Appropriate Route Of Administration Research Articles

Buprenorphine in the Intensive Care Unit: Commentary on the Unanswered Questions.

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the intensive care unit (ICU) including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients.

Peculiarities of personalized selection of antipsychotic drugs for schizophrenia treatment

Determining the optimal antipsychotic drugs, its effective dose, duration of therapy, form, and route of administration play a key role in the treatment of schizophrenia. In addition, special attention should be paid to the effectiveness of using different forms of antipsychotic drugs, in particular, the orally disintegrating form as exemplified by olanzapine. To study the peculiarities of a personalized approach in the use of antipsychotic drugs to achieve more effective results in treating schizophrenia, a content analysis was conducted using Ukrainian and English-language publications for the past 15 years. The search was conducted using the PubMed and CrossRef databases. An important conclusion is that the optimal therapeutic formula or drug should be selected individually, considering the specific patient's clinical condition. However, the most important factor in achieving successful results is the individually selected form and dose of the antipsychotic drugs. In addition to the patient's mental state, the choice of antipsychotic therapy is influenced by the spectrum of side effects, individual sensitivity to the active substance, pharmacological history, economic factors, etc. This is especially true for patients with insufficient adherence to treatment, which can often arise due to the side effects of drugs. In this case, it is important to correctly select both the active substance and the appropriate route of administration. Personalized selection of antipsychotic drugs also involves dynamic monitoring of changes in the patient's clinical condition, allowing for timely diagnosis of drug side effects, dose adjustments, or changes in the route of administration. These measures help increase patient adherence to treatment and improve their health-related quality of life.

Prescribing pattern of antibacterials as per dosage forms in various disease conditions at a rural tertiary care hospital

Background: The dosage form is useful in providing body to the drug, protecting the active ingredient of the drug and makes drug suitable for administration in a variety of ways. Selection of a suitable dosage form with appropriate route of administration in a particular infectious disease is an important aspect of rational prescribing. Aims and Objectives: For promoting the rational prescribing, the present study aims to estimate the pattern of antibacterial utilization in accordance with dosage forms in various disease conditions. Materials and Methods: A cross-sectional study was carried out which included 800 patients/prescription selected by simple random sampling technique. The study was conducted in OPD patients of SHKM, GMC, Nuh, Haryana for 12 months. Data analysis was done by using SPSS version 20. Results: Based on inclusion criteria, 800 patients were included for the study among 2105 screened patients. In our study, females (50.3%) out-numbered the male patients (49.8%). It was found that maximum antibacterials were prescribed in tablet form (74.6%), 13.7% were in drops form, followed by syrup (5.4%) and the remaining dosage forms (capsule, cream, gel, injection, ointment, and powder) were <6.3%. A total of 23.9% of the patients were suffering from respiratory infections, 23.6% were suffering from ear, nose, and throat infections, followed by genitourinary infections (10.6%). Conclusion: With the help of dosage forms and disease frequency patterns observed in this particular region, prescribers can improve and develop rational prescribing guidelines.

Optic Neuritis as Manifestation of Local Viral Encephalitis (Clinical Observation)

In the practice of an ophthalmologist and neurologist, the identification of relationship between optic neuritis and inflammation of the brain tissue is accompanied by significant diagnostic difficulties. In this regard, the role of interdisciplinary consultations is valuable, as an ophthalmologist knows the methods of ophthalmological diagnostics, which allow for topical diagnosis of the brain damage level, but for a neurologist, these methods are inaccessible. A clinical case of herpetic optoencephalitis (descending optic neuritis against the background of local encephalitis) in a teenager with a favorable outcome after conservative treatment is considered in the given paper. Conclusion: It is important to remember that during the optoencephalitis formation, its ophthalmic manifestations can remain not only the manifestation of this focal neurological pathology for a long time, but also require the timely appointment of appropriate routes of administration, doses and duration of etiotropic drugs use, therefore, the utmost diagnostic alertness regarding viral encephalitis (opticoencephalitis) is important at the slightest suspicion of a descending origin of the identified eye tissues inflammation.

Advanced Practice Provider Perspectives on Barriers to Managing Seizure Clusters

Patients with treatment-resistant epilepsy may experience seizure clusters. Such medical emergencies require urgent intervention with benzodiazepine rescue medication (RM). Approved RMs for administration in the community include rectal and intranasal routes. The latter provides a more socially acceptable, simple-to-administer option. All nurses, especially nurse practitioners, play a vital role in educating patients and caregivers on when and how to use RMs for seizure emergencies, as well as providing guidance on the selection of an appropriate route of administration. This article reviews barriers to effective management of seizure clusters and recommends treatment strategies to overcome them.

Wound Healing Properties of Natural Products: Mechanisms of Action.

A wound is the loss of the normal integrity, structure, and functions of the skin due to a physical, chemical, or mechanical agent. Wound repair consists of an orderly and complex process divided into four phases: coagulation, inflammation, proliferation, and remodeling. The potential of natural products in the treatment of wounds has been reported in numerous studies, emphasizing those with antioxidant, anti-inflammatory, and antimicrobial properties, e.g., alkaloids, saponins, terpenes, essential oils, and polyphenols from different plant sources, since these compounds can interact in the various stages of the wound healing process. This review addresses the most current in vitro and in vivo studies on the wound healing potential of natural products, as well as the main mechanisms involved in this activity. We observed sufficient evidence of the activity of these compounds in the treatment of wounds; however, we also found that there is no consensus on the effective concentrations in which the natural products exert this activity. For this reason, it is important to work on establishing optimal treatment doses, as well as an appropriate route of administration. In addition, more research should be carried out to discover the possible side effects and the behavior of natural products in clinical trials.

Challenges in tolerogenic dendritic cell therapy for autoimmune diseases: the route of administration.

Tolerogenic dendritic cells (tolDCs) are a promising strategy to treat autoimmune diseases since they have the potential to re-educate and modulate pathological immune responses in an antigen-specific manner and, therefore, have minimal adverse effects on the immune system compared to conventional immunosuppressive treatments. TolDC therapy has demonstrated safety and efficacy in different experimental models of autoimmune disease, such as multiple sclerosis (MS), type 1 diabetes (T1D), and rheumatoid arthritis (RA). Moreover, data from phase I clinical trials have shown that therapy with tolDCs is safe and well tolerated by MS, T1D, and RA patients. Nevertheless, various parameters need to be optimized to increase tolDC efficacy. In this regard, one important parameter to be determined is the most appropriate route of administration. Several delivery routes, such as intravenous, subcutaneous, intraperitoneal, intradermal, intranodal, and intraarticular routes, have been used in experimental models as well as in phase I clinical trials. This review summarizes data obtained from preclinical and clinical studies of tolDC therapy in the treatment of MS, T1D, and RA and their animal models, as well as data from the context of cancer immunotherapy using mature peptide-loaded DC, and data from in vivo cell tracking experiments, to define the most appropriate route of tolDC administration in relation to the most feasible, safest, and effective therapeutic use.

Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies.

Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a "galaxy" of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of "Exogenous Restitution of Intercellular Signalling of Stem Cells" (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.

Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19.

The recent outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China has spread rapidly around the world, leading to a widespread and urgent effort to develop and use comprehensive approaches in the treatment of COVID-19. While oral therapy is accepted as an effective and simple method, since the primary site of infection and disease progression of COVID-19 is mainly through the lungs, inhaled drug delivery directly to the lungs may be the most appropriate route of administration. To prevent or treat primary SARS-CoV-2 infections, it is essential to target the virus port of entry in the respiratory tract and airway epithelium, which requires rapid and high-intensity inhibition or control of viral entry or replication. To achieve success in this field, inhalation therapy is the most attractive treatment approach due to efficacy/safety profiles. In this review article, pulmonary drug delivery as a unique treatment option in lung diseases will be briefly reviewed. Then, possible inhalation therapies for the treatment of symptoms of COVID-19 will be discussed and the results of clinical trials will be presented. By pulmonary delivery of the currently approved drugs for COVID-19, efficacy of the treatment would be improved along with reducing systemic side effects.Graphical abstract

Evaluasi penggunaan profilaksis antibiotik bedah umum di Rumah Sakit Pemerintah di Yogyakarta

Surgical Site Infections (SSI) is an infection with surgery and surgical procedure, which occurs in the incision area or around the tissue. SSI increases the incidence of patients being admitted to the Intensive Care Units (ICU) by 60%, 5 times being hospitalized and 2 times dying. Giving prophylactic antibiotics before and after surgery will help reduce SSI if the administration of the appropriate type of drug, appropriate dose, appropriate time, and route of administration. The purpose of the study is to analyze the accuracy of the selection to reduce the incidence of SSI. This study is a cross-sectional study with retrospective data collection through the medical records of patients with general surgery in March 2019 with data from January until February 2019. The data collection technique was in the form of total sampling with inclusion and exclusion criteria. Data analysis was carried out by evaluating the use of prophylactic antibiotics and accompanying drugs descriptively and analytically in percentage. The result of the study using prophylactic antibiotics in 51 general surgery patients received the result that preoperative antibiotics were given in 98% of patients, all of the patients received antibiotics with the appropriate indication, an appropriate type of drug, and appropriate route of administration but 78,42% of patients received underdose for cefuroxime and ceftriaxone. Postoperative antibiotics were given to 80,39% of patients and all patients received appropriate indication and route of drug administration, but 15,68% of patients received an inappropriate type of antibiotic, namely ceftriaxone, and 52.93% of patients received an inappropriate dose, namely cefuroxime (underdose), cefazolin (underdose) and metronidazole (overdose). The results of this study can be used as a consideration for the selection of appropriate prophylactic antibiotics to prevent the occurrence of SSI. Keywords: prophylactic antibiotic, general surgery, cephalosporin

Inadequate practices for hepatic encephalopathy management in the inpatient setting.

Hepatic encephalopathy (HE) is an important complication of decompensated liver disease. Hospital admission for episodes of HE are very common, with these patients being managed by the hospitalists. These admissions are costly and burdensome to the health‐care system. Diagnosis of HE at times is not straightforward, particularly in patients who are altered and unable to provide any history. Precipitants leading to episodes of HE, should be actively sought and effectively tackled along with the overall management. This mandates timely diagnostics, appropriate initiation of pharmacological treatment, and supportive care. Infections are the most important precipitants leading to HE and should be aggressively managed. Lactulose is the front‐line medication for primary treatment of HE episodes and for prevention of subsequent recurrence. However, careful titration in the hospital setting along with the appropriate route of administration should be established and supervised by the hospitalist. Rifaximin has established its role as an add‐on medication, in those cases where lactulose alone is not working. Overall effective management of HE calls for attention to guideline‐directed nutritional requirements, functional assessment, medication reconciliation, patient education/counseling, and proper discharge planning. This will potentially help to reduce readmissions, which are all too common for HE patients. Early specialty consultation may be warranted in certain conditions. Numerous challenges exist to optimal care of hospitalized OHE patients. However, hospitalists if equipped with knowledge about a systematic approach to taking care of these frail patients are in an ideal position to ensure good inpatient and transition of care outcomes.

Nutritional support in the perioperative period of treatment of cancer patients: Retrospective cohort study

Background. The most important component of multimodality treatment of cancer is nutritional support. The management of the correct full nutritional support in the perioperative period will help to maintain body weight and muscle function, to reduce the frequency of development of postoperative complication severity and to reduce hospital length of stay. To provide full nutritional support is necessary to cover all energy requirements in patients (30 kcal/kg body weight per day), protein requirements (1.5 g of protein/kg of body weight per day) and eicosapentaenoic acid requirements (2 g/day), applying clinical nutrition through the appropriate routes of administration (oral, enteral, parenteral or combined).
 Materials and methods. The trial studied the dynamics of the nutritional status of 400 oncological patients who underwent surgical treatment at the Hertsen Moscow Oncology Research Institute the branch of the National Medical Research Radiology Centre from 2019 to 2021. The patients were divided into 2 groups: the main (n=200) and the control (n=200). The patients of the main group received full nutritional support. The control group consisted of the patients, according to retrospective analysis of the patients, with the traditional approach to nutritional support. The study included patients with nutritional deficiency confirmed by clinical criteria, as well as patients with malignant neoplasms of the upper gastrointestinal tract the gastrointestinal tract (esophagus and stomach), colon and rectum, as well as head and neck.
 Results. The application of nutritional therapy in the perioperative period can improve the nutritional status of the patients with head and neck and upper gastrointestinal tract cancer (the statistically significant increase in body weight by 1 kgs and 0.5 kgs, respectively). In patients with colorectal cancer, body weight during the treatment was stable with the tendency to increase by 0.4 kg. Perioperative nutritional support for patients with head and neck and upper gastrointestinal tract cancer showed statistically significant increase of the level of both complete protein by 2.8 and 4.1 g/l, respectively, as well as serum albumin by 5.2 and 3.3 g/l, respectively. The absolute lymphocyte count increased at the trend level. No statistically significant difference was obtained during treatment in patients with colorectal cancer. Nutritional support in cancer patients during the surgical treatment allowed to reduce the total number of surgical complications by 36%, including the incidence of anastomotic failure by 3 times (p=0.014), infectious complications by 1.5 times (p=0.074), to reduce the duration of stay in the intensive care unit, as well as inpatient stay in hospital to 0.3 and 1.08 bed days, respectively (p0.05).
 Conclusion. The application of nutritional support can help to reach more favorable perioperative course in cancer patients and also can lead to a decrease in the number of complications and early rehabilitation for patients, and on the other hand, will help to reduce the duration of stay in the intensive care unit as well as inpatient stay in hospital, reducing the cost of treating patients.

Диагностика и лечение нисходящего оптического неврита как проявления локального вирусного энцефалита (клиническое наблюдение)

It is well known that the incidence of encephalitis and optic neuritis is relatively high worldwide. Moreover, it is associated with high mortality and disability rates. At the same time, in 45–75% of cases, optic neuritis affects the central nervous system causing its disorders of various severity. Unfortunately, for practicing ophthalmologists and neurologists it is difficult to find a relationship between optical neuritis and inflammation of the brain tissue (especially when it is limited by a certain part of the brain) which underlies the diagnosis of opticoencephalitis. In this context, an ophthalmologist who can use methods of ophthalmological diagnostics will play a more important role. The ophthalmologist will be able to arrive at a topical diagnosis and localize a level of the brain tissue lesion, which is essential for determining the disease but cannot be done by neurologist. This publication presents our own clinical observation describing the specific aspects of diagnosis and treatment of descending optic neuritis co-occurring with viral inflammation of the brain tissue. The article provides analysis of the clinical signs which both impeded and facilitated the process of making the accurate diagnosis. It should be recognized that during the process of opticoencephalitis development, its ophthalmic manifestations for a long time will not only remain a single sign of this focal neurological disorder, but will require timely initiation of etiotropic drugs, using the appropriate routes of administration, doses, and duration of treatment. Thus, it is important to be aware and prepared for detecting viral encephalitis (opticoencephalitis) even at the slightest suspicion for a descending pathway of the diagnosed inflammation of the eye tissues. Keywords: optical neuritis, encephalitis, herpes virus, markers, antibodies, vesicles, ophthalmoscopy, perimetry. For citation: Korsakova N.V., Korsakova E.I. Diagnosis and treatment of descending optic neuritis developed as a manifestation of local viral encephalitis (a clinical case). Russian Journal of Clinical Ophthalmology. 2022;22(4):273–278 (in Russ.). DOI: 10.32364/2311-7729- 2022-22-4-273-278.

Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection.

Coronavirus disease-2019 (COVID-19) is caused by coronavirus-2 (SARS-CoV-2) and has produced a global pandemic. As of 22 June 2021, 178 million people have been affected worldwide, and 3.87 million people have died from COVID-19. According to the Centers for Disease Control and Prevention (CDC) of the United States, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. Since the location of initial infection and disease progression is primarily through the lungs, the inhalation delivery of drugs directly to the lungs may be the most appropriate route of administration for treating COVID-19. This review article aims to present possible inhalation therapeutics and vaccines for the treatment of COVID-19 symptoms. This review covers the comparison between SARS-CoV-2 and other coronaviruses such as SARS-CoV/MERS, inhalation therapeutics for the treatment of COVID-19 symptoms, and vaccines for preventing infection, as well as the current clinical status of inhaled therapeutics and vaccines.

Administration of 3% Sodium Chloride Through Peripheral Intravenous Access: Development and Implementation of a Protocol for Clinical Practice.

Patients with traumatic brain injury, cerebral edema, and severe hyponatremia require rapid augmentation of serum sodium levels. Three percent sodium chloride is commonly used to normalize or augment serum sodium level, yet there are limited data available concerning the most appropriate route of administration. Traditionally, 3% sodium chloride is administered through a central venous catheter (CVC) due to the attributed theoretical risk of phlebitis and extravasation injuries when hyperosmolar solution is administered peripherally. CVCs are associated with numerous complications, including arterial puncture, pneumothorax, infection, thrombosis, and air embolus. Peripherally infused 3% sodium chloride may bypass these concerns. To explore the evidence for peripherally infused 3% sodium chloride and to implement the findings. The Iowa Model of Evidence-Based Practice (EBP) was used to guide the project. A multidisciplinary team was established, and they developed an evidence-based protocol for the administration of 3% sodium chloride using peripheral intravenous catheters (PIVs), identified potential barriers to implementation, and developed targeted education to implement this practice change in a large academic medical center. Of the 103 patients in this project, only three (2.9%) identified adverse events. Two were associated with continuous infusions, and one was associated with a bolus infusion. This is the first study to describe a multidisciplinary protocol development and implementation process for the administration of 3% sodium chloride peripherally. Utilizing a multidisciplinary team is critical to the success of an EBP project. Implementing an evidence-based PIV protocol with stringent monitoring criteria for the administration of 3% sodium chloride has the potential to reduce adverse events related to CVC injury.

Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease

Recent advances in adeno-associated viral (AAV) capsid variants with novel oligotropism require validation in models of disease in order to be viable candidates for white matter disease gene therapy. We present here an assessment of the biodistribution, tropism, and efficacy of a novel AAV capsid variant (AAV/ Olig001) in a model of Canavan disease. We first define a combination of dose and route of administration of an AAV/Olig001-GFP reporter conducive to widespread CNS oligodendrocyte transduction in acutely symptomatic animals that model the Canavan brain at time of diagnosis. Administration of AAV/Olig001-GFP resulted in >70% oligotropism in all regions of interest except the cerebellum without the need for lineage-specific expression elements. Intracerebroventricular infusion into the cerebrospinal fluid (CSF) was identified as the most appropriate route of administration and employed for delivery of an AAV/Olig001 vector to reconstitute oligodendroglial aspartoacylase (ASPA) in adult Canavan mice, which resulted in a dose-dependent rescue of ASPA activity, motor function, and a near-total reduction in vacuolation. A head-to-head efficacy comparison with astrogliotropic AAV9 highlighted a significant advantage conferred by oligotropic AAV/Olig001 that was independent of overall transduction efficiency. These results support the continued development of AAV/Olig001 for advancement to clinical application to white matter disease.

Key Limitations and New Insights Into the Toxoplasma gondii Parasite Stage Switching for Future Vaccine Development in Human, Livestock, and Cats.

Toxoplasmosis is a parasitic disease affecting human, livestock and cat. Prophylactic strategies would be ideal to prevent infection. In a One Health vaccination approach, the objectives would be the prevention of congenital disease in both women and livestock, prevention/reduction of T. gondii tissue cysts in food-producing animals; and oocyst shedding in cats. Over the last few years, an explosion of strategies for vaccine development, especially due to the development of genetic-engineering technologies has emerged. The field of vaccinology has been exploring safer vaccines by the generation of recombinant immunogenic proteins, naked DNA vaccines, and viral/bacterial recombinants vectors. These strategies based on single- or few antigens, are less efficacious than recombinant live-attenuated, mostly tachyzoite T. gondii vaccine candidates. Reflections on the development of an anti-Toxoplasma vaccine must focus not only on the appropriate route of administration, capable of inducing efficient immune response, but also on the choice of the antigen (s) of interest and the associated delivery systems. To answer these questions, the choice of the animal model is essential. If mice helped in understanding the protection mechanisms, the data obtained cannot be directly transposed to humans, livestock and cats. Moreover, effectiveness vaccines should elicit strong and protective humoral and cellular immune responses at both local and systemic levels against the different stages of the parasite. Finally, challenge protocols should use the oral route, major natural route of infection, either by feeding tissue cysts or oocysts from different T. gondii strains. Effective Toxoplasma vaccines depend on our understanding of the (1) protective host immune response during T. gondii invasion and infection in the different hosts, (2) manipulation and modulation of host immune response to ensure survival of the parasites able to evade and subvert host immunity, (3) molecular mechanisms that define specific stage development. This review presents an overview of the key limitations for the development of an effective vaccine and highlights the contributions made by recent studies on the mechanisms behind stage switching to offer interesting perspectives for vaccine development.

Nutritional Issues in Head and Neck Cancer Patients.

The purpose of this paper is to update the oncologist on the correct approach to the nutritional care of the head and neck cancer patient. Recent scientific contributions on this issue, with a special emphasis on international guidelines and randomised clinical trials (RCTs), are reviewed. The following points are noteworthy: 1. Despite the advances in early diagnosis and modern treatment of head and neck cancer, this tumour still ranks first regarding frequency and severity of weight loss, both at the clinical presentation and during the therapy. 2. This is due to the combination of poor alimentation because of the tumour mass localization, as well as of the presence of an inflammatory response which furtherly drives catabolism. 3. Several studies have shown a very limited role for a dietary counselling unless it includes oral nutritional supplements which are protein or omega-3 fatty acid enriched. 4. A parental nutritional supplementation could represent an acceptable short-term alternative. 5. Long-term nutritional support relies on the use of percutaneous endoscopic gastrostomy (PEG), whereas the role of a prophylactic or “a la demande” PEG is still unsettled and requires further investigations. In conclusion, the nutritional approach using specific formulas and the appropriate route of administration should be part of the therapeutic armamentarium of the modern oncologist.

Involvement of the gabaergic, serotonergic and glucocorticoid mechanism in the anxiolytic-like effect of mastoparan-L

Mastoparan-L (mast-L) is a cell-penetrating tetradecapeptide and stimulator of monoamine exocytosis. In the present study, we evaluated the anxiolytic-like effect of mast-L. Preliminary pharmacological tests were conducted to determine the most appropriate route of administration, extrapolate dose and detect potential toxic effects of this peptide. Oral and intracerebroventricular administration of mast-L (0.1, 0.3 or 0.9 mg.kg−1), diazepam (1 or 5 mg.kg−1), buspirone (10 mg.kg−1) or vehicle 10 mL.kg−1 was carried out prior to the exposure of mice to the anxiety models: open field, light-dark box and elevated plus-maze. To characterize the mechanism underlying the antianxiety-like effect of mast-L, pharmacological antagonism, blood plasma analysis, molecular docking, and receptor binding assays were performed. The absence of a neurotoxic sign, animal's death as well as lack of significant changes in the relative organ weight, hematological and biochemical parameters suggest that mast-L is relatively safe. The anxiolytic-like effect of mast-L was attenuated by flumazenil (antagonist of benzodiazepine binding site) and WAY100635 (selective antagonist of 5-HT1A receptors) pretreatments. Mast-L reduced plasma corticosterone and lowered the scoring function at GABAA −18.48 kcal/mol (Ki = 155 nM), 5-HT1A −22.39 kcal/mol (Ki = 130 nM), corticotropin-releasing factor receptor subtype 1 (CRF1) −11.95 kcal/mol (Ki = 299 nM) and glucocorticoid receptors (GR) −14.69 kcal/mol (Ki = 3552 nM). These data fit the binding affinity (Ki) and demonstrate the involvement of gabaergic, serotonergic and glucocorticoid mechanisms in the anxiolytic-like property of mast-L.

Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice.

The cyclic hexapeptides PMX53 and PMX205 are potent noncompetitive inhibitors of complement C5a receptor 1 (C5aR1). They are widely utilized to study the role of C5aR1 in mouse models, including central nervous system (CNS) disease, and are dosed through a variety of routes of administration. However, a comprehensive pharmacokinetics analysis of these drugs has not been reported. In this study, the blood and CNS pharmacokinetics of PMX53 and PMX205 were performed in mice following intravenous, intraperitoneal, subcutaneous, and oral administration at identical doses. The absorption and distribution of both drugs were rapid and followed a two-compartment model with elimination half-lives of ∼20 min for both compounds. Urinary excretion was the major route of elimination following intravenous dosing with ∼50% of the drug excreted unchanged within the first 12 h. Oral bioavailability of PMX205 was higher than that of PMX53 (23% versus 9%), and PMX205 was also more efficient than PMX53 at entering the intact CNS. In comparison to other routes, subcutaneous administration of PMX205 resulted in high bioavailability (above 90%), as well as prolonged plasma and CNS exposure. Finally, repeated daily oral or subcutaneous administration of PMX205 demonstrated no accumulation of drug in blood, the brain, or the spinal cord, promoting its safety for chronic dosing. These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.