Response to Levetiracetam Treatment and Long-Term Follow-Up in Dogs With Reactive Seizures Due to Probable Exogenous Toxicity

Limited information is available on the long-term follow-up and seizure recurrence in dogs with reactive seizures due to suspected exogenous toxicity. The purpose of this study was to report the long-term follow-up of 13 dogs referred to a single referral hospital, diagnosed with reactive seizures and treated with a standardized levetiracetam protocol. All dogs received a loading levetiracetam dose of 60 mg/kg/IV once, followed by a maintenance dose of 20 mg/kg every 8 h as part of an open-label clinical study. Levetiracetam was withdrawn after a 6-months seizure-free period by reducing levetiracetam to 20 mg/kg every 12 h for a 4-week seizure-free period, followed by levetiracetam 20 mg/kg every 24 h for a 4-week seizure-free period, before levetiracetam treatment was stopped. No adverse effects of the treatment were reported. No dogs experienced any seizures after discharge or after levetiracetam withdrawal. Median follow-up time from time of discharge was of 78 months (=6 years 6 months). The result of this study supports the use of levetiracetam for treatment of reactive seizures due to exogenous substance intoxication. Moreover, our results do not support the need for long-term antiepileptic treatment in cases of reactive seizures due to exogenous intoxication.

Theoretical and experimental study of interaction of macroheterocyclic compounds with ORF3a of SARS-CoV-2

The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV–Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.

Acute urinary retention in a 27-year-old male secondary to benign prostatic hyperplasia treated with Holmium Enucleation of the Prostate (HOLEP)

Introduction: Benign prostatic hyperplasia (BPH) is common in the ageing male. Clinical manifestations like retention impact on a patient’s quality of life. Alterations in androgen activity at the androgen receptor complex level in the prostate contribute to prostatic hyperplasia with the highest incidence occurring in males in their 70’s. There remains a paucity of cases in young males who develop acute urinary retention secondary to BPH. We present a case of a 27-year-old male who developed acute urinary retention secondary to BPH who required a Holmium Laser Enucleation of his Prostate (HOLEP). Case description: A 27 year old man was admitted in acute urinary retention. BPH was diagnosed via way of radiological imaging and histological assessment. After pre-operative sperm banking and suprapubic catheterisation, the patient underwent a HOLEP. He had biochemically confirmed hypogonadotrophic hypogonadism which was at odds with his muscular, physical appearance. Total testosterone levels had fluctuated following admission suggesting an exogenous substance was interfering with the hypothalamic-pituitary-gonadal axis but he denied exogenous steroid use. Result: The patient successfully passed his voiding trial on the second post-operative day and remained catheter free. Post-operative uroflowmetry and sexual function remain unknown as patient disengaged with follow up. Conclusion: HOLEP prostatectomy is a safe and effective way of managing BPH in younger patients following sperm banking and assessment by endocrinology.

THE HUMAN HAIR FOLLICLE AS SENTINEL FOR DRUGS EVALUATION: DEMONSTRATION OF TETRACYCLINE ADHESION TO HAIR FOLLICLE AS PROPOSED MECHANISM IN DYSFUNCTIONAL HAIR LOSS

One mechanism of action of antibiotics such as tetracyclines involves the disruption of pathogens cell membranes. This author had previously demonstrated in vitro and in vivo the utility of a human miniorgan, a.k.a. hair follicle as sentinel in demonstrating the deleterious effect of alcohol by showing a disruption in metabolism. In this manuscript, the hair follicle was again used in vitro as sentinel in direct contact with another exogenous substance in two forms, namely liquid and powder tetracycline. The results demonstrate the adhesion property of tetracycline as a mechanism causing deleterious effect on the biological active cells of the follicle’s dermal papilla, and the consequent disruption in metabolism. Notably, it was documented a strong affinity of the antibiotic to the keratin skeleton of the hair follicle. In a recent published report, the adverse effect of tetracycline induction on experimentally deficient mitochondrial DNA (mtDNA) mouse was reversed and documented 30 days after discontinuation of the tetracycline diet. The experiments herein presented correlate and confirm previous findings of long term exposure to tetracycline causing not only damage the pathogen; but also healthy human cells. Since mtDNA may play a role in aging and age-associated diseases: Beware of tetracycline therapy on the elderly.

Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%–10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40–400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%–10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a “normal” HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.

SENSITIVE SKIN SYNDROME AND ENDOCRINE DISRUPTORS - IS THERE A CONNECTION?

Background: Sensitive Skin Syndrome (SSS) is predominantly a self-defined condition without an objective pathological finding. The syndrome presents with sudden and easily provoked flushes accompanied by unpleasant sensations like itching, pain, numbness in response to stimuli that usually do not cause such sensations. Endocrine disruption (ED) is an exogenous substance or mixture that induce negative health problems through affecting function(s) of the endocrine system in an intact organism. The Aim of The Study: was to establish the role of ED as a causative agent in SSS. Objective and Methods: The presented study includes 304 female self-diagnosed with SSS. Demographic data were collected from registers of Medico-Aesthetic Center “Medea” Varna from April 2017 till April 2019. The model of the study investigates the causes of SSS. Results: Results show the overall frequency of SSS was 31, 97%. As 174 (57, 23%) diagnosed in aesthetic visitors and 130 (42, 77%) in those with some health problem. The distribution according to the trigger factor show the prevalence of cosmetic products -56, 90%, detergents 21.05% and cosmetic procedures- 40, 88%. Conclusion: SSS is a serious health problem. The data from our study show that trigger factors, which are closely connected with EDC have a significant impact on this syndrome. In addition, adding topical treatment worsen rather than improve SSS. The literature sources reveal that this is first study of the role of ED as a causative agent in SSS in our country.

Cytochrome P450-Mediated Metabolic Characterization of a Mono-Carbonyl Curcumin Analog WZ35

WZ35 is a monocarbonyl analog of curcumin, which had been proved advantage over curcumin in chemical stability and antitumor activity. However, its pharmacokinetic profile has not been determined. In the present study, an ultraperformance liquid chromatography-tandem mass spectrometry assay was developed to detect concentration of WZ35 in rat plasma. Subsequently, pharmacokinetic study showed that the oral bioavailability of WZ35 is 10.56%. Cytochrome P450 (CYP450) plays a major role in metabolizing exogenous substance. The concentration of WZ35 was sharply decreased while incubating with microsome. It’s indicated that WZ35 is a substrate of CYP450s. Molecular docking assay showed that WZ35 can combine with CYP2B6 and CYP2C9 to form much more stable complex. The lowest docking energy was generated in complex with CYP2E1. The inhibition of CYP450s by WZ35 was also evaluated. Pan inhibitions of WZ35 on rat CYP3A2, CYP2B1, CYP2C11, CYP2D1, and ­CYP2E1 were observed by detecting probe substrates (midazolam, bupropion, tolbutamide, dextromethorphan, chlorzoxazone) and metabolites accordingly. On an average, 80% activities of enzymes were blocked. Mechanistically, the inhibitions of WZ35 on CYP3A2, CYP2B1, CYP2E1 were in a time-dependent manner according to the results of IC50 shift assay. The collective data demonstrated that the oral bioavailability of monocarbonyl analog of curcumin has significantly improved compared to curcumin. It’s both the substrate and inhibitor of CYP450s through in a time-dependent mechanism.

Possible Migration and Histopathological Analysis of Injections of Polymethylmethacrylate in Wistar Rats

Objective. To evaluate the possible migration of polymethylmethacrylate after injections in various corporal compartments of Wistar rats. Methods. The experimental work consisted in the injection of PMMA in corporal compartments for later histopathological analysis of the locations of implants and of distant filtering organs. The dose applied in each implant was of 0.2 mL. The animals were divided into groups according to the location of the implant realized: group GB had intradermic injections in the glabella. Group SD had subdermal injections in dorsal subcutaneous tissue cells. Group IP had intraperitoneal injections in the abdomen. Group PD had intramuscular injections in the right rear leg. The rats were sacrificed 30 days after realization of the implants and tissue samples from the lung, liver, spleen, and kidney, and locations of implantation were removed for histopathological analysis. Results. Characteristic microspheres that were compatible with the presence of PMMA in any of the histological slides analyzed were not observed. One animal had an amorphous exogenous substance, with a histiocytic reaction. Twelve of the 16 lungs analyzed had locations of intraalveolar hemorrhaging. Two animals had nonspecific spleen alterations. Conclusion. The histopathological analysis of this study found no PMMA microspheres in any of the tissues analyzed.