How to measure pharmacokinetics in critically ill patients?

There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups.     

A model to measure anticipatory anxiety in mice?

Among animals from the same cage, mice removed last had a higher temperature compared to those removed first. This phenomenon a) persisted 2 and 24 h later; b) was present regardless of the number of the animals (5, 10, 15 and 20) in each cage, c) was independent of whether the number of animals was reduced or maintained constant in the cage and d) could even be observed by reversing the order of removal of the animals from the cage. In addition, the fewer the animals allocated to a cage the greater the percentage of those which became hyperthermic. This rise in rectal temperature of mice removed last was prevented by diazepam (2.5 and 5 mg/kg PO, 30 min), nitrazepam (2 and 4 mg/kg PO, 30 min) but not by imipramine (15 and 30 mg/kg PO, 30 min) or haloperidol (0.5 and 1 mg/kg PO, 60 min) and was observed in a greater opercentage of mice following subcutaneous yohimbine treatment (2 mg/kg, 60 min). This phenomenon does not seem to depend on physical exercise due to an attempt to escape, since no correlation appears to exist between motor activity (open-field) and rise in rectal temperature. These data would seem to indicate that hyperthermia in the last animals may represent a new tool for studying the neurobiology of anticipatory(?) anxiety.Preliminary results were presented at the XVI C.I.N.P. Congress and at the XXIV National Congress of the Italian Society of Pharmacology     

Is heart rate in fish a sensitive indicator to evaluate acute effects of β-blockers in surface water?

We have investigated if propranolol, a non-selective β-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48 h exposure to a very high concentration of propranolol (70.9 μg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naïve fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets.     

Is heart rate in fish a sensitive indicator to evaluate acute effects of β-blockers in surface water?

We have investigated if propranolol, a non-selective β-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48 h exposure to a very high concentration of propranolol (70.9 μg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naïve fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets.     

Propranolol increases the complexity of heart rate fluctuations--a mode of antiarrhythmic action?

OBJECTIVE: To study the beta-blocking effect of propranolol on heart rate and arterial blood pressure fluctuations in healthy subjects using linear methods and a set of nonlinear models. METHODS: In a randomized, double-blind, placebo-controlled study, healthy young adults received a 40 mg oral dose of propranolol (n = 12) or placebo (n = 12). The effects of propranolol and placebo were assessed using time series of the RR interval (RRI) and systolic arterial blood pressure (SAP) obtained from continuous ECG and blood pressure signal recordings. Heart rate and systolic arterial blood pressure fluctuations were analyzed using nonlinear and linear methods of time series statistics. RESULTS: Propranolol significantly increased the complexity of heart rate fluctuations in terms of symbol dynamic (SymDyn) entropy and symbol dynamic percentage of forbidden words. Propranolol augmented cross entropy between RRI and SAP and increased fractal dimension of RRI. beta-blockade also affected linear measures of RRI fluctuations by increasing parasympathetic, respiration-related high-frequency (HF) variability and arterial baroreflex-related low-frequency (LF) variability. Propranolol administration, however, had no effect on the complexity of SAP fluctuations assessed using nonlinear time series statistics. CONCLUSIONS: beta-blockade by propranolol has a differential effect on RRI and SAP fluctuations in healthy subjects. Propranolol increases the complexity of RRI fluctuations. The effect is associated with the cardiac vagotonic drug action of propranolol. SAP fluctuations are almost unchanged. The increased complexity of RRI fluctuations may be a beneficial feature of beta-blockade, since many cardiovascular diseases decrease the complexity of RRI time series by dampening cardiovascular reflex actions.     

How to unleash mitochondrial apoptotic blockades to kill cancers?

Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.     

How to manage pouchitis in ulcerative colitis?

It is estimated that 50% of patients who have undergone ileal pouch-anal anastomosis (IPAA) surgery for UC will develop at least one episode of pouchitis. The risk of developing pouchitis is much higher in patients with preoperative extraintestinal manifestations and primary sclerosing cholangitis. In acute pouchtis metronidazole or ciprofloxacin have shown efficacy, however there is some evidence that ciprofloxacin may have better and has less toxic. In patients with chronic pouchitis antibiotics are less effective, and maintenance therapy may be required. In cases of refractoriness to conventional therapy a combination of two antibiotics for a prolonged period or infliximab may be effective. Starting maintenance treatment with highly concentrated probiotics is recommended as primary and secondary prophylaxis.     

How circadian variability of the heart rate and plasma electrolytes concentration influence the cardiac electrophysiology – model-based case study

Journal of Pharmacokinetics and Pharmacodynamics - The circadian rhythm of cardiac electrophysiology is dependent on many physiological and biochemical factors. Provided, that models describing the...     

Combinatorial effect of nicotine and black tea on heart rate variability: Useful or harmful?

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Is it possible to measure differences in the cost of antidepressant overdoses?

In this paper an attempt is described to measure the cost differential between treating episodes of overdose on older antidepressants (e.g. TCAs) and those involving newer antidepressants (e.g. SSRIs). Data is presented showing that it is possible to demonstrate a marked cost differential between older and newer agents; although there are difficulties in precisely quantifying the difference. The limitations of the data are discussed and recommendations made for the methodology of a larger, more sensitive, study. Copyright © 1999 John Wiley & Sons, Ltd.     

How can high-throughput screening deliver drugs to treat atherosclerosis?

Importance of the field: Atherosclerosis is a progressive disease that is characterized by the accumulation of lipid-rich plaques within the artery walls. Despite the past 3 decades witnessing the most significant advances in the pharmacotherapy of atherosclerosis with statins, atherosclerosis is still one of the leading causes of mortality in industrialized and developing nations. The applications of high-throughput screening (HTS) have retrieved hits and lead compounds which may be further developed to new promising therapeutics to achieve more effective reductions in the risk of cardiovascular morbidity and mortality. Areas covered in this review: The review provides a summary of potential drug targets other than HMG-CoA reductase (primary target of statins) and their application in biochemical or cell-based HTS assays used by pharmaceutical companies and academic laboratories for anti-atherosclerotic drug discovery. What the reader will gain: The reader will gain an overview of the HTS strategies currently used in the development of anti-atherosclerotic agents. The reader is also provided with some abortive examples in anti-atherosclerotic drug discovery as well as the associated limitations and challenges of the process that HTS delivers new drugs to treat atherosclerosis. Take home message: HTS can assist in the efficient discovery of new drugs towards the potential targets involved in the progress of atherosclerosis.