Drug Contraindications in Comorbid Diseases: a Protein Interactome Perspective

Adverse drug reactions (ADRs) are leading causes of death and drug withdrawals and frequently co-occur with comorbidities. However, systematic studies on the effects of drugs in comorbidities are lacking. Drug interactions with the cellular protein-protein interaction (PPI) network give rise to ADRs. We selected 6 comorbid disease pairs, identified the drugs used in the treatment of the individual diseases A and B — 44 drugs in anxiety and depression, 128 in asthma and hypertension, 48 in chronic obstructive pulmonary disease and heart failure, 58 in type 2 diabetes and obesity, 58 in Parkinson′s disease and schizophrenia, and 84 in rheumatoid arthritis and osteoporosis — and categorized them based on whether they aggravate the comorbid condition. We constructed drug target networks (DTNs) and examined their enrichment among genes in disease A/B PPI networks, expressed across 53 tissues and involved in ≈1000 pathways. To pinpoint the biological features characterizing the DTNs, we performed principal component analysis and computed the Euclidean distance between DTN component scores and feature loading values. DTNs of disease A drugs not contraindicated in B were affiliated with proteins common to A/B networks or uniquely found in the B network, similarly regulated common pathways, and disease-B specific pathways and tissues. DTNs of disease A drugs contraindicated in B were affiliated with common proteins or those uniquely found in the A network, differentially regulated common pathways, and disease A-specific pathways and tissues. Hence, DTN enrichment in pathways, tissues, and PPI networks of comorbid diseases will help identify drugs contraindications in comorbidities.

A Review Study on Prakriti (Body Constitution) Specific Herbal Tea in Diabetes Mellitus

: Among the health challenges management of Diabetes is very important. This is on account of the decrease in the age of incidence, high prevalence and systemic complications that reduce the quality of life of patients. The age-standardised DALY rate was highest among major non-communicable diseases for Diabetes which is increased in India by 39·6% from 1990 to 2016. Further, the conservative management through modern medicine has produced many adverse effects along with invariable systemic complications. Personalised Prakriti-based medicine is the most unique feature of Ayurveda as compared to modern medicine which advocates disease specific management irrespective of personal factors. This personalised Prakriti specific management offered by Ayurveda will play a vital role in changing the scenario of global health wisdom. It offers holistic package of modalities encompassing diet, lifestyle, and medication. Prakriti-based herbs are likely to offer remedies for the health issues like adverse drug reactions, drug withdrawals, and economic disparities. Hence, review study on personalised Prakriti specific herbal tea for Diabetes mellitus (Madhumeha) throws light on the various herbs along with their mode of action which can be very effective remedy.

A Highly Sensitive Fluorogenic Assay for the Detection of Nephrotoxin-Induced Oxidative Stress in Live Cells and Renal Tissue

A common manifestation of drug toxicity is kidney injury or nephrotoxicity. Nephrotoxicity frequently leads to termination of clinical trials and drug withdrawals, which jeopardize biomedical progress. Efficient preclinical screening platforms capable of detecting mild signs of kidney damage, which may elicit considerable toxic response in vivo, are essential. A common manifestation of chemical toxicity is oxidative modification of cellular biomolecules. Therefore, we have developed a facile biomolecule carbonyl detection assay that well surpasses the sensitivity of the standard assays in identifying modest forms of renal injury. Using a novel fluorogenic sensor, TFCH, we have demonstrated the applicability of the assay in live kidney cells and in renal tissue. This robust assay can help inform preclinical decisions to recall unsafe drug candidates. Application of this assay in identifying and analyzing diverse pathologies is envisioned.

Simultaneous explantation and implantation of intrathecal pumps: a case series

OBJECTIVEIntrathecal drug delivery devices (IDDDs) are a mainstay in the treatment of spasticity and refractory pain. While these devices have been shown to greatly improve the quality of life for patients, they also have a high perioperative complication and failure rate. A major complication of IDDD implantation is infection. The current standard of care in the treatment of IDDD infection necessitates that the pump be explanted and the infection treated prior to implantation of a new IDDD. This process leads to long hospital stays, interruptions in optimal medical management, and a high risk for dangerous drug withdrawals. The authors describe a technique that allows for the explantation of the infected pump and implantation of a new pump concurrently, which they have named the “Turner Switch” technique in honor of its inventor.METHODSThe authors conducted a retrospective analysis of cases of infected IDDDs in which patients underwent simultaneous explantation of the infected pump and implantation of a new pump. Demographics and clinical data were collected.RESULTSData from a total of 17 patients (11 male, 6 female) who underwent simultaneous IDDD explantation and implantation to treat infections were analyzed from a 3-year period. No patients experienced infection of the newly implanted pump or catheter. Of the 17 patients, 14 (82.4%) had baclofen pumps to treat spasticity and 3 (17.6%) had fentanyl pumps to treat chronic pain. The median hospital stay was 7 days, with 16 of 17 (94.1%) patients able to be discharged home or to a facility with a level of care similar to their preoperative care. All patients ultimately experienced complete resolution of their initial infections. Five patients (29.4%) required a return to the operating room within the next 5 months (for repair of a CSF leak in 2 cases, for treatment of infection at the old pump site in 2 cases, and for treatment of a CSF leak compounded with infection in 1 case). No patient experienced infection of the newly implanted pump or catheter.CONCLUSIONSIDDD infections represent a large portion of morbidity associated with these devices. The current standard of care for deep pump infections requires pump explantation and a course of antibiotics prior to reimplantation of the IDDD. The authors demonstrate the effectiveness of a procedure involving simultaneous explantation of an infected pump and implantation of a new pump on the contralateral side in the treatment of IDDD infections.

Pharmacovigilance in perspective: drug withdrawals, data mining and policy implications

Considering that marketed drugs are not free from side effects, many countries have initiated pharmacovigilance programs. These initiatives have provided countries with methods of detection and prevention of adverse drug reactions at an earlier stage, thus preventing harm occurring in the larger population. In this review, examples of drug withdrawals due to effective pharmacovigilance programs have been provided with details. In addition, information concerning data mining in pharmacovigilance, an effective method to assess pharmacoepidemiologic data and detecting signals for rare and uncommon side effects, is also examined, which is a method synchronized with information technology and advanced electronic tools. The importance of policy framework in relation to pharmacovigilance is discussed in detail, and country experiences upon implementation of pharmacovigilance policies is highlighted.

Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

ECG in a dish: A credible alternative to animal pre-clinical cardiovascular safety models?

The rhythmic beating of the heart is attributable to the interplay of numerous ion channels expressed in the cardiac muscle. One of these ion channels, the human ether-à-go-go related gene (hERG) K+ channel, is responsible for curtailing the excitability or action potential that initiates the cardiac muscle contraction. Unfortunately, the pore of the hERG K + channel is particularly susceptible to blockade by drugs. Disruption of hERG K+ channel activity can prolong the depolarization of the heart sufficiently to perturb regular beating which, if not corrected, can result in sudden cardiac death. When this drug-induced irregular beating of the heart, or proarrhythmia, is associated with ventricular arrhythmias, this phenomenon is termed Torsades de Pointes (TdP). TdP has resulted in many marketed drug withdrawals (e.g. the antihistamine terfenadine) and termination of promising pre-clinical and clinical drug development candidates.