Intranasal Drug Administration Research Articles

Efficacy and safety of intranasal dexmedetomidine premedication for children undergoing CT or magnetic resonance imaging: a systematic review and meta-analysis

Objective: To review the efficacy and safety in children receiving intranasal dexmedetomidine premedication before CT or magnetic resonance imaging (MRI). Methods: A literature search (search terms included "dexmedetomidine" "intranasal drug administration" "children" "CT" and "MRI") was conducted using Embase, PubMed, the Cochrane Library, ClinicalTrials.gov, CNKI, Wanfang, VIP database and Chinese Biomedical Literature Database (searched from inception to March 18, 2019). Randomized controlled trials of children receiving intranasal dexmedetomidine versus chloral hydrate, ketamine or midazolam premedication before CT or MRI were included. The Cochrane Reviewers' Handbook 5.1.0 was used to evaluate the quality of the enrolled studies. The primary outcomes were sedation success rate and sedation induction time. The secondary outcomes included respiratory depression, heart rate, systolic blood pressure and blood oxygen saturation. Statistical analyses were performed using the Review Manager 5.3 software. Results: A total of 1 167 participants in 9 randomized controlled trials were included. The results of meta-analysis showed that intranasal dexmedetomidine premedication provided higher sedation success rate than oral chloral hydrate (relative risk (RR) =1.13, 95% confidence interval (CI) 1.02 to 1.26, P=0.020). There was no significant difference between intranasal dexmedetomidine and midazolam. In addition, the sedation induction time of intranasal dexmedetomidine group was significantly shorter than that in the oral chloral hydrate group (weighted mean difference -1.49, 95% CI -2.87 to -0.11; P=0.030), but showed no significant difference as compared with that of intranasal ketamine or midazolam. The patients treated with intranasal dexmedetomidine also showed significantly lower heart rate (RR=4.78, 95%CI 1.85-12.35, P=0.001) and less respiratory depression (RR=0.28, 95%CI 0.09-0.87, P=0.030). There were no intergroup differences in systolic blood pressure and blood oxygen saturation. Conclusions: Intranasal dexmedetomidine provided more effective sedation and higher safety in children undergoing CT or MRI. As this meta-analysis is limited by the small sample size, further high-quality randomized controlled trials are needed.

Developing Biodegradable Nanoparticles Loaded with Mometasone Furoate for Potential Nasal Drug Delivery.

Intranasal drug administration is considered a routine in the treatment of many nasal conditions including chronic rhinosinusitis (CRS), which is a common disease involving long-term inflammation of the nasal mucosa. Topical nasal steroid treatment is safe and easy to use and plays a basic role in both nonsurgical and surgical treatments for CRS. Intranasal steroid therapy for various time intervals is commonly used before and after endoscopic CRS nasal surgeries to reduce inflammation and edema and to improve mucosal healing. The medication is currently administered via conventional nasal sprays; therefore, there is an incentive to develop more efficient drug delivery systems for the controlled release of topical steroids into the sinonasal cavities over a prolonged period of time. In this study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with mometasone furoate (MF) were generated using the nanoprecipitation method and characterized physicochemically and morphologically. MF NPs exhibited adequate physicochemical properties and high drug encapsulation efficiency and loading content. MF exhibited sustained release from NPs over 7 days in vitro with an initial burst release; various mathematical models were applied to determine the kinetics of drug release. Having demonstrated the ability to load MF in PLGA-NPs using the nanoprecipitation method for the first time, these NPs urge the need for additional investigations to demonstrate their therapeutic potential in nasal delivery applications.

Drug delivery through nose: A noninvasive technique for brain targeting

Majority of drugs are usually introduced through oral or intra-venous route for fast action, better patient compliance and ease of drug administration. However, the low bioavailability and limited brain exposure of orally administered drugs pose a huge challenge to treat neurodegenerative and psychiatric disorders. So, the situation demands for targeting the drug to brain. For brain targeting, a number of factors are considered viz. molecular weight, route of administration, lipophilic character of drug and blood brain barrier (BBB). These factors limit the movement of drug into brain tissue through BBB. To overcome these problems, intranasal drug administration is one of the promising routes that bypasses BBB and cuts down the dose to be administered with better brain exposure to drug. Nasal route has been used for the administration of antihistamines, local analgesics and corticosteroids intended for local drug delivery in nasal allergy, nasal congestion and nasal infection. However, systemic drug delivery through this route has also been explored in recent times. For nose to brain drug delivery, olfactory and respiratory region are utilized which also enable delivery of larger molecules to reach brain tissues. Such delivery systems are generally pH or temperature dependent. Certain diseases of nervous system like migraine, dementia, parkinsonism, epilepsy and Alzheimer’s disease can be successfully treated through this route. This review attempts to highlight the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of delivery systems, nasal formulations and applications of nasal route for delivery of various drugs.

The effectiveness of topical lidocaine in relieving pain related to intranasal midazolam sedation: a randomized, placebo-controlled clinical trial.

Intranasal midazolam (INM) is an increasingly popular agent for sedation in the emergency department and outside the hospital in physician, imaging, and dental offices, to facilitate diagnostic and minor surgical procedures and avoid the need for an operating room and general anesthesia. The use of INM has been commonly associated with a burning sensation of the nasal mucosa. Despite its significance, this subject has received little adequate research focus. The objective of the current study was to evaluate the effectiveness of topical lidocaine in relieving pain related to INM administration. This was a blinded, randomized placebo-controlled trial. Sixty-three uncooperative children undergoing dental treatment, aged 4 to 11 years, were randomly assigned to one of three groups to receive the drug nasally via a precalibrated spray as per the following assignments: group A received 0.5 mg/kg midazolam, group B received lidocaine 2% prior to 0.5 mg/kg midazolam, and group C received saline 0.9% (placebo), 0.5 mg/kg. Children were asked to record the degree of pain using the Wong-Baker faces scale. Parental acceptance was also rated. Topical lidocaine prior to INM administration reduced the burning sensation in the nasal mucosa and improved the drug acceptance. The median score of pain was 8, 1, and 4 in groups A, B, and C, respectively. The differences among the three groups were statistically significant (P > .05). The children's acceptance and parents' future acceptance regarding the intranasal drug administration was significantly higher in group B. INM administration results in burning sensation in the nasal mucosa with high levels of pain. Using topical lidocaine 2% counteracted the burning sensation and achieved a higher acceptance rate and lower pain scores.

Intranasal premedication with dexmedetomidine versus midazolam for pediatric patients in ophthalmic surgery: a randomized controlled study

Background Excessive anxiety has a bad implication on anesthetic practice in pediatric anesthesia; therefore, decreasing anxiety by premedication is an important issue. Intranasal administration of various drugs is an easy route with rapid onset of action allowing administration of variable drugs such as midazolam and dexmedetomidine used in pediatric preoperative sedation. Patients and methods A total of 64 pediatric patients who were subjected to elective ophthalmic surgeries received either 0.5 mg/kg midazolam or 1 μg/kg dexmedetomidine intranasally. Basal heart and respiratory rate, blood pressure, sedation score, and oxygen saturation were recorded initially and every 5 min till the transfer to the operating room. Sedation score was also assessed at 30 min after drug administration. Postoperative monitoring was continued, and any postoperative complications were recorded. Results Oxygen saturation, heart rate, systolic blood pressure, and respiratory rate values showed insignificant differences when both groups were compared together but showed significance differences when compared with the basal value in each group separately after 30 min. Sedation score was faster and child–parents separation score was higher in dexmedetomidine group when compared with midazolam group, and also both groups showed significant sedation score less than 3 when compared with the basal value at 15, 20, 25, and 30 min. Conclusion Midazolam and dexmedetomidine were nearly equally effective as intranasal premedication for pediatric patients subjected to elective ophthalmic surgery with minimal adverse effects, and we recommend the use of midazolam owing to its safety, effectiveness, and lower cost.

Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives.

Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs.

Recent Advances and Novel Approaches for Nose to Brain Drug Delivery for Treatment of Migraine

Background:Nasal drug delivery has been used since ancient times for therapeutic and recreational purposes. For the last decades, nasal drug delivery has been extended for drug delivery to the brain. Therefore, it is important to understand the several physiological and physicochemical factors of the nose for brain drug delivery.Objective:A major highlight of the present review article is the several aspects of the nose to brain delivery for migraine treatment. This review will help to understand different factors which are needed to be considered for intra-nasal formulations to achieve the desired therapeutic effects.Method:There are different drug delivery routes available for migraine treatment. Nasal route of administration may be optimal for migraine treatment which has better drug concentration in the brain. These approaches may be associated with limiting the adverse effects of drug therapeutics.Results:A list of total FDA approved approaches has been provided. Novel approaches used for drug targeting to get maximum drug concentration in the brain have been highlighted. Several novel drug delivery approaches such as nanoparticle, nanoemulsion, microspheres, etc. have been reported and better therapeutic effects have been observed. Among the novel approaches, some of them are currently under either Phase II or Phase III development but may prove to offer better clinical effects. These approaches would become the alternate choice for migraine treatment with patients experiencing symptoms consistent with gastrointestinal dysfunction associated with migraine.Conclusion:Intra-nasal administration of drugs for migraine treatment may offer an interesting alternative for achieving therapeutic effects of drugs which are comparable to the parenteral route. Nasal drug delivery can be an alternative route of drug administration for migraine treatment to achieve better bioavailability.

Nose-to-brain delivery of hyaluronate – FG loop peptide conjugate for non-invasive hypoxic-ischemic encephalopathy therapy

The intranasal drug administration has attracted great interest as a non-invasive route allowing targeted delivery of drugs directly to the brain. However, one of the main issues in nasal drug administration is mucociliary clearance. Hyaluronate (HA) has been widely used as a mucoadhesive excipient for ocular, rectal, and vaginal delivery. Here, FG loop peptide (FGL) was conjugated to HA for improving enzymatic stability and delivery efficiency from the nose to the brain. The successful conjugation of FGL to aldehyde modified HA was confirmed by gel permeation chromatography (GPC) and 1H nuclear magnetic resonance (NMR). The outstanding enzymatic stability of HA–FGL conjugate was also corroborated by the GPC. The HA–FGL conjugate showed enhanced binding affinity onto nasal epithelial cells. In addition, in vivo nose-to-brain delivery of HA–FGL conjugate could be visualized by using an IVIS imaging system and fluorescence microscopy. Finally, in vivo therapeutic effect of HA–FGL conjugate was successfully confirmed by histological analysis, transferase-mediated uridine 5-triphosphate-biotin nick end-labeling (TUNEL) assay, immunofluorescent staining, transmission electron microscopy (TEM), and rotarod tests in hypoxic-ischemic encephalopathy model animals.

Перспективы использования интраназального введения для доставки нейропептидов в головной мозг

Преимуществами интраназального метода введения (ИМВ) лекарственных препаратов является неинвазивность, безболезненность, простота и удобство применения. Показаны основные подходы, связанные с решением задач по эффективной доставке в мозг пептидов через слизистую носа с учетом особенности анатомии и физиологии носовой полости. ИМВ позволяет обойти гематоэнцефалический барьер, но сталкивается с проблемой протеолиза пептидов под действием компонентов слизи обонятельного эпителия — с ферментативным барьером. В качестве реперных пептидов для экспериментов in vivo использовали Pro-Gly-Pro, Pro-Gly-Pro-Leu, семакс, селанк. В плазме крови крыс максимальное содержание Pro-Gly-Pro-Leu, семакса, Pro-Gly-Pro и селанка составило 0,54, 1,69, 1,30 и 1,04 % от введенного количества меченого пептида. В мозге крыс соответствующие значения для Pro-Gly-Pro-Leu, семакса, Pro-Gly-Pro и селанка достигали 0,0013, 0,13, 0,04 и 0,16 %. Для уменьшения протеолиза семакса при преодолении им ферментативного барьера в нем заменяли метионин на аланин, глицин, треонин и триптофан. Для повышения устойчивости семакса использовали также липосомы и ацетилирование N-концевой аминокислоты. Показано, что использование N-ацетил-семакса наиболее перспективно. Для экспериментов in vitro использовали лейцинаминопептидазу (в инкубационной среде через 60 мин содержалось 12,6 % семакса), дипептидную пептидазу (95,4 %), карбоксипептидазу B (96,8 %) и Y (51,0 %), ферменты назальной слизи (4,0 %), микросомальной фракции мозга (9,0 %) и плазму крови (0,7 %) крыс. При протеолизе семакса в основном образуются His-Phe-Pro-Gly-Pro, Phe-Pro-Gly-Pro, Pro-Gly-Pro.

NOVEL DRUG DELIVERY SYSTEM THROUGH NASAL (NON-INVASIVE)

Intranasal route is the best method for high absorption and direct delivery to the brain. The interests and importance, of this route, are that the systemic effects of drugs when administered through the nasal route, have expanded over recent decades and it used for therapeutic and recreational purposes. In comparison with the parenteral route of drug administration, intra-nasal administration of drugs offers an interesting alternative for achieving systemic therapeutic effects of drugs. The oral administration of the drug produces low drug bioavailability, and this can be minimized using this nasal route. Moreover, the advantage of this route is that it can bypass the first-pass metabolism. Therefore, it is important to understand the potential and limitations of various nasal drug delivery systems. The aim of this review article is to discuss the various pharmaceutical dosage forms that have the potential to be utilized for local or systemic drug administration. It is assumingly expected that this review will help to understand about this route and also to develop suitable intra-nasal formulations to achieve specific therapeutic objectives. The different types of nasal drug formulations that can be used are nasal drops, nasal sprays, nasal gels, nasal suspensions and emulsion, and nasal powders.

Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.

Efficacy of two methods of intranasal administration of anaesthetic drugs in red-eared terrapins (Trachemys scripta elegans)

The aim of the study was to evaluate the efficacy of ketamine, dexmedetomidine, atipamezole and alfaxalone delivered by two methods of intranasal administration in terrapins. The two methods were used in 21 healthy adult female red-eared terrapins: (A) with fully extended neck and restrained head, (B) with head hidden inside the shell. Ketamine (10 mg/kg) and dexmedetomidine (0.2 mg/kg) were delivered using a micropipette in the left and the right naris, respectively. Atipamezole (2 mg/kg) was administered 60 minutes later. Heart rate, head withdrawal reflex, palpebral reflex, toe-pinch reflex on the pelvic limb and glottal control enabling the insertion of the tracheal tube were recorded at 10-minute intervals. After a washout period of six months, alfaxalone (5 mg/kg) was tested. The first measurement in the alfaxalone trial started 5 minutes after the drug was administered and continued at 10-minute intervals. Heart rate decreased significantly in response to both methods of ketamine and dexmedetomidine administration. There were no significant differences between methods in time to loss of reflexes and full recovery of reflexes. Intranasal administration of atipamezole enabled rapid return to full activity. Alfaxalone administration decreased heart rate non-significantly and did not result in loss of evaluated reflexes. Both methods of drug administration of ketamine, dexmedetomidine and atipamezole resulted in a safe form of sedation and recovery. Intranasal administration of 5 mg/kg of alfaxalone was not effective.

Intranasal drug administration for procedural sedation in children admitted to pediatric Emergency Room.

Pain relief is a very important aspect in Pediatrician's clinical practice. It is often thought that young children, particularly infants, do not perceive as much pain as adults because of their immature nervous system and that untreated pain would not have adverse long-term consequences. Instead, it has been demonstrated that infants and children experience pain in a similar manner to adults. Many factors, particularly emotional factors, can increase the child's pain perception. Children live with anxiety even minor procedures. This suggests the need for an adequate sedation and the way of sedation should be free of pain itself. We believe the route to be followed may be the intranasal (IN) administration of sedative drugs. We have conducted a brief review of the literature by Pubmed about the most commonly used sedative drugs: sufentanyl, fentanyl, midazolam, ketamine, nitrous oxide and dexmedetomidine. We have investigated in the literature the type of administration of IN drugs: drop instillation or by a mucosal atomizer device (MAD). In our study, it was noted that IN drugs administration is an effective and safe method to reduce anxiety and to deliver analgesia because it is practical and non-invasive. Moreover, therapeutic levels of sedatives are low due to the presence of a rich vascular plexus in the nasal cavity, which communicates with the subarachnoid space via the olfactory nerve and reduce the time of medication delivery, that is, the onset of action. The use of MAD even gives as better bioavailability of drugs. IN sedation via MAD is effective and safe and should be one of the first choices for procedural sedation in children.

The pharmacokinetics of intranasal droperidol in volunteers characterised via population modelling.

Background:Droperidol is used parenterally to treat nausea and vomiting, migraine and acute behavioural disturbance. Intranasal use is not reported for droperidol. Intranasal drug administration reduces need for intravenous line placement and risk of needle-stick.Objective:To model population pharmacokinetics of intranasal droperidol.Method:Single doses of intranasal and intravenous droperidol (0.02 mg/kg) were studied in an open-label crossover-trial in seven volunteers with a 1-week washout period. Blood samples collected over 10-h were analysed by liquid chromatography tandem mass spectrometer. Droperidol plasma concentrations following intravenous and intranasal administration were subjected to non-compartmental analysis and population pharmacokinetic modelling using S-ADAPT. Monte Carlo simulations were conducted for various potential intranasal dosage regimens.Results:The droperidol concentration-time profiles following intravenous and intranasal administration were best described by a model with two equilibrating disposition compartments and linear elimination. The apparent elimination clearance for intranasal dosing was 87.9 L/h and apparent central volume of distribution 18.2 L. Monte Carlo simulations of 5 mg droperidol (corresponding to the maximum volume that can be practically administered intranasal at a time) given intranasally at 0 and 5 min or 0 and 10 min indicated peak concentrations would reach those seen at 25 min after single intravenous administration of 1.5 mg. No adverse clinical effects or QT interval prolongation were observed.Conclusion:Given the reduced bioavailability of intranasal droperidol, Monte Carlo simulations suggested that it could potentially be used at a higher dose (2.5–5 mg) than currently used intravenously in clinical trials assessing the effectiveness in treatment of nausea, vomiting and migraine.

Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning

Organophosphate chemical threat agents (OP-CTA) exert toxic effects through cholinergic over-activation. However, after the initial cholinergic phase, the pathophysiology shifts to a non-cholinergic phase which leads to prolonged status epilepticus (SE), irreversible neuronal degeneration and long-term damage to the central nervous system. The efficacy of delayed treatments against OP-CTA is generally low due to the fact that most drugs fail to inhibit the later phase of non-cholinergic activation. Recently, we reported that intranasal brain delivery of obidoxime (OBD) provides complete neuroprotection against a lethal dose of paraoxon when administered 5min after intoxication. In follow-up studies, we examined the window of effectiveness and found that OBD lost effectiveness around 15min post-exposure, which corresponds to the onset of the non-cholinergic phase of intoxication. However, we observed that a brief isoflurane administration, the inhalation anesthetic used to facilitate intranasal drug administration, was effective against paraoxon-induced neurotoxicity. Thus, the present study aimed to investigate the time-course and dose-response efficacy of a brief 4min isoflurane administration as a treatment for neurotoxicity induced by OP-CTA. We found that isoflurane is a potent anti-seizure agent and neuroprotectant when administered between 20 and 30min after paraoxon exposure, stopping SE within 10min of administration and preventing acute neurodegeneration seen 24h later. We also found that the seizure blocking and neuroprotectant properties of isoflurane, when administered 30min after paraoxon, are dose-dependent. The effectiveness and current clinical use of isoflurane support its use as an innovative approach for post exposure treatment of organophosphate poisoning.

The effect of the ghrelin receptors inhibitor [D-Lys3]-GHRP-6 on the levels and metabolism of monoamines in symmetric brain areas of rats treated chronically with alcohol

Aim. In the course of the study, the impact of the ghrelin receptor GHS-R1a on the condition of symmetric monoaminergic systems of the rat brain was investigated. In particular, it was intended to find out whether the treatment with the ghrelin receptor antagonist [D-Lys3]-GHRP-6, recover the original content of monoamines and their metabolites in the brain of chronic alcoholic rats.
 Methods. The experiments were performed on 22 Wistar male rats. Experimental animals instead of drinking water received 10 % ethanol solution. Rats of the control groups continued to consume tap water. 6 months after the beginning of forced chronic alcohol treatement, 6 rats treated with alcohol, and 6 rats received water, in a month, once in three days, were instilled intranasally with the ghrelin antagonist [D-Lys3]-GHRP-6 (1 мкг/мкл, with 10 µl to each nostril). The other animals in the same manner were administered an equivalent volume of saline. 80 minutes after the last intranasal administration of drugs, rats were decapitated. With the HPLC-method, in the hypothalamus, olfactory tubercle, striatum and hippocampus of the left and right sides of the brain the contents of noradrenaline (NA), dopamine (DA), dioxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured. The results were processed by Student’s t-test using the statistical software package GraphPad Prism 6.0.
 Results. In the control rats (not exposed to either ethanol or drug) in the left striatum revealed a significant predominance of 5-HIAA compared to the same parameter of the other side of the brain. Under the condition of chronic ethanol intake, the initial left-sided asymmetry disappeared. Ethanol increased the content of 5-HT in the left hippocampus, 5-HIAA in the right olfactory tubercle and DA – in the right hypothalamus. [D-Lys3]-GHRP-6, when administered intranasally to the intact rats, significantly increased the 5-HIAA/5-HT ratio in the right olfactory tubercle, and the 5-HIAA, DOPAC and HVA levels – in the right striatum. In contrast, the left-sided effects in hippocampus were observed: the 5-HT levels increased and the 5-HIAA/5-HT ratio decreased. When instilled to intact rats, [D-Lys3]-GHRP-6 does not alter the monoaminergic systems of the hypothalamus. Between the monoaminergic systems of intact animals and alcoholic rats treated with [D-Lys3]-GHRP-6, the significant differences were shown. So, in the left hippocampus of alcoholic rats treated with [D-Lys3]-GHRP-6, the 5-HT level was higher, and the 5-HIAA/5-HT ratio was lower than in the control intact animals. Besides, in the right striatum of alcoholic rats treated with [D-Lys3]-GHRP-6, the DA metabolites levels were higher than those in the intact control animals. When comparing two groups of rats treated with [D-Lys3]-GHRP-6 (consumed water and alcoholic), the only difference was found: the alcoholic animals the content of DA in the left hypothalamus was lower than that of rats consumed water.
 Conclusion. Thus, by its influence on the monoaminergic system of the brain, [D-Lys3]-GHRP-6 is not an antagonist of the ethanol. Rather ethanol, when administered chronically, reduces the reactivity of the majority of monoaminergic systems to the ghrelin antagonist. Herewith, the forced chronic treatement with ethanol selectively increases the sensitivity to the [D-Lys3]-GHRP-6 in the hypothalamus DA-ergic system

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Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model.

The blood-brain barrier (BBB) limits entry of most chemotherapeutic agents into the CNS, resulting in inadequate exposure within CNS tumor tissue. Intranasal administration is a proposed means of delivery that can bypass the BBB, potentially resulting in more effective chemotherapeutic exposure at the tumor site. The objective of this study was to evaluate the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model. Three chemotherapeutic agents with known differences in CNS penetration were selected for intranasal administration in a NHP model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. Intravenous (IV) temozolomide (TMZ), oral (PO) valproic acid, and PO perifosine were administered to adult male rhesus macaques. The animals received a single dose of each agent systemically and intranasally in separate experiments, with each animal acting as his own control. The dose of the agents administered systemically was the human equivalent of a clinically appropriate dose, while the intranasal dose was the maximum achievable dose based on the volume limitation of 1mL. Multiple serial paired plasma and CSF samples were collected and quantified using a validated uHPLC/tandem mass spectrometry assay after each drug administration. Pharmacokinetic parameters were estimated using non-compartmental analysis. CSF penetration was calculated from the ratio of areas under the concentration-time curves for CSF and plasma (AUCCSF:plasma). Intranasal administration was feasible and tolerable for all agents with no significant toxicities observed. For TMZ, the degrees of CSF drug penetration after intranasal and IV administration were 36 (32-57) and 22 (20-41)%, respectively. Although maximum TMZ drug concentration in the CSF (Cmax) was lower after intranasal delivery compared to IV administration due to the lower dose administered, clinically significant exposure was achieved in the CSF after intranasal administration with the lower doses. This was associated with lower systemic exposure, suggesting increased efficiency and potentially lower toxicities of TMZ after intranasal delivery. For valproic acid and perifosine, CSF penetration after intranasal delivery was similar to systemic administration. Although this study demonstrates feasibility and safety of intranasal drug administration, further agent-specific studies are necessary to optimize agent selection and dosing to achieve clinically-relevant CSF exposures.

Pharmacological approaches for correction of thyroid dysfunctions in diabetes mellitus

Thyroid diseases are closely associated with the development of types 1 and 2 diabetes mellitus (DM), and as a consequence, the development of effective approaches for their treatment is one of the urgent problems of endocrinology. Traditionally, thyroid hormones (TH) are used to correct functions of the thyroid system. However, they are characterized by many side effects, such as their negative effect on the cardiovascular system as well as the ability of TH to enhance insulin resistance and to disturb insulin-producing function of pancreas, exacerbating thereby diabetic pathology. Therefore, the analogues of TH, selective for certain types of TH receptors, that do not have these side effects, are being developed. The peptide and low-molecular weight regulators of thyroid-stimulating hormone receptor, which regulate the activity of the thyroid axis at the stage of TH synthesis and secretion in thyrocytes, are being created. Systemic and intranasal administration of insulin, metformin therapy and drugs with antioxidant activity are effective for the treatment of thyroid pathology in types 1 and 2 DM. In the review, the literature data and the results of own investigations on pharmacological approaches for the treatment and prevention of thyroid diseases in patients with types 1 and 2 DM are summarized and analyzed.

Lipid Nanoparticles for Nasal/Intranasal Drug Delivery.

Studies on the development of drug delivery systems have increased because these systems have particular characteristics that allow them to improve therapeutics. Among these, lipid nanoparticles (solid lipid nanoparticles, SLNs; and nanostructured lipid carriers, NLCs) have demonstrated suitability for drug targeting. The nasal administration of drug-loaded lipid nanoparticles showed effectiveness in treating central nervous system (CNS) disorders, particularly neurodegenerative diseases, because the nasal route (also called intranasal route) allows direct nose-to-brain drug delivery by means of lipid nanoparticles. Nonetheless, the feasibility of this application remains an open field for researchers. Drawbacks must be overcome before reaching the clinic (e.g., drug absorption at subtherapeutic levels, rapid mucociliary clearance). The intranasal administration of drugs for systemic absorption is effective for treating other conditions, such as cardiovascular diseases, infections, severe pain, and menopausal syndrome. In the near future, it is expected that patients will benefit from the advantages of lipid nanoparticle-based formulations, via the nasal/intranasal route, which bypasses the blood-brain barrier (BBB), avoiding first-pass metabolism and gastrointestinal degradation. This review discusses the use of SLNs and NLCs for nasal drug administration. A brief description of the nasal route and the features of SLNs and NLCs is initially provided.