Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study.

BACKGROUND: Itch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study. RESULTS: We successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4. CONCLUSIONS: Our findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.

Topical Delivery of Tofacitinib in Dermatology: The Promise of a Novel Therapeutic Class Using Biodegradable Dendritic Polyglycerol Sulfates.

Inflammatory skin diseases, such as psoriasis, atopic dermatitis, and alopecia areata, occur when the regulatory tolerance of the innate immune system is disrupted, resulting in the activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory signaling pathway by interleukin 6 (IL-6) and other key inflammatory cytokines. JAK inhibitors, such as tofacitinib, bind to these enzymes which are coupled to receptors on cell surfaces and block the transcription of inflammatory cytokine-induced genes. The first topical applications are being marketed, yet insufficient effects regarding indications, such as alopecia areata, suggest that improved delivery technologies could help increase the efficacy. In this study, we used sulfated dendritic polyglycerol with caprolactone segments integrated in its backbone (dPGS-PCL), with a molecular weight of 54 kDa, as a degradable carrier to load and solubilize the hydrophobic drug tofacitinib (TFB). TFB loaded in dPGS-PCL (dPGS-PCL@TFB), at a 11 w/w% loading capacity in aqueous solution, showed in an ex-vivo human skin model better penetration than free TFB in a 30:70 (v/v) ethanol/water mixture. We also investigated the anti-inflammatory efficacy of dPGS-PCL@TFB (0.5 w/w%), dPGS-PCL, and free TFB in the water/ethanol mixture by measuring their effects on IL-6 and IL-8 release, and STAT3 and STAT5 activation in ex vivo skin models of simulated inflamed human skin. Our results suggest that dPGS-PCL@TFB reduces the activation of STAT3 and STAT5 by increasing the penetration of the tofacitinib. However, no statistically significant differences with respect to the inhibition of IL-6 and IL-8 were observed in this short incubation time.

Behavioral observations, heart rate and heart rate variability in horses following oral administration of a cannabidiol containing paste in three escalating doses (part 1/2).

Cannabidiol (CBD) products have been proposed to exert stress- and anxiety-relieving effects in animals. Despite the increasing popularity of CBD for veterinary use, the available research detailing the effects of CBD in horses is limited. The aim of this study (part 1 of 2) was to analyze stress parameters via behavioral observations and heart rate monitoring in healthy horses following single oral administration of a CBD containing paste in different doses. Study products were two pastes for oral administration, one containing CBD and one containing no active ingredient. Pastes were applied as single administrations in consecutive trials with escalating dosages (doses: 0.2, 1.0, 3.0 mg CBD/kg) to a treatment (trial 1: n = 3, trial 2: n = 3, trial 3: n = 5 horses) and a control group (trial 1: n = 3, trial 2: n = 3, trial 3: n = 6 horses) with minimum wash-out periods of seven days in between. Behavioral parameters were evaluated using video recordings to score the levels of sedation including the horses' reactions to acoustic and visual stimuli. Facial expression was assessed using photographs. Evaluation was based on the previously described facial sedation scale for horses (FaceSed) and the Horse Grimace Scale. For baseline values, identical observations were recorded on the day before each paste administration. Both paste administration and behavioral evaluation were performed double blinded. Cardiac beat-to-beat (R-R) intervals were continuously recorded throughout the trial and assessed using heart rate and heart rate variability parameters. Statistical analysis included comparison between treatment and control group over escalating doses and time points using linear mixed models. The CBD paste was well tolerated, and no side effects were observed. Analysis of sedation scores and facial expressions did not indicate significant differences between treatment and control group over the escalating doses. The heart rate was neither reduced, nor were significant changes in heart rate variability observed compared to the control group. Main limitation of this study is the small sample size. Further research is required to determine adequate doses and indications for the use of CBD products in horses.

Extracellular Matrix Remodeling in Atopic Dermatitis Harnesses the Onset of an Asthmatic Phenotype and Is a Potential Contributor to the Atopic March.

The development of atopic dermatitis in infancy, and subsequent allergies, such as asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, however the course of disease indicates an inter-epithelial crosstalk, through the onset of inflammation in the skin and progression to other mucosal epithelia. In this study, we investigated if and how skin-lung epithelial crosstalk contributes to the development of the atopic march. First, we emulated inter-epithelial crosstalk through indirect coculture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified thrombospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. Because these mediators are extracellular matrix-related proteins, we then studied the involvement of the extracellular matrix, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated extracellular matrix remodeling triggering the release of the above-mentioned mediators. In vivo mouse data showed that exposure to these mediators dysregulated activated circadian clock genes which are increasingly discussed in the context of atopic diseases and asthma development. Our data point toward the existence of a skin-lung axis that could contribute to the atopic march driven by skin extracellular matrix remodeling.

[Use of drugs in pregnant dogs and puppies - what should be considered from a pharmacological point of view?] / Arzneimittelanwendung bei trächtigen Hündinnen und Welpen ­ was ist aus pharmakologischer Sicht zu beachten?

The administration of drugs to pregnant bitches may not only pose a potential danger to the bitch but also to the fetuses. In this context, the extent of the risk also depends on the stage of gestation. Although a number of agents are known to have a fetotoxic and/or teratogenic potential, insufficient knowledge concerning their potential risk to the embryo/fetus is available for the majority of drugs.Arranged in groups of active substances, a selection of drugs that are assumed to be safe according to the current state of knowledge is provided. Drugs for which there is insufficient knowledge or which are clearly contraindicated are also mentioned.The second part of this overview covers the use of medicines in puppies. The physiology of a puppy does not simply correspond to that of a small dog. Only very few drugs posess valid pharmacological data for use in puppies. However, a subset of restrictions on the use of pharmacologic agents may be derived from the specifics of puppy physiology.The recommendations made do not claim to be complete and no guarantee for accuracy is provided, as these have been compiled from a literature review. In certain cases, the recommendations are even contradictory.Veterinarians are therefore encouraged to report all adverse events associated with treatments of pregnant bitches and puppies within the framework of pharmacovigilance. This is the only way to close gaps in knowledge about the treatment of these special patients.

Pharmacokinetic modelling of orally administered cannabidiol and implications for medication control in horses.

Cannabidiol (CBD) products gain increasing popularity amongst animal owners and veterinarians as an alternative remedy for treatment of stress, inflammation or pain in horses. Whilst the use of cannabinoids is banned in equine sports, there is limited information available concerning CBD detection times in blood or urine. The aim of this study was to determine the pharmacokinetic properties of CBD following oral administration in the horse to assist doping control laboratories with interpreting CBD analytical results. Part 1: dose escalation study: Single oral administration of three escalating doses of CBD paste (0.2 mg/kg, n = 3 horses; 1 mg/kg, n = 3; 3 mg/kg, n = 5) with >7 days wash-out periods in between. Part 2: multiple dose study: oral administration of CBD paste (3 mg/kg, n = 6) twice daily for 15 days. Multiple blood and urine samples were collected daily throughout both studies. Following study part 2, blood and urine samples were collected for 2 weeks to observe the elimination phase. Concentrations of CBD, its metabolites and further cannabinoids were evaluated using gas-chromatography/tandem-mass-spectrometry. Pharmacokinetic parameters were assessed via two approaches: population pharmacokinetic analysis using a nonlinear mixed-effects model and non-compartmental analysis. AUC0-12 h and Cmax were tested for dose proportionality. During the elimination phase, the CBD steady-state urine to serum concentration ratio (Rss) was calculated. Oral CBD medication was well-tolerated in horses. Based on population pharmacokinetics, a three-compartment model with zero-order absorption most accurately described the pharmacokinetic properties of CBD. High volumes of distribution into peripheral compartments and high concentrations of 7-carboxy-CBD were observed in serum. Non-compartmental analysis identified a Cmax of 12.17 ± 2.08 ng/mL after single administration of CBD (dose: 3 mg/kg). AUC0-12 h showed dose proportionality, increase for Cmax leveled off at higher doses. Following multiple doses, the CBD terminal half-life was 161.29 ± 43.65 h in serum. Rss was 4.45 ± 1.04. CBD is extensively metabolized and shows high volumes of tissue distribution with a resulting extended elimination phase. Further investigation of the potential calming and anti-inflammatory effects of CBD are required to determine cut-off values for medication control using the calculated Rss.

Plasma pharmacokinetics of tigolaner, emodepside, and praziquantel following topical administration of a combination product (Felpreva®) and of intravenous administration of the individual active ingredients in cats.

Felpreva® for cats contains the new acaricidal/insecticidal active ingredient tigolaner in a fixed combination with the nematocidal and cestocidal compounds emodepside and praziquantel, respectively. The plasma pharmacokinetics of tigolaner, emodepside, and praziquantel were evaluated in clinically healthy cats following topical (spot-on) treatment as fixed combination Felpreva®. For the determination of bioavailability intravenous administration of single active ingredients was also performed. After a single topical administration of Felpreva® using the target dose volume of 0.148 â€‹ml/kg to cats, tigolaner reached mean peak concentrations of 1352 â€‹µg/l with a Tmax of 12 days and a mean half-life of 24 days. Simulation of repetitive topical administration every 91 days indicates only a low risk of accumulation after reaching steady state within two to three administrations. The volume of distribution calculated after intravenous dosing was 4 â€‹l/kg and plasma clearance was low with 0.005 â€‹l/h/kg. Overall plasma exposure was 1566 â€‹mg∗h/l after topical administration, providing an absolute bioavailability of 57%. Tigolaner was mainly cleared via the faeces (54% within 28 days), renal clearance was neglectable (< 0.5% within 28 days). Emodepside and praziquantel showed mean peak concentrations of 44 â€‹µg/l and 48 â€‹µg/l (reached after 1.5 days and 5 â€‹h, respectively). Overall plasma exposures were 20.6 and 3.69 â€‹mg∗h/l, respectively. The elimination half-life was 14.5 days for emodepside and 10 days for praziquantel after topical administration. After topical administration of Felpreva® using 2.5× and 5× dose multiples an almost proportional increase of plasma exposure was observed for all three active ingredients. With the addition of tigolaner, Felpreva® combines the established pharmacokinetic (PK) characteristics of emodepside and praziquantel contained in Profender® spot-on for cats with the favourable PK of tigolaner suitable for a 3-months protection against fleas and ticks.

Occurrence of Antimicrobial Resistance in Canine and Feline Bacterial Pathogens in Germany under the Impact of the TÄHAV Amendment in 2018.

The occurrence of antimicrobial resistance due to the use of antimicrobials is considered to be a main cause for treatment failure of bacterial infections in humans and animals. The right of German veterinarians to use and prescribe medications such as antimicrobials is regulated by the Regulation of Veterinary Pharmacies (TÄHAV). The aim of this study was to investigate the impact of the second amendment to the TÄHAV in 2018 on the occurrence of antimicrobial resistance in selected bacterial pathogens isolated from dogs and cats in Germany. For this purpose, we analyzed antimicrobial susceptibility data from 38 German small animal practices gathered between 2015 and 2021 in cooperation with Laboklin (Labor für klinische Diagnostik GmbH & Co.KG, Bad Kissingen, Germany). Annual cumulative susceptibility data of eight bacterial species were analyzed and compared. The mean value of resistant isolates was determined for each year and supplemented by 95% confidence intervals. Encouraged by the amendment, an increase in sample submissions was observed in Germany. The highest resistance rates to the analyzed substances penicillin G, ampicillin, amoxicillin-clavulanic acid, cefovecin, and enrofloxacin were found for Staphylococcus pseudintermedius (S. pseudintermedius), S. aureus, and Escherichia coli (E. coli). In contrast, resistance rates were low for Pasteurella multocida (P. multocida) and ß-hemolytic streptococci. Significant resistance trends (p < 0.05) assumed as influenced by the TÄHAV amendment could be the significant decreases in resistance rates of S. pseudintermedius against penicillin G to 67% (n = 322/479), and ampicillin to 63% (n = 286/453), as well as S. felis against amoxicillin-clavulanic acid and cefovecin to 2% (n = 2/109), furthermore, the reduction in the occurrence of resistance of S. aureus against enrofloxacin to 4% (n = 3/76) in 2021. Moreover, for all species, the efficacy against the analyzed substances was maintained over the study period.

Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses.

Insect bite hypersensitivity (IBH) is the most common allergic skin disease of horses. It is caused by insect bites of the Culicoides spp. which mediate a type I/IVb allergy with strong involvement of eosinophil cells. No specific treatment option is available so far. One concept could be the use of a therapeutic antibody targeting equine interleukin 5, the main activator and regulator of eosinophils. Therefore, antibodies were selected by phage display using the naïve human antibody gene libraries HAL9/10, tested in a cellular in vitro inhibition assay and subjected to an in vitro affinity maturation. In total, 28 antibodies were selected by phage display out of which eleven have been found to be inhibiting in the final format as chimeric immunoglobulin G with equine constant domains. The two most promising candidates were further improved by in vitro affinity maturation up to factor 2.5 regarding their binding activity and up to factor 2.0 regarding their inhibition effect. The final antibody named NOL226-2-D10 showed a strong inhibition of the interleukin 5 binding to its receptor (IC50 = 4 nM). Furthermore, a nanomolar binding activity (EC50 = 8.8 nM), stable behavior and satisfactory producibility were demonstrated. This antibody is an excellent candidate for in vivo studies for the treatment of equine IBH.

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice.

BACKGROUND: Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells. OBJECTIVE: During the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca2+ flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated. RESULTS: We show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca2+ flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model. CONCLUSIONS: Our results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.

Sphingosine 1-Phosphate as Essential Signaling Molecule in Inflammatory Skin Diseases.

Sphingolipids are crucial molecules of the mammalian epidermis. The formation of skin-specific ceramides contributes to the formation of lipid lamellae, which are important for the protection of the epidermis from excessive water loss and protect the skin from the invasion of pathogens and the penetration of xenobiotics. In addition to being structural constituents of the epidermal layer, sphingolipids are also key signaling molecules that participate in the regulation of epidermal cells and the immune cells of the skin. While the importance of ceramides with regard to the proliferation and differentiation of skin cells has been known for a long time, it has emerged in recent years that the sphingolipid sphingosine 1-phosphate (S1P) is also involved in processes such as the proliferation and differentiation of keratinocytes. In addition, the immunomodulatory role of this sphingolipid species is becoming increasingly apparent. This is significant as S1P mediates a variety of its actions via G-protein coupled receptors. It is, therefore, not surprising that dysregulation in the signaling pathways of S1P is involved in the pathophysiological conditions of skin diseases. In the present review, the importance of S1P in skin cells, as well as the immune cells of the skin, is elaborated. In particular, the role of the molecule in inflammatory skin diseases will be discussed. This is important because interfering with S1P signaling pathways may represent an innovative option for the treatment of inflammatory skin diseases.

Behavioral observations, heart rate and cortisol monitoring in horses following multiple oral administrations of a cannabidiol containing paste (part 2/2).

As a remedy against stress and anxiety, cannabidiol (CBD) products are of increasing interest in veterinary medicine. Limited data is available describing the actual effectiveness of CBD in horses. The aim of this study (part 2 of 2) was to analyze stress parameters via behavioral observation, heart rate monitoring and assessment of blood and saliva cortisol levels in healthy horses treated repeatedly with a CBD containing paste. Twelve horses were randomly assigned to a treatment or a control group. Two pastes were orally administered in a double-blinded study design, one paste containing CBD and one paste without active ingredient. Both pastes were administered twice daily over 15 days (dose: 3 mg CBD/kg). Behavioral observations were conducted daily using a sedation score and a rating of facial expressions, based on the previously described facial sedation scale for horses (FaceSed) and the Horse Grimace Scale. Blood and saliva samples were obtained regularly to determine cortisol levels throughout the study. Cortisol levels were analyzed by means of liquid chromatography/tandem mass spectrometry (LC/MS/MS). Behavioral observations and cortisol levels were compared between groups. Prior to paste administration, a novel object test was performed and the horses' reaction to loading on a trailer was recorded. Both tests were repeated after 13 days of paste application. Movement patterns such as different gaits during the novel object test were evaluated and an ethogram was designed to assess exhibited behavioral traits. Cardiac beat-to-beat (R-R) intervals were recorded throughout and evaluated using heart rate (HR) and heart rate variability (HRV) parameters. Blood and saliva samples for cortisol analysis were taken before and after the tests. Daily behavioral observations and cortisol levels did not differ between the treatment and the control group. Similarly, analysis of movement patterns, HR, HRV and cortisol levels during the novel object test and trailer test did not identify significant differences between the groups. Regularly administered oral CBD (3 mg/kg BID over 15 days) had no statistically significant effect on behavioral observations, cortisol levels, HR and HRV in horses. Further research is required to establish adequate doses and indications for the use of CBD in horses.

A Cross-Sectional Study of Veterinarians in Germany on the Impact of the TÄHAV Amendment 2018 on Antimicrobial Use and Development of Antimicrobial Resistance in Dogs and Cats.

To minimize the use of third- and fourth-generation cephalosporins and fluoroquinolones, the 2018 amendment to the regulations of veterinary pharmacies (TÄHAV) introduced legal restrictions in Germany. In an online survey among German veterinarians, we investigated the influence of these requirements on the use of antibiotics in the treatment of dogs and cats and the development of resistance rates. It was found that, on average, between 21% and 30% of daily treated dogs and cats received antimicrobial therapy. The TÄHAV amendment led to a less frequent use of highest priority critically important antimicrobials (HPCIA) in 79% (240/303) of respondents and less antimicrobial use in general in 36% (108/303). As a result of these legal changes, 63% (190/303) of participants requested antimicrobial susceptibility testing (AST) more frequently. Participants consulted ASTs particularly frequently for treatment of otitis externa with 63% (190/303), cystitis with 55% (168/303), wounds with 44% (132/303), and pyoderma with 29% (88/303). Veterinarians also noted an increased loss of antimicrobial efficacy, especially when treating these diseases. The results of our survey confirm that the TÄHAV amendment is having a positive impact on prudent antibiotic use, with participants performing more ASTs, using HPCIA less frequently, and choosing alternative antimicrobials for therapy.

Early inflammatory events of mastitis-a pilot study with the isolated perfused bovine udder.

BACKGROUND: Bovine mastitis is an important health and cost factor in the milk industry. To elucidate whether isolated perfused bovine udders can be used to study early inflammatory events of mastitis, 1 mg of lipopolysaccharide (LPS) was instilled into quarters of 10 isolated perfused bovine udders. Three hours and 6 h after LPS instillation, tissue samples were taken from the gland cistern and base of the udder, subsequently stored in RNAlater and processed for the determination of inflammation-dependent gene regulation by real-time RT-qPCR. Gene expression analysis was performed using delta-delta Ct method. To translate mRNA results to protein, IL-1ß and IL-6 were determined in tissue homogenate by ELISA. RESULTS: The instillation of 1 mg LPS lead to an increased expression of pro-inflammatory cytokines and chemokines like TNF-α, CCL20, CXCL8 as well as of IL-1 ß, IL-6 and IL-10, lingual antimicrobial peptide (LAP) and S100A9. However, the degree of elevation differed slightly between gland cistern and udder base and markedly between 3 and 6 h after instillation, with a distinct increase in mediator expression after 6 h. IL-1ß protein increased in a time-dependent manner, whereas IL-6 was unchanged within 6 h of LPS instillation. CONCLUSION: Compared to in vivo studies with instillation of LPS into udders of living cows, a similar inflammation-dependent gene regulation profile can be mimicked in the isolated perfused bovine udder, indicating a supplementation of animal experiments.

TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch.

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.

Irradiation of the Normal Murine Tongue Causes Upregulation and Activation of Transient Receptor Potential (TRP) Ion Channels.

Signal transduction at sensory neurons occurs via transmembrane flux of cations, which is largely governed by the transient receptor potential (TRP) family of ion channels. It is unknown whether TRP channel activation contributes to the pain that accompanies radiation-induced oral mucositis. This study sought to characterize changes in TRP channel expression and function that occur in the locally irradiated tissues and afferent neurons of mice. Female CD-1 mice received single high-dose (27 Gy) tongue irradiation, or sham irradiation. Animals were euthanized either before overt glossitis developed (days 1 and 5 postirradiation), when glossitis was severe (day 11), or after mice had recovered (days 21 and 45). Tongue irradiation caused upregulation of the Trpv1 gene in trigeminal ganglia (TG) neurons. Other TRP genes (Trpv2, Trpv4, Trpa1, Trpm8) and Gfrα3 (which acts upstream of several TRP channels) were also upregulated in TGs and/or tongue tissue, in response to radiation. Ex vivo calcium imaging experiments demonstrated that the proportions of TG neurons responding to histamine (an activator of TRPV1, TRPV4 and TRPA1), TNF-α (an activator of TRPV1, TRPV2 and TRPV4), and capsaicin (a TRPV1 agonist), were increased as early as one day after tongue irradiation; these changes persisted for at least 21 days. In a subsequent experiment, we found that genetic deletion of TRPV1 mitigated weight loss (a surrogate marker of pain severity) in mice with severe glossitis. The results intimate that various TRP channels, and TRPV1 in particular, should be explored as analgesic targets for patients experiencing pain after oral irradiation.

The Decline and Fall of Materia Medica and the Rise of Pharmacology and Therapeutics in Veterinary Medicine.

Materia Medica is a Latin term, relating to the history of pharmacy. It describes the sources (vegetable, animal and mineral), nature, preparation, and properties of substances or mixtures of substances, which were used as remedies for the treatment of diseases. Bourgelat authored the first veterinary Materia Medica book. This review describes the evolution and ultimate downfall of Materia Medica concepts and practices. Its survival for more than two millennia reflected the impact of religion and dogmas on therapy. The consignment of Materia Medica to history was signified by publication of the first modern book of veterinary pharmacology and therapeutics by Meyer Jones in 1953. Previously, the dominance of Materia Medica was linked to an hippiatry culture, which was shared with farriers and quacks. The Pasteurian and pharmacological revolutions of the second half of the nineteenth century led to its gradual abandonment. This review explains why the existence of authentically active substances, such as opioid analgesics, cardiotonics and general anesthetics either were not used for those actions or were badly prescribed, in part because of historical precedence and in part from lack of pathophysiological knowledge to justify rational use. The modern concept of dosage, in particular inter-species differences, was not understood. There were also major dogmas, supporting false indications, such as failure to recognize pain as a symptom to be treated, whereas inflammation was only a disease symptom involving excess of activity of the blood system, which had to be vigorously addressed by bleeding and purging. This review covers a well-defined period, ranging from Bourgelat, who wrote the first book of Materia Medica for veterinary studies to the first edition of Meyer Jones textbook in 1953, which marked the end of Materia Medica and the beginning of pharmacology in veterinary medicine.

Surface distribution of pyrethroids following topical application to veterinary species: Implications for lateral transport.

Pyrethroids like permethrin have been used as topical formulations for their ectoparasiticidal effects since the 1970s. There are numerous efficacy studies in dogs and livestock animals that indicate a fast spread of pyrethroids after topical administration onto rather confined areas of the skin. Some studies correlate the efficacy against ticks, fleas or lice with concentrations of pyrethroids in hair and, less frequently, stratum corneum samples. It is often stated that lateral transport is responsible for the distribution of the pyrethroids over the body surface. With this review, we attempt to demonstrate evidence for lateral transport of pyrethroids after topical administration in dogs, cattle and sheep and to present data gaps that should be addressed in follow-up studies.

Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases.

Tofacitinib (TFB), a Janus kinase inhibitor, has shown excellent success off-label in treating various dermatological diseases, especially alopecia areata (AA). However, TFB's safe and targeted delivery into hair follicles (HFs) is highly desirable due to its systemic adverse effects. Nanoparticles (NPs) can enhance targeted follicular drug delivery and minimize interfollicular permeation and thereby reduce systemic drug exposure. In this study, we report a facile method to assemble the stable and uniform 240 nm TFB loaded squalenyl derivative (SqD) nanoparticles (TFB SqD NPs) in aqueous solution, which allowed an excellent loading capacity (LC) of 20%. The SqD NPs showed an enhanced TFB delivery into HFs compared to the aqueous formulations of plain drug in an ex vivo pig ear model. Furthermore, the therapeutic efficacy of the TFB SqD NPs was studied in a mouse model of allergic dermatitis by ear swelling reduction and compared to TFB dissolved in a non-aqueous mixture of acetone and DMSO (7:1 v/v). Whereas such formulation would not be acceptable for use in the clinic, the TFB SqD NPs dispersed in water illustrated a better reduction in inflammatory effects than plain TFB's aqueous formulation, implying both encouraging good in vivo efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA.

Histamine 2 Receptor Agonism and Histamine 4 Receptor Antagonism Ameliorate Inflammation in a Model of Psoriasis.

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and immune cell infiltration into the skin, often accompanied by itch. Histamine, acting via histamine 1-4 receptors, is known to modulate immune responses in the skin and to induce itch. The aim of this study was to test the role of histamine 2 receptors and histamine 4 receptors in the imiquimod-induced psoriasis-like skin inflammation model. BALB/c mice were treated intraperitoneally with amthamine (histamine 2 receptor agonist), JNJ-39758979 (histamine 4 receptor antagonist), a combination of both, or vehicle twice daily in a preventive manner. Imiquimod was applied once daily onto the back skin for 10 consecutive days. Stimulation of histamine 2 receptors and blockade of histamine 4 receptors ameliorated imiquimod-induced skin inflammation. The combination of amthamine and JNJ-39758979 reduced skin inflammation even more pronounced, diminished epidermal hyperproliferation, and inhibited spontaneous scratching behaviour. A combination of histamine 2 receptor agonist and histamine 4 receptor antagonists could represent a new strategy for the treatment of psoriasis.