A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.     

Lead retention in blood and brain after preweaning low-level lead exposure in the rat

Newborn rats of the albino Wistar strain were exposed to lead from birth to 20 days of age through mothers milk, from dams which were fed diets containing 0, 0.25, 0.5 or 1.0% powdered lead. Subsequent determination of tissue lead revealed a direct relationship between the lead levels in both blood and brain of the pups and the lead dosage to which they were indirectly exposed via the dams' milk. Lead retention in both tissues was still evident at 100 days of age, with the relative elevation of lead levels being an order of magnitude higher in brain than in blood. There were no obvious signs of lead intoxication in the pups, apart from mild growth retardation in the group with the highest lead burden. However there was a significant retardation in behavioral development observed on two of four measures which were employed. It was concluded that brief exposure to low lead levels in infancy can have long lasting consequences in the brain and in behavior.     

Multi-slice CT contrast enhancement regimens

Historically, the development of progressively faster Computed Tomography (CT) technology has dictated a recurrent need to re-examine intravenous contrast agent enhancement regimens. The most recently introduced development, the very fast, multi-slice helical/spiral systems, have raised the same issue yet again. It is possible, exploiting the technology to its maximum potential as regards speed, to perform an examination many times faster (depending on the number of detector rings from 4 to 64) even than with earlier single slice spiral instruments. In order to optimise image quality, such maximal speed gains will not usually be sought but, nevertheless, imaging time will generally be substantially reduced. It is natural that the question of a possible need to modify contrast agent enhancement protocols designed for an earlier generation of slower machines should again be considered. Using as a basis known contrast agent pharmacokinetics and results of modelling techniques, the matter is tackled in this paper.     

Design principles for the use of simulation as an aid in interventional cardiology training

Learning complex skills through simulation is a goal for training physicians in specialties such as interventional cardiology, where traditional training puts patients at risk. Intuitively, interactive simulation of anatomy, pathology and therapeutic actions should lead to shortening of the learning curve for novice or inexperienced physicians. An accurate recreation of the interactions among anatomy, pathology and therapeutic actions is a necessary, but not sufficient, condition for the development of a simulation-based training system. In addition to real-time graphic interactivity coupled with haptic response, a successful training tool will require features of a 'learning system' such as: an embedded curriculum, functionality that allows rehearsal and practice, hypertext links to educational information, personal archiving, and instructor review and testing capabilities. We describe how such a system might look for the field of interventional cardiology, and suggest that designing a simulation with both technical and pedagogical fidelity is essential in developing simulation-based training systems in any field of medicine.     

Acute haemodynamic and metabolic effects of dopexamine, a new dopaminergic receptor agonist, in patients with chronic heart failure.

Dopexamine, a new compound with postjunctional dopamine receptor activating and beta adrenoceptor agonist properties, was given to 10 patients with chronic heart failure at diagnostic cardiac catheterisation to investigate its acute haemodynamic and metabolic effects. The drug was administered by intravenous infusion in three incremental doses and produced significant dose related increases in cardiac index, stroke volume index, and heart rate and falls in systemic vascular resistance and left ventricular end diastolic pressure; aortic and pulmonary artery pressures were unchanged. Isovolumic phase (max dP/dt and KVmax) and ejection phase (peak aortic blood velocity, maximum acceleration of blood, and maximum rate of change of power with time during ejection) indices of myocardial contractility were all increased by dopexamine but these changes were hard to interpret in the presence of an increase in heart rate. Myocardial efficiency and ejection fraction were both increased and left ventricular end diastolic and end systolic volumes fell. These largely beneficial changes were achieved without a statistically significant increase in myocardial oxygen consumption or disturbance of myocardial metabolic function. Dopexamine was well tolerated but tremor was reported by two patients at the intermediate dose and mild chest pain by two patients at the high dose.     

The QRS complex during transient myocardial ischemia: studies in patients with variant angina pectoris and in a canine preparation

We made continuous electrocardiographic recordings on magnetic tape during 15 episodes of ischemia in five patients with variant angina to determine the characteristics of the QRS changes. Orthogonal leads were used and the electrocardiograms were analyzed visually and by digital computer. Changes were quantified by subtracting baseline electrocardiograms from those obtained during ischemia. Large changes in the QRS occurred during ischemia but the waveform quickly returned to baseline when the episode subsided. In all patients there was prolongation of the QRS duration and an increase in QRS voltage during the terminal 40 msec of the waveform in the lead(s) showing the most marked ST displacement. The increase in the terminal QRS could be represented by a vector directed toward the ischemic zone. In a given patient the amplitude of ST displacement varied between episodes, presumably because of variation in the intensity of ischemia, but the QRS changes were directionally similar in each episode. In two patients there was also a smaller change involving the initial 40 msec of the QRS that could be represented by a vector directed away from the ischemic zone. To determine the possible mechanism for the electrocardiographic changes, ischemic episodes of 120 to 150 sec were produced in seven dogs and electrocardiographic recording and analysis techniques similar to those used in patients were employed. Myocardial conduction velocity was measured in three directions in the ischemic zone and was correlated with simultaneous electrocardiographic recordings from the body surface. The electrocardiographic changes in the dog preparation were virtually identical to those in the patients and strongly correlated with a fall in myocardial conduction velocity. We conclude that the QRS changes during variant angina result from the altered excitation pattern produced by conduction delay in the ischemic zone. The probable cause for the increase in terminal QRS voltage is delayed (and uncancelled) activation of the ischemic zone.