scholarly journals A High Fidelity Transmural Anisotropic Ventricular Tissue Model Function to Investigate the Interaction Mechanisms of Drug: An In-Silico Model for Pharmacotherapy

2021 ◽  
Author(s):  
Srinivasan Jayaraman ◽  
Ponnuraj Kirthi Priya
Keyword(s):  
Drug Interaction ◽  
In Silico ◽  
Drug Dosage ◽  
Severe Hypoxia ◽  
High Fidelity ◽  
Fatality Rate ◽  
Tissue Model ◽  
Ventricular Tissue ◽  
Mild Hypoxia ◽  
Epicardial Myocytes

A high fidelity transmural anisotropic ventricular tissue model consisting of endocardial, mid myocardial, and epicardial myocytes were configured to investigate drug interaction, such as Hydroxychloroquine (HCQ), under hypoxia conditions without and with pro-arrhythmic comorbidity like hypokalemia in (a) ventricular tissue b) its arrhythmogenesis for different dosages and (b) two different pacing sequences (Normal and tachycardiac). In-silico ventricular modeling indicates HCQ has an insignificant effect on hypoxia with and without comorbidities, except in the combination of mild hypoxia with moderate hypokalemia condition and severe hypoxia with mild hypokalemia where it initiated a re-entrant arrhythmia. Secondly, incorporating drug dosage variations indicates the 10 μM HCQ created PVCs for all settings except in severe hypoxia conditions where re-entrant arrhythmia occurred. In addition to the dosage of HCQ utilized for treatment, the pacing protocol also influences the appearance of re-entrant arrhythmia only for severe hypoxia with 10 μM HCQ dosage alone. For all other conditions, including tachycardiac pacing protocol, no arrhythmia occurred. These findings infer that the arrhythmic fatality rate due to HCQ treatment for hypoxia can be effectively alleviated by subtly altering or personalizing the dosage of HCQ and aid in the treatment of hypoxia-induced symptoms caused by COVID.

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance

1991 ◽  
Vol 71 (2) ◽  
pp. 709-715 ◽  
Author(s):  
R. J. Salmone ◽  
E. Van Lunteren
Keyword(s):  
Force Production ◽  
Upper Airway ◽  
Muscle Performance ◽  
Severe Hypoxia ◽  
Force Frequency ◽  
Force Output ◽  
Frequency Curve ◽  
Dilator Muscle ◽  
Index Ratio ◽  
Mild Hypoxia

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45–65 Torr), and hypercapnia (PCO2 55–80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.

Effects of hypoxia on thermal polypnea in intact and carotid body-denervated conscious cats

1989 ◽  
Vol 67 (2) ◽  
pp. 578-583 ◽  
Author(s):  
M. Bonora ◽  
H. Gautier
Keyword(s):  
Body Temperature ◽  
Carotid Body ◽  
Heat Load ◽  
Heat Exposure ◽  
Ambient Air ◽  
Severe Hypoxia ◽  
Central Action ◽  
Lower Body ◽  
Respiratory Response ◽  
Mild Hypoxia

The effects of the level of oxygenation on the respiratory response to heat exposure have been studied in conscious cats during normoxia, severe or mild hypocapnic hypoxia [inspired O2 fraction (FIO2) = 0.11 or 0.13], or hyperoxia. Several cats were also studied during severe normocapnic hypoxia. Experiments were repeated while the same animals were chronically carotid body denervated (CBD). The increase in respiratory frequency (f) leading to thermal tachypnea occurred at a lower body temperature (Tb) in severe hypocapnic hypoxia than in ambient air, but this effect was less pronounced when hypocapnia was corrected. No significant changes were observed during mild hypoxia or hyperoxia compared with normoxia in intact animals. After CBD, thermal tachypnea occurred at lower Tb in air than it did with intact animals in three of five cats, and it also occurred at lower Tb in mild hypocapnic hypoxia compared with air. It appears, therefore, that in conscious cats exposed to heat load 1) severe hypoxia enhances thermal tachypnea, 2) this effect persists after CBD, which suggests that it originates from a central action of hypoxia, and 3) the chemoreceptor afferents, to some degree, inhibit the onset of thermal tachypnea, as was previously observed for hypoxic tachypnea, which appears only in CBD cats (J. Appl. Physiol. 49: 769–777, 1980). Therefore, triggering of thermal and hypoxic tachypnea may involve common central mechanisms, probably located in the diencephalic structures under the control of afferents from arterial chemoreceptors.

RESPONSE OF ANTIDIURETIC HORMONE TO ACUTE EXPOSURE TO MILD AND SEVERE HYPOXIA IN MAN

1978 ◽  
Vol 77 (2) ◽  
pp. 157-160 ◽  
Author(s):  
J. R. CLAYBAUGH ◽  
J. E. HANSEN ◽  
D. B. WOZNIAK
Keyword(s):  
Carbon Dioxide ◽  
Partial Pressure ◽  
Antidiuretic Hormone ◽  
Plasma Osmolality ◽  
Gas Mixtures ◽  
Renin Activity ◽  
Severe Hypoxia ◽  
Partial Pressure Of Oxygen ◽  
Nitrogen Gas ◽  
Mild Hypoxia

SUMMARY Eight men, 19-35 years of age, breathed 20·9% (normal oxygen), 13·9% (mild hypoxia) or 11·1% (severe hypoxia) oxygen in nitrogen gas mixtures during three 20 min periods, which were separated by 1 h recovery periods. The order in which the gas mixtures were breathed was random. The partial pressure of oxygen decreased from a mean of 93·5 during exposure to normal oxygen to 53·9 and 36·7 mmHg during mild and severe hypoxia respectively. There were corresponding decreases in haemoglobin saturation. The partial pressure of carbon dioxide was lower and the pH higher during severe hypoxia than during exposure to normal oxygen. There were no changes in the plasma osmolality or in the concentrations of sodium or potassium in the plasma. There was a tendency for both the renin activity and the concentration of aldosterone in the plasma to decrease progressively as the percentage of oxygen breathed decreased. Unlike severe hypoxia, mild hypoxia suppressed the concentration of antidiuretic hormone (ADH) in the plasma of all subjects by about 59%; during severe hypoxia the reduction was not significant, being only about 33%. These data are consistent with the suggestion that the effect of hypoxia on the release of ADH is dependent on the level of hypoxia.

scholarly journals In Silico Prediction of Cytochrome P450-Drug Interaction: QSARs for CYP3A4 and CYP2C9

2016 ◽  
Vol 17 (6) ◽  
pp. 914 ◽  
Author(s):  
Serena Nembri ◽  
Francesca Grisoni ◽  
Viviana Consonni ◽  
Roberto Todeschini
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
In Silico ◽  
In Silico Prediction

scholarly journals COMEDICATION OF RABEPRAZOLE SODIUM CAUSES POTENTIAL DRUG-DRUG INTERACTION WITH DIABETIC DRUG LINAGLIPTIN: In-vitro AND In-silico APPROACHES

2021 ◽  
Vol 9 (4) ◽  
pp. 528-542
Author(s):  
Md. Jamal Hossain ◽  
◽  
Md. Shamiul Islam ◽  
Saimon Shahriar ◽  
Sherejad Sanam ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Melting Point ◽  
In Silico ◽  
Synchronous Fluorescence ◽  
Current Evidence ◽  
Diabetic Patients ◽  
Potential Drug ◽  
Rabeprazole Sodium ◽  
Drug Drug Interaction

Drug-drug interaction is a notable concern among physicians when prescribing multi-therapy to the patients as concomitant administration of multi-drugs might cause unexpected adverse drug reactions. The main objective of this research is to predict a potential drug-drug interaction between two frequently used drugs by diabetic patients, an antidiabetic drug (linagliptin) and a proton pump inhibitor (rabeprazole sodium). Here, several in vitro techniques, including thermal (melting point, thermogravimetric analysis [TGA]), morphological (scanning electron microscopy [SEM] and X-ray powder diffraction [XRPD] analysis), highly sophisticated synchronous fluorescence, and in silico methods were applied to anticipate the potential drug-drug interaction between these stated drugs quickly. The melting point and TGA study revealed thermochemical properties, thermal stability profiles, and degradation patterns upon temperature rising of the formed complex and these precursor drugs. The SEM and XRPD have provided the morphological changes like particle shape and size distribution of the desired molecule that might be caused due to the potential drug-drug interactions. Besides, the drastic reduction of the quenching rate constant of linagliptin during interaction with bovine serum albumin in synchronous fluorescence also endorsed the potential drug-drug interaction. Furthermore, the drug-receptor docking analysis demonstrated that the binding affinity of the precursor ligands might be reduced due to the predicted drug-drug interaction. However, the current evidence warrants extensive investigation to confirm the above-stated potential drug-drug interaction in the larger animal model. Finally, clinical data need to be closely monitored during the treatment of diabetic patients prescribed with linagliptin and rabeprazole sodium.

scholarly journals Drug Interaction Management in Critically Ill Patient

2021 ◽  
pp. 396-416
Author(s):  
Hemraj Singh Rajput ◽  
Nirmal V. Shah
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Critically Ill ◽  
Clinical Pharmacist ◽  
Alternative Therapy ◽  
Drug Dosage ◽  
Critically Ill Patient ◽  
Time Interval ◽  
Patient Health ◽  
Interaction Management

Drug interaction in critically ill patient is very common and affecting patients Physically, Mentally and Financially. There are various measures which has been taken to minimize this burden on patient, such as books being prepared which include various drug interaction, maintain websites and database that provides information regarding drug interactions. With the use of these website and databases the drug interaction can be managed. It is common practice that side effects of drug interaction are being managed by additional drugs, the main reason behind it could be non-availability of alternative drugs or costlier alternative. These factors remain the main cause of treatment failure in majority of patients leading to prolong. The current study was performed for the duration of 12 months, from this study it was identified that 113 types of major drug interactions commonly found in total 250 prescriptions which were evaluated and managed accordingly. Suggestions being prescribed by various sites were, avoid concomitant use of drug, use alternative therapy, and monitor closely for any adverse effect. During suggestion made by the Clinical Pharmacist, for the same drug interactions it was identified that more of drug therapy adjustment can be done then provided by the online database. The parameter on which the drug interactions management are being suggested were focused on just type of drug interaction and its effect, it does not include the actual pharmacodynamic and pharmacokinetic changes in therapy. The suggestion made by the clinical pharmacist were includes drug removal, drug dosage changes, alternative therapy, alternative route of administration, change in time interval etc. From this study it was concluded that the drug interaction management can be done at various stages of treatment with proper therapy modification by the clinical pharmacist, and if done properly it will improve the overall outcome of patient health care.

Fetal breathing, sleep state, and cardiovascular responses to graded hypoxia in sheep

1987 ◽  
Vol 62 (3) ◽  
pp. 1033-1039 ◽  
Author(s):  
B. J. Koos ◽  
H. Sameshima ◽  
G. G. Power
Keyword(s):  
Low Voltage ◽  
Cardiovascular Responses ◽  
Severe Hypoxia ◽  
Sleep State ◽  
Fetal Sheep ◽  
Fetal Bradycardia ◽  
O2 Concentration ◽  
Fetal Breathing ◽  
The Mean ◽  
Mild Hypoxia

Graded isocapnic hypoxemia was produced in unanesthetized fetal sheep by varying the inspired O2 concentration (21, 12, 10.5, and 9%) of the ewe. This produced corresponding mean preductal arterial O2 tension (PaO2) values of 25.2 +/- 1.1 (control), 20.1 +/- 1.0 (mild hypoxia), 17.8 +/- 0.9 (moderate hypoxia), and 16.8 +/- 1.4 Torr (severe hypoxia). These were associated with mean arterial O2 contents (CaO2) of 7.18 +/- 0.44, 5.19 +/- 0.34, 4.24 +/- 0.33, and 3.27 +/- 0.20 ml/dl, respectively. The most severe hypoxia was associated with metabolic acidosis and fetal bradycardia. Hypoxia did not reduce significantly the incidence of low-voltage electrocortical activity. The incidence of breathing and rapid eye movements was not affected by mild hypoxia; however, the incidence of both was significantly reduced during moderate and severe hypoxia. It is concluded that 1) acute reductions in the mean PaO2 of 5.9 +/- 0.6 Torr and CaO2 of 2.00 +/- 0.23 ml/dl are critical in that greater reductions inhibit fetal eye and breathing activity and 2) hypoxia probably inhibits eye and breathing movements by altering sleep state.

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