Alternative Routes Of Administration Research Articles

OP23 Efficacy and safety of vedolizumab SC in patients with moderately to severely active Crohn’s disease: Results of the VISIBLE 2 study

Abstract Background Vedolizumab (VDZ) is a gut-selective, humanised, monoclonal α 4β 7 integrin antibody for the treatment of patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). VDZ is currently an intravenous (IV) therapy; a subcutaneous (SC) formulation is under development to provide patients with an alternative route of administration for maintenance treatment for UC and CD. Here we present the first data from the phase 3 study of VDZ SC maintenance treatment in CD. Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a randomised, double-blind, placebo (PBO)-controlled phase 3 trial of VDZ SC as maintenance treatment in adults with moderately to severely active CD. Patients (n = 644) received open-label VDZ 300mg IV induction therapy at Weeks 0 and 2. At Week 6, clinical responders (defined as patients with a ≥70-point decrease in CD Activity Index [CDAI] from baseline) were randomly assigned to receive vedolizumab SC (108 mg every 2 weeks [Q2W]), or placebo (Q2W) for up to 52 weeks. The primary endpoint was clinical remission at Week 52 (defined as CDAI score ≤150). Rank-ordered secondary endpoints were enhanced clinical response at Week 52 (a drop of ≥100 in CDAI score), corticosteroid (CS)-free clinical remission at Week 52, and clinical remission at Week 52 in anti-tumour necrosis factor (TNF)-naïve patients. Finally, VDZ immunogenicity and predefined adverse events of special interest were assessed. Results Patients who responded to VDZ IV induction at Week 6 (n = 409) were randomised to VDZ SC (n = 275) or PBO (n = 134) maintenance and received at least 1 dose of study drug; 61% and 53%, respectively, were previously exposed to anti-TNF therapy. At Week 52, 48.0% of patients on VDZ SC vs. 34.3% on PBO were in clinical remission (p = 0.008, Figure). Enhanced clinical response at Week 52 was reached by 52.0% vs. 44.8% of patients on VDZ SC vs. PBO, respectively (p = 0.167). Among patients on concomitant CS at baseline (VDZ SC, n = 95; PBO, n = 44), 45.3% receiving VDZ SC vs. 18.2% receiving PBO achieved CS-free clinical remission at Week 52. Of anti-TNF-naïve patients (VDZ SC, n = 107; PBO, n = 63), 48.6% vs. 42.9% were in clinical remission at Week 52 in the VDZ SC and PBO arms, respectively. Injection-site reactions were reported for <3% of patients treated with VDZ SC. Serious infections, malignancy, and liver injury were ≤5% for both arms. Anti-VDZ antibodies were detected in 7 (2.5%) patients treated with VDZ SC arm; 4 of 7 patients developed neutralising antibodies. No new safety signals were observed. Conclusion Among VDZ IV induction responders, significantly more patients on maintenance VDZ SC than PBO achieved clinical remission at Week 52. The safety findings with VDZ SC remain in line with the known safety profile of VDZ IV in patients with CD.

Insulin-delivery methods for children and adolescents with type 1 diabetes

Efforts directed toward restoring normal metabolic levels by mimicking the physiological insulin secretion, thereby ensuring safety, efficacy, minimal invasiveness and conveniences, are of great significance in the management of type 1 diabetes among children and adolescents. Regardless of the various technologies being discovered in addressing invasiveness and enhancing medication adherence in the management of type 1 diabetes, yet limited success had been observed among children and adolescents. The multiple daily subcutaneous insulin injections route using vial and syringe, and occasionally insulin pens, remain the most predictable route for insulin administration among children and adolescents. However, this route has been associated with compromised patient compliance, fear of injections and unacceptability, resulting in poor glycemic control, which promote the demand for alternative routes of insulin administration. Alternative routes for delivering insulin are being investigated in children and adolescents with type 1 diabetes; these include the hybrid closed-loop ‘artificial pancreas’ system, oral, inhalation, intranasal routes, and others. This review article explores the current advances in insulin-delivery methods that address the needs of children and adolescents in the treatment of type 1 diabetes.

Intravenous versus Subcutaneous Immunoglobulin in Primary Immunodeficiency: Real-World Evaluation of Safety, Efficacy, and Patient Perceptions

Background: Patients with primary immunodeficiency disorders (PIDD) typically require life-long immunoglobulin (IG) replacement therapy. There are two routes of IG administration: intravenous (IVIG) and subcutaneous (SCIG). To better understand routes of IG administration in the real-world, use in a home infusion setting was evaluated. Objective: To evaluate the safety, efficacy, and perceived responses in PIDD patients on IVIG versus SCIG in a realworld, home infusion setting. Methods: Retrospective data were collected from 2010 to 2018 from a national home infusion pharmacy of PIDD patients receiving IVIG or SCIG therapy for at least 6 months with evaluations for safety, efficacy, and patient perception of response. Results: A total of 149 patients were identified for analysis: IVIG (n=84) and SCIG (n=65). Overall, patients in the SCIG group had higher rates of local adverse reactions, while patients receiving IVIG had higher rates of systemic adverse reactions. Both SCIG and IVIG were effective as the majority of patients had ≤ 1 infection or hospital visit within the study period. However, patients in the SCIG group had fewer hospital visits and lower rates of infections overall. Patients receiving SCIG also perceived a faster speed of response. Conclusion: SCIG infusions are safe, efficacious, and well tolerated when compared to IVIG, providing PIDD patients with an alternative route of IG administration. Notably, hospital visits and infection rates were significantly reduced in patients receiving SCIG. The overall findings of this study contribute to growing evidence that demonstrates the benefits of SCIG in adult and pediatric patients with PIDD.

Allergy immunotherapy for inhalant allergens: Strategies to improve efficacy.

Background: Allergy immunotherapy (AIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is an effective and safe treatment for allergic rhinitis and allergic asthma due to inhalant allergens. However, there are many variables in how it is administered. Objective: To review the evidence that suggests the optimum practices to enhance the efficacy of AIT. Methods: Articles that reported the results of various approaches to the practice of AIT and evidence-based guidelines were consulted for guidance on what approaches would enhance the efficacy of AIT. Results: Evidence is presented that supports optimum dosing for SCIT, a discussion of dosing with liquid SLIT, the management of the patient who is polyallergic, considerations in mixing allergen extracts, advantages and disadvantages of different up-dosing regimens with SCIT, the optimum duration of AIT, the comparative efficacy of SCIT and SLIT, and improving adherence to AIT. Also reviewed were two approaches, the use of adjuvants and of alternative routes of administration of currently available extracts, which may be useful in the future after further studies have defined their effectiveness. Conclusion: Although there is still controversy about some aspects of AIT, there is literature to support approaches that enhance the efficacy of both SCIT and SLIT.

Transmucosal drug administration as an alternative route in palliative and end-of-life care during the COVID-19 pandemic.

The Coronavirus disease 2019 (COVID-19) pandemic has led to a surge in need for alternative routes of administration of drugs for end of life and palliative care, particularly in community settings. Transmucosal routes include intranasal, buccal, sublingual and rectal. They are non-invasive routes for systemic drug delivery with the possibility of self-administration, or administration by family caregivers. In addition, their ability to offer rapid onset of action with reduced first-pass metabolism make them suitable for use in palliative and end-of-life care to provide fast relief of symptoms. This is particularly important in COVID-19, as patients can deteriorate rapidly. Despite the advantages, these routes of administration face challenges including a relatively small surface area for effective drug absorption, small volume of fluid for drug dissolution and the presence of a mucus barrier, thereby limiting the number of drugs that are suitable to be delivered through the transmucosal route. In this review, the merits, challenges and limitations of each of these transmucosal routes are discussed. The goals are to provide insights into using transmucosal drug delivery to bring about the best possible symptom management for patients at the end of life, and to inspire scientists to develop new delivery systems to provide effective symptom management for this group of patients.

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin.

The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol−1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.

Diagnosis and prevention of infectious complications of acute pancreatitis

Based on the analysis of domestic and foreign literature, promising and most frequently used methods of diagnosis and prevention of infectious complications of acute pancreatitis are highlighted. The literature increasingly raises the question of the insufficient efficiency of the study of the concentration of C-reactive protein and procalcitonin samples and suggests new markers of systemic infection. The interest of experts in recent years turned to the study of CD64-neutrophil index, which showed a number of advantages over the previously mentioned methods of diagnosis of infectious complications of acute pancreatitis. Presepsin is actively investigated from humoral markers of inflammation. In prospective studies, he also showed high sensitivity and specificity in the diagnosis of pancreatogenic infection. Approaches to the study of the cultural composition of flora in the developed infectious complications have changed. Gas chromatography - mass spectrometry and matrix associated laser desorption/ionization combined with time-of-flight separation and ion detection mass spectrometry are successfully used in this field. From the methods of prevention of infectious complications of acute pancreatitis actively investigated the effectiveness of minimally invasive surgical techniques, selective intestinal decontamination, alternative routes of administration of drugs. In this area, the latest trend is the most popular, which is confirmed by publications on the effectiveness of endarterial and endolymphatic administration of antibiotics and other drugs. Unsolved problems of accurate prediction, prevention, timely diagnosis of infectious complications of acute pancreatitis justifies the urgency of the problem and the need for further comprehensive research in this area.

20 Antibody response, lesions, and performance do not differ between injection site (ischiorectal fossa or neck) after multivalent modified-live virus vaccination in Jersey steers

Abstract The study objective was to explore the feasibility of an alternative injection site, ischiorectal fossa (IRF), for modified-live virus (MLV) vaccination in Jersey steers. We hypothesized administration of MLV in the IRF would not cause injection site lesions and result in similar antibody response against bovine viral diarrhea virus (BVDV) compared to the neck. Jersey steers (n = 28; BW=517 ± 116 kg) were stratified by a previously assigned growth implant treatment and day-35 BVDV antibody titer and randomly assigned to 1 of 2 treatments with injection treatment equivalently represented in each of 2 pens. Treatments consisted of: 1) 2 mL MLV vaccine administered s.c. in the neck (NECK); or 2) 2 mL MLV vaccine administered s.c. in the IRF. Blood was collected on days -35, 0, 35, 70, and 105 to determine BVDV-specific antibody titers using the virus neutralization assay and BW was recorded on the same days to determine gain performance. Steers were harvested on day 106 and examined for lesions respective to injection site. Antibody titers and performance variables were statistically analyzed via a mixed model with animal as the experimental unit. Concentration of BVDV antibody increased (P = 0.05) with time, but there was no treatment difference (P = 0.94) or treatment × day interaction (P = 0.70). There was no treatment difference for BW on any day (P ≥ 0.78). There was also no treatment difference in ADG (P ≥ 0.45). However, there was a period effect, where ADG was reduced markedly (P < 0.0001) for the day 0 to 35 interim period immediately following MLV vaccination compared to day -35 to 0 (0.79 vs. 0.18 kg/d). No injection site lesions were observed during harvest and results from BVDV antibody titers and performance indicate IRF as a potential alternative route of administration for MLV vaccines.

Structural Refinement of Glucagon for Therapeutic Use.

Glucagon counters insulin's effects on glucose metabolism and serves as a rescue medicine in the treatment of hypoglycemia. Acute hypoglycemia, a common occurrence in insulin-dependent diabetes, is the central obstacle to correcting high blood glucose, a primary cause of long-term microvascular complications. As a result, there has been a resurgence of interest in improved glucagon therapy, including nonconventional liquid formulations, alternative routes of administration, and novel analogs with optimized biophysical properties. These options collectively minimize the complexity of glucagon delivery and enable its application in ways not feasible with conventional emergency rescue kits. These advances have indirectly promoted the integrated use of glucagon agonism with other hormones in a manner that runs counter to the long-standing pursuit of glucagon antagonism. This review summarizes novel approaches to glucagon optimization, methods with potential application to the broader family of therapeutic peptides, where biophysical challenges may be encountered.

Intranasal Pregabalin Administration: A Review of the Literature and the Worldwide Spontaneous Reporting System of Adverse Drug Reactions.

Background: It is repeatedly reported that pregabalin (PRG) and gabapentin feature a potential for abuse/misuse, predominantly in patients with former or active substance use disorder. The most common route of use is oral, though reports of sublingual, intravenous, rectal, and smoking administration also exist. A narrative review was performed to provide an overview of current knowledge about nasal PRG use. Methods: A narrative review of the currently available literature of nasal PRG use was performed by searching the MEDLINE, EMBASE, and Web of Science databases. The abstracts and articles identified were reviewed and examined for relevance. Secondly, a request regarding reports of cases of nasal PRG administration was performed in the worldwide spontaneous reporting system of adverse drug reactions of the European Medicines Agency (EMA, EudraVigilance database). Results: The literature search resulted in two reported cases of nasal PRG use. In the analysis of the EMA-database, 13 reported cases of nasal PRG use (11 male (two not specified), mean age of users = 34.2 years (four not specified)) were found. In two cases fatalities occurred related to PRG nasal use. Conclusions: Even if only little evidence can be found in current literature, the potential for misuse/abuse of PRG via nasal route might be of particular importance in the near future in PRG users who misuse it. Physicians should be aware of these alternative routes of administration.

Improved transdermal delivery of cetirizine hydrochloride using polymeric microneedles.

The aim of this study was to design and characterize microneedle patch formulation containing cetirizine hydrochloride. Chitosan was co-formulated with cetirizine hydrochloride. Transdermal patches were prepared by casting this solution to microneedle molds. Control patches were formulated by casting this solution to a plain cuvet of same area as mold but lacking microneedles. An array of methods namely; differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM) were employed for the characterization of the films and the microneedles accordingly whereas in vitro permeation studies were conducted across rat skin. Light microscopy was performed to assess any histological changes upon microneedles application onto the rat skin. The patches had a reproducible thickness (0.86 ± 0.06mm) and folding endurance. Both the blank and drug loaded patches had 100 microneedles each of 300 micrometre length. In addition, the microneedle patches were ascribed with a two-fold increase in drug permeation across rat skin in the presence of microneedles as compared to the control formulations. Histological examination confirms a minimal invasion of the skin conferred by the microneedles. The microneedle patches serve as an alternate route of drug administration in patients with nausea and swelling difficulties. Graphical abstract Microneedle patch manifest a two-fold increase in the skin permeation of Cetirizine Hydrochloride as compared to the control that is drug loaded patch without microneedles.

Evaluation of Abuse and Route of Administration of Extended-Release Tapentadol Among Treatment-Seeking Individuals, as Captured by the Addiction Severity Index-Multimedia Version (ASI-MV).

BackgroundTapentadol is a molecule incorporating mu opioid receptor agonism and norepinephrine reuptake inhibition to provide analgesia, with the potential for a lower incidence of gastrointestinal side effects than full mu opioid agonists. Postmarketing surveillance of tapentadol as an active pharmaceutical ingredient has consistently revealed low levels of abuse and diversion.ObjectiveThe purpose of the present study was to further characterize the abuse liability of tapentadol extended-release (ER) by evaluating the prevalence of past 30-day tapentadol ER abuse and reported routes of administration as compared with ER opioids with Food and Drug Administration (FDA) abuse-deterrent labeling (“ADF opioids”) and ER opioids without FDA abuse-deterrent labeling (“non-ADF opioids”).MethodsData were collected from January 2014 through December 2017 from 776 centers located in 43 states throughout the United States using the Addiction Severity Index–Multimedia Version (ASI-MV), an instrument that is integral to the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO, Inflexxion, an IBH Company, Costa Mesa, CA, USA).ResultsTapentadol ER had lower rates of past 30-day abuse than ADF ER and non-ADF ER opioid comparators, both at a population level and when adjusted for drug utilization. Tapentadol ER was primarily abused orally, although it was also abused through alternate routes of administration. Cumulative rates of tapentadol ER abuse by alternative routes of administration were lower than both ADF and non-ADF ER opioid comparators, although large confidence intervals resulting from the small sample size of reported tapentadol ER use limit firm conclusions.ConclusionsIn summary, tapentadol ER was found to have lower rates of both past 30-day abuse and use via alternate routes of administration, specifically snorting and smoking, than ADF and non-ADF ER comparators.

Preparation, Characterization and Dermal Delivery of Methadone.

The use of methadone for the management of pain has received great interest in recent years. Currently, oral and intravenous formulations are available for clinical use. Dermal delivery represents an attractive alternative route of administration for this drug as it is associated with comparatively fewer side effects. The first stage of the work was the preparation of methadone free base as this form of the drug is expected to permeate the skin to a greater extent than the hydrochloride salt. Subsequently the molecule was characterized with Nuclear Magnetic Resonance (NMR) and thermal analysis, the distribution coefficient was determined and solubility studies were conducted in a range of solvents. In vitro permeation and mass balance studies were conducted under finite dose conditions (5 μL/cm2) in porcine skin. The results confirmed the more favorable penetration of methadone free base compared with the salt. The highest cumulative amount of methadone (41 ± 5 μg/cm2) permeated from d-limonene (LIM). Ethyl oleate (EO), Transcutol® P (TC) and octyl salicylate (OSAL) also appear to be promising candidate components of dermal formulations for methadone base. Future work will focus on further formulation optimization with the objective of progressing to evaluation of prototype dosage forms in clinical trials.

Unidirectional drug release from 3D printed mucoadhesive buccal films using FDM technology: In vitro and ex vivo evaluation

Oromucosal delivery of active pharmaceutical ingredients provides an attractive alternative route of administration, due to avoidance of the first pass effect and improved patient compliance. In the current work, fused deposition modelling (FDM) 3D printing was investigated as an additive manufacturing approach for poly(vinyl alcohol)-based mucoadhesive films, enabling unidirectional drug release. For this purpose, chitosan was incorporated as a permeation and mucoadhesion enhancer whereas ethylcellulose and commercial wafer sheets were evaluated as backing layers. The formulated films were initially assessed for structural integrity and dose uniformity. Solid-state characterization of the films, including thermal methods (DSC, TGA), diffraction (XRPD) and Raman spectroscopy, was implemented to characterize the physicochemical properties of the produced polymeric filaments and buccal films. The mechanical properties of the products were investigated by instrumented indentation and tensile tests. Evaluation of buccal films was assessed in vitro, to study the effect of backing-layer type on hydration capacity of the films, diffusion of the drug throughout the restricting layer and release profiles in simulated saliva. The ex vivo performance of the manufactured products, associated with the presence of chitosan, was investigated by textural analysis for mucoadhesion properties, whereas permeation studies and histological studies were performed across porcine buccal epithelium. The results demonstrated that FDM printing is a timesaving and versatile approach in the context of manufacturing multi-layered mucoadhesive buccal films, providing unidirectional release properties.

Hepatitis B Vaccination and Waning Hepatitis B Immunity in Persons Living with HIV.

Persons with HIV are at a higher risk for acquiring HBV (hepatitis B virus) than the general population due to shared modes of transmission and are significantly more likely to develop and die from sequelae of chronic HBV infection. Early vaccination is key to achieving HBV protective immunity, but response rates are still much lower than in the general population, ranging from 35 to 70%. Individuals with HIV also experience more rapidly waning immunity than those without HIV. Strategies to augment initial response and improve long-term immunity in individuals with HIV include alterations in dose, frequency, and the use of immune adjuvants. Recent studies have focused on the use of different vaccine formulations, the use of vaccine adjuvants, increased number and strength of vaccine dosages, increased dose frequency, alternative routes of administration, dual vaccinations, and the use of booster vaccines. Although no consensus has been reached on the use of certain vaccination regimens, three and four double-dose vaccine schedules via the intramuscular route have demonstrated higher initial response rates. Early vaccination when CD4 cell counts are greater than 350/mm3 with low viral loads has been shown to improve initial response, along with completion of immunization series. Adjuvants such as TLR4 and TLR9 agonists appear to improve response to HBV vaccination, but further research is needed in individuals with HIV. Persons with HIV have significant lower initial and long-term seroresponse rates after HBV vaccination than immunocompetent individuals. Recent and ongoing studies continue to evaluate multiple strategies to improve these rates within a uniquely susceptible population.

Polymer-Based Nanoparticle Strategies for Insulin Delivery.

Diabetes mellitus (DM) is a chronic metabolic illness estimated to have affected 451 million individuals to date, with this number expected to significantly rise in the coming years. There are two main classes of this disease, namely type 1 diabetes (T1D) and type 2 diabetes (T2D). Insulin therapy is pivotal in the management of diabetes, with diabetic individuals taking multiple daily insulin injections. However, the mode of administration has numerous drawbacks, resulting in poor patient compliance. In order to optimize insulin therapy, novel drug delivery systems (DDSes) have been suggested, and alternative routes of administration have been investigated. A novel aspect in the field of drug delivery was brought about by the coalescence of polymeric science and nanotechnology. In addition to polymeric nanoparticles (PNPs), insulin DDSes can incorporate the use of nanoplatforms/carriers. A combination of these systems can bring about novel formulations and lead to significant improvements in the drug delivery system (DDS) with regard to therapeutic efficacy, bioavailability, increased half-life, improved transport through physical and chemical barriers, and controlled drug delivery. This review will discuss how recent developments in polymer chemistry and nanotechnology have been employed in a multitude of platforms as well as in administration routes for the safe and efficient delivery of insulin for the treatment of DM.

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.

Cell Adhesive Character of Phenylboronic Acid-Modified Insulin and Its Potential as Long-Acting Insulin

Phenylboronic acid (PBA) derivatives have attracted substantial attention owing to their unique character of forming dynamic covalent bonds with polyol compounds. Recent studies have shown interactions between PBA and sugar chains on the cell surface; they have interesting applications for sensors and drug delivery systems. In this study, we prepared phenylboronic acid-modified insulin (PBA-Ins) to evaluate its glucose-lowering activity and cell adhesiveness. In the case of intravenous injection, PBA-Ins showed longer glucose-lowering activity than native insulin. We hypothesized that this prolonged effect was the result of the interaction between the PBA moiety and sugar chains on the cell surface. Red blood cells (RBCs) were used as a cell model, and we confirmed PBA-Ins’s affinity for RBCs, which induced RBC agglutination. Interestingly, using an alternative PBA-Ins administration route markedly changed its glucose-lowering activity. Unlike the intravenous injection of PBA-Ins, the subcutaneous injection showed a small effect on glucose level, which indicated that a small amount of PBA-Ins was absorbed into the bloodstream. This suggested the importance of investigating the interaction between the PBA moiety and many types of cells, such as adipocytes, in subcutaneous tissues.

Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies.

Subcutaneous administration of insulin in patients suffering from diabetes is associated with the distress of daily injections. Among alternative administration routes, the oral route seems to be the most advantageous for long-term administration, also because the peptide undergoes a hepatic first-pass effect, contributing to the inhibition of the hepatic glucose output. Unfortunately, insulin oral administration has so far been hampered by degradation by gastrointestinal enzymes and poor intestinal absorption. Loading in lipid nanoparticles should allow to overcome these limitations. Entrapment of peptides into such nanoparticles is not easy, because of their high molecular weight, hydrophilicity and thermo-sensitivity. In this study, this objective was achieved by employing fatty acid coacervation method: solid lipid nanoparticles and newly engineered nanostructured lipid carriers were formulated. Insulin and insulin analog-glargine insulin-were entrapped in the lipid matrix through hydrophobic ion pairing. Bioactivity of lipid entrapped peptides was demonstrated through a suitable in vivo experiment. Ex vivo and in vivo studies were carried out by employing fluorescently labelled peptides. Gut tied up experiments showed the superiority of glargine insulin-loaded nanostructured lipid carriers, which demonstrated significantly higher permeation (till 30% dose/mL) compared to free peptide. Approximately 6% absolute bioavailability in the bloodstream was estimated for the same formulation through in vivo pharmacokinetic studies in rats. Consequently, a discrete blood glucose responsivity was noted in healthy animals. Given the optimized ex vivo and in vivo intestinal uptake of glargine insulin from nanostructured lipid carriers, further studies will be carried out on healthy and diabetic rat models in order to establish a glargine insulin dose-glucose response relation.

Advances in Bovine Digital Diseases

A full week was devoted to discussion, sometimes heated, of bovine digital problems at a meeting organized by the British Cattle Veterinary Association in Liverpool, England, July 16-20, 1990. The first and last days, confined to members of the international study group on diseases of the ruminant digit (sixth meeting) involved twenty papers and considerable discussion on recent observations and studies. The three intervening days' program was a forum for an "Update in Cattle Lameness" (US $20 or £12 sterling post free from Dr. R. D. Murray, Department of Veterinary Clinical Studies, University of Liverpool Field Station, "Leahurst", Neaton, S. Wirral, Cheshire L64 7TE, England) attended by over 200 veterinarians and others, including large, predominantly European and Japanese contingents. This study was conceived in response to NCA's resolution to encourage biological and pharmaceutical manufacturers to provide tissue reaction data on all animal health products and to encourage development of acceptable alternative routes of administration to the problematic IM method.