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Neha Maharao,* Victor Antontsev,* Hypatia Hou, Jason Walsh, Jyotika Varshney VeriSIM Life Inc., San Francisco, CA, USA*These authors contributed equally to this workCorrespondence: Jyotika VarshneyVeriSIM Life Inc, 315 Montgomery St,10th Floor, San Francisco, CA 94104 USAEmail jo.varshney@verisimlife.comIntroduction: Transdermal drug delivery is gaining popularity as an alternative to traditional routes of administration. It can increase patient compliance because of its painless and noninvasive nature, aid compounds in bypassing presystemic metabolic effects, and reduce the likelihood of adverse effects through decreased systemic exposure. In silico physiological modeling is critical to predicting dermal exposure for a therapeutic and assessing the impact of different formulations on transdermal disposition.Methods: The present study aimed at developing a physiologically based transdermal platform, “BIOiSIM”, that could be globally applied to a wide variety of compounds to predict their transdermal disposition. The platform integrates a 16-compartment model of compound pharmacokinetics and was used to simulate and predict drug exposure of three chemically and biologically distinct drug-like compounds. Machine learning optimization was composed of two components: exhaustive search algorithm (coarse-tuning) and descent (fine-tuning) integrated with the platform used to quantitatively determine parameters influencing pharmacokinetics (eg permeability, kperm) of test compounds.Results: The model successfully predicted drug exposure (AUC, Cmax and Tmax) following transdermal application of morphine, buprenorphine and nicotine in human subjects, mostly with less than two-fold absolute average fold error (AAFE). The model was further able to successfully characterize the relationship between observed systemic exposure and intended pharmacological effect. The predicted systemic concentration of morphine and plasma levels of endogenous pain biomarkers were used to estimate the effectiveness of a given therapeutic regimen.Conclusion: BIOiSIM marks a novel approach to in silico prediction that will enable leveraging of machine learning technology in the pharmaceutical space. The approach to model development outlined results in scalable, accurate models and enables the generation of large parameter/coefficient datasets from in vivo clinical data that can be used in future work to train quantitative structure activity relationship (QSAR) models for predicting likelihood of compound utility as a transdermally administered therapeutic.Keywords: transdermal absorption, computational modeling, machine learning, BIOiSIM

Pyoderma is one of the most challenging infectious skin disease of canines difficult to treat due to rapid emergence of resistance to routinely used antimicrobial drugs. Linezolid, an oxazolidinone, which targets bacterial protein synthesis, is the promising drug to treat such resistant bacteria causing recurrent episodes of pyoderma. A total of 40 clinical client owned refractory cases of canine pyoderma were enrolled in the study. Cultural examination of 40 swabs resulted in the recovery of Staphylococcus aureus as the bacterial isolate. Clinico-pathological and microbiological examinations confirmed that the superficial pyoderma in the dogs was due to infection of Staphylococcus aureus. In vitro antibiotic sensitivity test (AST) revealed macrolide-lincosamide-streptogramin B (MLSB) resistant phenotype of S. aureus that was highly sensitive to linezolid. MLSB resistance phenotypes were investigated by the D-test method using erythromycin (15 µg) and clindamycin (2 µg) disks. To check clinical efficacy of linezolid, treatment was initiated with linezolid (@ 10 mg/kg b.wt. PO BID for 4 wks), omega-3 and omega6 fatty acids with zinc (0.5 ml/kg b.wt. PO for 4 wks) and hydroxyzine (@ 0.5 mg/kg b.wt. PO, TID for one week or until pruritus ceased). Application of antibacterial shampoo containing chlorhexidine gluconate (4.0%) weekly and povidone iodine 5% spray on whole body daily was advised in all cases. All cases responded well to the treatment with reduction in pruritus within one week of therapy and skin lesion disappeared completely following one month of therapy. Cultural evaluation on the last day of therapy did not yield any growth of organisms thus, confirming complete recovery. [ABSTRACT FROM AUTHOR]

The study was undertaken to assess the level of cTn-I in severely ill dogs with non-cardiac diseases. The study revealed an increase in cTn-I level (>0.1 ng/ml) in dogs with renal failure (5th grade), tracheal constriction, liver cirrhosis, lung tumor, pyometra, pancreatitis and blunt chest injury indicating cardiac muscle damage. Thus, detection of myocardial insult/ damage in severely ill dogs with non-cardiac diseases is of great clinical significance in managing dogs as myocardial injury may contribute to unexpected deaths even in non cardiac diseases. [ABSTRACT FROM AUTHOR]

Eleven clinical cases of snake bite in dogs, referred at the hospital with in 2.5 to 6 hrs of envenomation, were subjected to cardiac evaluation. The snake bites were characterized by fang's mark associated with skin discolouration surrounding fang marks in all cases. Cardiac auscultation was almost normal in three dogs while othes showed variations in heart rate. The electrocardiographic examination revealed sinus rhythm with normal heart rate, multifocal continuous atrial tachycardia, sinus bradycardia, sinus tachycardia, ventricular premature complexes, ventricular flutter and ventricular tachycardia in 3, 1, 1, 2, 1, 1 and 2 envenomed dogs, respectively. The levels of cTn-I varied from< 0.1 to 5.8 ng/ml. The study revealed varying level of cardio-toxicity (based on cTn-I levels) in seven (63.63%) dogs naturally bitten by viper snakes. The dogs were treated with polyvalent anti-snake venom, tetanus toxoid, dexamethasone, fluid, enrofloxacin and vitamin K. Despite treatment four dogs, with multiple bite marks, severe arrhythmia (multifocal continuous atrial tachycardia, ventricular tachycardia and ventricular flutter) with high level of cTn-I could not survive. [ABSTRACT FROM AUTHOR]

A clinical case of ascites in an Indian gray mongoose due to liver cirrhosis/fibrosis, diagnosed on the basis of electrocardiography, radiography and ultrasonography, is reported and discussed. Treatment with furosemide, colchicine, ursodeoxycholic acid, propranolol, vitamin B-complex drops and an Ayurvedic liver protective and corrective liquid was promising. This seems to be the first report of ascites, ascribed to liver cirrhosis/fibrosis, diagnosed and managed successfully in an Indian gray mongoose in India. [ABSTRACT FROM AUTHOR]

Heart failure is an important cause of morbidity and mortality in canines. With the improvement in diagnostic technology, diagnosis of heart failure has become a routine in referral clinics. Sixteen dogs diagnosed with congestive left heart failure, employing history, clinical signs, radiography and electrocardiography were studied for level of cardiac troponin-I and vitamin D3; and treatment response to pimobendan. Beside orthopoenia, panting and coughing, oedema in dorso-caudal area of the lungs was predominant feature of congestive left heart failure. Higher level of cardiac troponin-I in these dogs indicated cardiac muscle insult and lower level of vitamin D3 might have been the risk factor in the development of congestive heart failure. Survival time of dogs, undergone therapy using pimobendan, varied from 4 days to 6 months and seemed related to level of cardiac troponin-I. The present study revealed increased level of cardiac troponin-I and decreased level of vitamin D3 in dogs with congestive left heart failure. Pimobendan alongwith enalapril, furosemide, diazepam and vitamin D could sustain the comfortable life up to 6 month in 13 dogs. [ABSTRACT FROM AUTHOR]

Radiographic investigations were carried out on eight hundred thirty seven chelonians (turtles/ tortoises) referred with complaints of anorexia, dyspnoea, weakness and dullness. Out of 837 chelonians, 221 (26.4 percent) did not reveal any radiographic abnormality. In clinically normal chelonians, heart, ovaries, liver, pancreas, urinary bladder and kidneys were not discernible radiographically. In 62.48 percent chelonians single disease viz. lung congestion/ lung odema/ lung infection, gastric gaseous distension, gaseous enteric distension, ileus, foreign bodies in intestines, esophagus, entroliths, heart enlargement, liver enlargement and gall bladder distension, cystoliths, metabolic bone disease or eggs in coelomic cavity were diagnosed. 11.2 percent chelonians had more than one radiographic diagnoses. Radiography is a useful diagnostic tool in chelonian medicine. [ABSTRACT FROM AUTHOR]

The investigation was undertaken in 250 adult pigeons of which 180 pigeons were clinically healthy having no signs of illness and were used to determine reference values of electrocardiographic parameters in standard lead II. P wave was positive and monophasic in all leads except aVR and aVL. PR segment was almost absent, ‘R’ was very small rather imperceptible in many pigeons, ’S’ wave was marked and ‘QRS’ pattern was of the rS type and negative in lead II,III and avF, ST slurring (absence of ST) was observed in 95% pigeons, ‘T’ wave was generally positive in lead I,II,III and avF and negative in aVL and aVR. The mean electrical axis on frontal plane was -83.52±6.080 with a predominant negative ‘S’ wave. Remaining 70 pigeons with various ailments showed various types of electrocardiographic abnormalities (sinus bradycardia, sinus tachycardia, atrial fibrillation/flutter, ventricular premature complex, ventricular tachycardia, ventricular flutter, ventricular asystole, 2nd degree heart blocks, right bundle branch block, low voltage complex and Ta wave). [ABSTRACT FROM AUTHOR]

The investigation was undertaken to study the prevalence of cardiac arrhythmias and conduction disturbances in crossbred cattle. The electrocardiograms (ECGs) were recorded in Base-Apex system in lead I. The prevalence of arrhythmia and conduction disturbance was recorded as 20 percent. The study revealed different types of electrocardiographic abnormalities such as sinus tachycardia, sinus bradycardia, sinus arrest, atrial fibrillation, ventricular premature complexes, ventricular tachycardia, accelerated idioventricular rhythm, ventricular asystole, right bundle branch block and 2nd degree AV block Mobitz type 1. Of these sinus tachycardia was commonly seen in healthy as well as sick animals. Ventricular arrhythmias were of serious and fatal nature. [ABSTRACT FROM AUTHOR]

The study was undertaken to evaluate the base line data to compare changes in electrocardiographic indices for detecting arrhythmias and conduction abnormalities in ruminants. The evaluation was undertaken in Holstein crossbred calves employing base-apex lead system which revealed mean values of heart rate, 'P' amplitude, 'P' durations' P-R' interval, 'QRS' amplitude, 'QRS' duration, 'S-T'segments, T amplitude, T duration and 'Q-T' interval as 85.2±4.23 bpm, 0.234 ± 0.031 mV, 0.05 ± 0.0024 sec, 0.125 ± 0.025 sec, 0.884 ± 0.06 mV, 0.054 ± 0.0001 sec, 0.182 ± 0.038 sec, 0.318 ± 0.088 mV, 0.069 ± 0.0037 sec and 0.308 ± 0.0017 sec respectively. [ABSTRACT FROM AUTHOR]

Twenty eight clinical cases of canine monocytic ehrlichiosis were diagnosed on the basis of buffy coat cytology and evaluated for myocardial injury employing electrocardiography and estimation of cardiac troponin-l before and after standard ehrlichicidal drug (Doxycycline) and supportive therapy. Of 28 dogs with acute symptoms associated with Ehrlichia canis infection, 21 (75%) showed electrocardiographic changes such as sinus tachycardia, sinus arrhythmia, atrial fibrillation, 2nd degree Mobitz type B heart block, right bundle branch block, atrial premature complexes ST depression, ST elevation and complex changes as sinus arrest with LVC, sinus arrest with VPC, sinus arrest with ST elevation and LVC, VPC, broad QRS with tachycardia at the time of referral and these changes were resolved after 14 days therapy. Nevertheless, these changes lack specificity to predict myocardial insult as diagnostic sensitivity of electrocardiography (ECG) or echocardiography to diagnose minor myocardial injury is poor. The estimation of cardiac troponin I levels at the time of referral revealed increased levels of cTn-l varying from 0.04-3.36 ng/ml with an average of 1.154 ±0.247 ng/ml and median of 0.92 ng/ml suggesting varying level of cardiac injury in acute monocytic ehrlichiosis in 60.71% dogs (17/28). Unexpected fatal outcome in many cases of canine monocytic ehrlichiosis could possibly be due to cardiac injury. The levels of cTn-l reduced drastically (0.11 ±0.007 ng/ml, range 0.05 to 0.26 ng/ml, median 0.09 ng/ml) on 14th day post therapy substantiated that there was reversible cardiac injury in dogs with ehrlichiosis due to Ehrlichia canis infection. [ABSTRACT FROM AUTHOR]