hippocampus. The NGF concentrations in the olfactory bulb and hippocampus in IN NGF group were markedly higher than that in IV NGF and control groups. The infarct volume in IN NGF group was markedly reduced by 38.8% compared with IN vehicle group. IN NGF group vestibulum function markedly improved compared with IN vehicle group at 24 and 48 hours after onset of MCAO (P 24 h = 0.02 and P 48 h = 0.04, respectively). Conclusion Intranasal NGF could pass through the blood-brain barrier, reach the central nervous system, reduce infarct volume, and improve neurologic function in rats following MCAO. Intranasal delivery of NGF may be a promising treat-ment for stroke.

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice

In Alzheimer’s disease and ischemic stroke,intranasal insulin can act as a neuroprotective agent.However,whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood.In this study,a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5,1,or 2 IU insulin via intranasal delivery,twice per day,until 24 or 72 hours after surgery.Compared with saline treatment,1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage,decreased blood-brain barrier permeability and neuronal degeneration damage,reduced neurobehavioral deficits,and improved the survival rate of mice.Expression levels of p-AKT and p-GSK3βwere significantly increased in the perihematoma tissues after intranasal insulin therapy.Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3βsignaling pathway.The study was approved by the Ethics Committee of the North Sichuan Medical College of China(approval No.NSMC(A)2019(01))on January 7,2019.

Intranasal delivery of paeoniflorin nanocrystals for brain targeting

Paeoniflorin(PA) is an anti-Parkinson Chinese medicine with inferior bioavailability and difficulty in delivery to the brain. This research is to develop an efficacious PA nanocrystal formulation(PA-NCs) that is suitable for intranasal administration to treat Parkinson’s disease(PD). PA-NCs were fabricated through an antisolvent precipitation method using TPGS as the stabilizer. The rod-shaped PA-NCs had particle size of 139.6 ± 1.3 nm and zeta potential of-23.2 ± 0.529 mV. A molecular dynamics simulation indicated that van der Waals forces are the primary drivers of interactions between PA and TPGS. In the ex vivo nasal mucosa permeation assay, the cumulative drug release at 24 h was 87.14% ± 5.34%,which was significantly higher than that of free PA. PA-NCs exhibited substantially improved cellular uptake as well as permeability on Calu-3 cells as compared to PA alone. FRET imaging analysis demonstrated that intact NCs could be internalized into Calu-3 cells.Moreover, PA-NCs conferred desirable protective effect against MPP+-induced SH-SY5Y cellular damage. Pharmacokinetic studies revealed a higher PA concentration in the brain following intranasal delivery of PA-NCs. In summary, the intranasal administration of PANCs is a promising treatment strategy for PD.

Intranasal neprilysin rapidly eliminates amyloid-beta plaques, but causes plaque compensations: the explanation why the amyloid-beta cascade may fail?

Neurodegenerative brain disorders are a major burden in our society,such as Alzheimer´s disease.In order to repair or prevent such diseases,drugs are designed which enter the brain,but the blood-brain barrier limits their entry and the search for alternative pathways is important.Recently,we reported that intranasal delivery of the amyloid-beta degrading enzyme neprilysin eliminated amyloid-beta plaques in transgenic Alzheimer´s disease mice.This review describes the anatomical structure of the intranasal pathway,explains the intranasal delivery of pure neprilysin,cell-loaded neprilysin(platelets)and collagen-embedded neprilysin to destruct amyloid-beta plaques in Alzheimer´s disease in transgenic APP_SweDI mice and hypothesizes why this may cause compensation and why the amyloid-beta cascade hypothesis may fail.

Intranasal sufentanil combined with intranasal dexmedetomidine: A promising method for non-anesthesiologist sedation during endoscopic ultrasonography

Intranasal sufentanil combined with intranasal dexmedetomidine exhibited an estimated sedation success probability as high as 94.9%,higher satisfaction scores,and only minor adverse events during endoscopic ultrasonography(EUS).This is a promising method for EUS sedation that does not require the presence of an anesthesiologist.

Determination of the ED95 of intranasal sufentanil combined with intranasal dexmedetomidine for moderate sedation during endoscopic ultrasonography

BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids.However,this combination has some limitations.Intranasal medication delivery may be an alternative to this sedation regimen.AIM To determine,by continual reassessment method(CRM),the minimal effective dose of intranasal sufentanil(SUF)when combined with intranasal dexmedetomidine(DEX)for moderate sedation of EUS in at least 95%of patients(ED95).METHODS Thirty patients aged 18-65 and scheduled for EUS were recruited in this study.Subjects received intranasal DEX and SUF for sedation.The dose of DEX(1μg/kg)was fixed,while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95.The sedation status was assessed by modified observer’s assessment of alertness/sedation(MOAA/S)score.The adverse events and the satisfaction scores of patients and endoscopists were recorded.RESULTS The ED95 was intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,with an estimated probability of successful moderate sedation for EUS of 94.9%(95%confidence interval:88.1%-98.9%).When combined with intranasal 1μg/kg DEX,probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows:0μg/kg SUF,52.8%;0.1μg/kg SUF,75.4%;0.2μg/kg SUF,89.9%;0.3μg/kg SUF,94.9%;0.4μg/kg SUF,98.0%;0.5μg/kg SUF,99.0%.CONCLUSION The ED95 needed for moderate sedation for EUS is intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,based on CRM.

Intranasal ketamine for the treatment of patients with acute pain in the emergency department

BACKGROUND:Pain in the emergency department(ED)is common but undertreated.The objective of this study was to examine the efficacy and safety of intranasal(IN)ketamine used as an analgesic for patients with acute injury with moderate to severe pain.METHODS:This study was a cross sectional,observational study of patients more than 8 years old experiencing moderate to severe pain[visual analog score(VAS)>50 mm].The initial dose of IN ketamine was 0.7 mg/kg with an additional dose of 0.3 mg/kg if VAS was more than 50 mm after 15minutes.Pain scores and vital signs were recorded at 0,15,30 and 60 minutes.Side-effects,sedation level and patient's satisfaction were also recorded.The primary outcome was the number of patients achieving≥20 mm reductions in VAS at 15 minutes.Other secondary outcome measures were median reduction in VAS at 15,30 and 60 minutes,changes of vital signs,adverse events,satisfaction of patients,and need for additional ketamine.RESULTS:Thirty-four patients with a median age of 29.5 years(IQR 17.5–38)were enrolled,and they had an initial median VAS of 80 mm(IQR 67–90).The VAS decreased more than 20 mm at15 minutes in 27(80%)patients.The reduction of VAS from baseline to 40 mm(IQR 20–40),20 mm(IQR 14–20)and 20 mm(IQR 10–20)respectively at 15,30 and 60 minutes(P<0.001).No critical changes of vital signs were noted and adverse effects were mild and transient.CONCLUSION:This study showed that IN ketamine is an analgesic choice for patients with acute injury in moderate to severe pain in an overcrowded and resource limited ED.

Case of Advanced Recurrent Glioblastoma Successfully Treated with Monoterpene Perillyl Alcohol by Intranasal Administration

We report a case of recurrent glioblastoma (GBM) successfully treated with the Ras inhibitor monoterpene perillyl alcohol by intranasal administration. A 37-years-old white woman had been previously submitted to three neurosurgical procedures, in June 2000 for radical tumor excision of grade II astrocytoma;in July 2003 for first recurrence of type IV glioma and in August 2004 for GBM recurrence. After last surgery, patient started a new cycle of chemotherapy but was refractory to treatment, presented clinical adverse effects and resonance image scan showed no reduction of tumoral lesion. Patient was then considered out of therapeutic possibilities and indicated for supportive treatment. On March 2005 patient joined Phase I/II clinical trial for assess the efficacy of the monoterpene POH, a Ras inhibitor. POH was administered by intranasal route four times a day (268 mg daily) as single chemotherapy agent. Image scans performed 3 and 5 years later revealed marked reduction of enhancing lesion. This illustrative case demonstrates that intranasal administration of the monoterpene POH as a single agent was an effective therapeutic strategy capable to sustain long-term regression of recurrent glioma without clinical and laboratory toxicity.

Antidepressant and cognitive activities of intranasal piperine-encapsulated liposomes

Antidepressant and cognitive effects of piperine -encapsulated liposomes (PL) were investigated in male Wistar rats. Oral piperine (5 mg/kg body weight/day) and intranasal PL (7.2 μg/day) were randomly assigned to daily administer for 14 days to rats which were subjected to forced swimming, Mor-ris water maze and spontaneous motor behavior tests. PL significantly exhibited anti-depression like activity and cognitive enhancing effects, in comparison to the control groups after the first dose (p < 0.01) and the effects could be maintained throughout the period of study. Quantitative analysis of the brain homogenates by HPLC indicated that piperine, delivered either orally or nasally, distributed to the hippocampus at a higher extent than the cortex and that the time to peak concentration of nasal PL was shorter than for the oral piperine. Intranasal PL was, thus, potential in delivery of piperine, at a low dose, to exert its an-tidepressant and cognitive enhancing activities.

Effect of intranasal stents(AlaxoLito, AlaxoLito Plus and AlaxoLito Xtreme) on the nasal airway:A case report

BACKGROUND The study of intranasal stents on the nasal airway is limited in the medical literature. The authors aim to provide objective measurements on their effects on the nasal airway. The aim is to study the feasibility of three novel intranasal stenting devices, AlaxoLito, AlaxoLito Plus, and AlaxoLito Xtreme, as treatment for nasal obstruction.CASE SUMMARY A 58-year-old man, who had right sided nasal obstruction, used stents during sporting activities intermittently for four years and subsequently in addition to intermittent sports use regularly for sleep for another two years. Magnetic resonance imaging(MRI) of the nasal passages and rhinomanometric measurements were taken with and without stents in situ. The stents tested are all braided from thin nitinol wires. The AlaxoLito Nasal Stent has a length of 35 mm.The AlaxoLito Plus and AlaxoLito Xtreme Nasal Stents have a length of 60 mm.Both have a diameter of about 10 mm in unloaded state and comprise a widened,ball-shaped section(which is positioned at the nasal alar) of about 11 and 14 mm,respectively. Rhinomanometric nasal airflow after application of the stents improved 1.11, 1.23, and 1.38 fold, respectively, with application of the AlaxoLito,AlaxoLito Plus and AlaxoLito Xtreme stents. MRI showed that after application of the stents, the nasal passage increased in diameter.CONCLUSION Intranasal stenting shows improvement in nasal airflow. Intermittent and regular longterm use had been shown to be safe, with no discomfort and no side effects.

Intranasal ketamine as an analgesic agent for acute pain management in emergency department: A literature review

Ketamine is a well-known dissociative anesthetic agent, and has been used over 50 years. Intranasal pathway is a mucosal way for absorbing agents to directly affect in brain via olfactory sheets, bypassing first pass metabolism and the blood brain barrier. The current uses of intranasal ketamine as an analgesic agent for acute pain management in emergency department are discussed in this review article. Using 'ketamine', 'pain or analgesia', and'intranasal' as keywords, a search of google scholar, Pubmed, web of science, and Medline database from 1970 until 2017 was performed. Finally, from 1204 papers extracted via primary search, 1088 papers were omitted and finally 10 studies were considered for further assessment. There were four observational studies, one case series and report and 5 clinical trials. Ketamine was used for acute pain control due to musculoskeletal trauma, burns, and painful procedures. A total of 390 cases were included in these studies. The studies used ketamine with doses ranging 0.45-1.25 mg/kg via intranasal pathway. Intranasal ketamine provides relatively rapid, well tolerated, and clinically significant analgesia for emergency department patients. Considering the lack of adequate studies and undetermined intranasal dose, it is better to conduct further high quality investigation in both adults and pediatrics.

Protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration

OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.

Comparison of pharmacokinetics of Alprazolam after intranasal and intragastric administration in rats

Objective To compare the pharmacokinetics of Alprazolam after intranasal and intragastic administration in rats and evaluate the practicability of Alprazolam as a nasal drug delivery system.Methods 12 rats were randomly divided into two groups.The fate of drug in the serum of rats was monitered after intranasal and intragastic administration of Alprazolam 2 mg·kg-1.Serum levels of Alprazolam were determined by reversed-phase HPLC with Diode array detectors(DAD).Chromatographic conditions were adopted with ODS column as solid phase,methanaol-0.02 M ammonium acetate(pH=5.0)(60∶40)as mobile phase at a flow rate of 1.0 mL·min-1.The detection wavelength was 223 nm.The concentration-time data were analyzed using 3P87 program,and the pharmacokinetic parameters were compared by t-test.Results The pharmacokinetic characteristics were fit to two and one compartment opened model after intranasal and intragastic administration of Alprazolam,respectively.The drug absorption was quicker and the serum concentrations of Alprazolam was significantly higher in rats after intranasal administration group than that intragastic administration group(P<0.05).The eliminate parameters between the two groups were no significant difference(P>0.05).Means of pharmacokinetic parameters in intranasal and intragastic groups were:Ka 37.35±22.98 vs 11.57±12.47 h-1(P<0.05),t1/2ka0.025±0.013 vs 0.156±0.122 h(P<0.05),β(Ke)0.3131±0.1194 vs 0.3091±0.1216 h-1(P>0.05),t1/2β(t1/2Ke)2.51±0.99 vs 2.54±0.97 h(P>0.05),tmax 0.156±0.069 vs 0.618±0.414 h(P<0.01),Cmax 353.11±96.30 vs 62.09±35.08 μg·L-1(P<0.01),AUC 1111.6±473.2 vs 274.1±185.3 μg·L-1·h(P<0.01).Conclusions Alprazolam was absorbed quickly in rats after intranasal administration.And the serum concentration and bioavailability can be significantly increased after intranasal administration,which may be an effective preparation as nasal drug delivery system.

Effect of intranasal structure-normalizing surgery on allergic rhinitis: A primary report of 41 cases

Objective: To evaluate intranasal structure-normalizing Surgery (ISNS) in the managemint of allergic rhinitis Methods: 41 cases of allergic rhinitis beated with ISNS were retrospectively analysed. The efficiency of ISNS was quantita- quantitatively evaluated with scoring the symptoms and signs before and for ISNS according to the National Criteria of Haikou Revision in 1977. Results: The loud efficient rate was 75% for ISNS in 41 cases of allergic rhinitis. Conclusion: ISNS is an valuable procedure and should be firstly considered in treatment of allergic rhinitis when abnormality of intranasal structure exists.

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

Nasal application of benzodiazepines might be an alternative to intravenous administration in acute clinical situations such as seizures emergencies. However, irritation and pain as well as symptoms like teary eyes, dizziness, discomfort, nasal drainage and bad taste usually accompany subject received midazolam and diazepam via the nasal route. The purpose of this study was to evaluate the use of a new alcohol-free microemulsion system as a carrier for diazepam or midazolam given intranasally. Midazolam (base) or diazepam was solubilized in the microemulsion to obtain a high drug concentration of 25 mg/g (2.5% by weight), to provide 2.5 mg drug in 100 μl spray (d ≈ 1.00 g/ml). The nasal absorption of both drugs from the same microemulsion formulation (containing 20% aqueous phase) was found to be fairly rapid after administration of 0.4 mg/kg to rabbits. The absolute bioavailability of diazepam after intranasal administration using this formulation was 33.45% ± 12.36% and the tmax was 18.33 ± 23.09 min, which was twice longer than the tmax obtained after midazolam administration, 9.25 ± 6.75 min. The pharmacokinetic parameters of midazolam in W/O (20% water) microemulsion and their comparison with midazolam in O/W (50% water) microemulsion have shown that both formulations resulted in a relatively short time to reach the peak plasma level (tmax), that is, 9.25 ± 6.75 min and 6.75 ± 5.67 min, respectively. However, the peak plasma levels (Cmax) and the absolute bioavailability (FA) of midazolam were significantly higher after administration of the W/O formulation than those obtained after application of O/W formulation, i.e., 46.62 ± 17.38 μg/ml vs. 15.44 ± 4.00 μg/ml, and 35.19% ± 11.83% vs. 19.83% ± 16.32%, respectively. Our results suggest that the new microemulsion system may be useful for getting rapid-onset of midazolam and diazepam following intranasal administration, resulting in reasonable peak plasma levels and bioavailability, but most importantly, providing a high measure of tolerability and comfort.