Biomodification of acenocoumarol by bifidobacteria

ABSTRACT The increased interest of consumers in probiotic foods requires a deeper knowledge on the possible interactions with drugs, because their pharmacological properties could be modified. In this context, these studies are relevant for drugs such as acenocoumarol, whose dosage must be controlled due to, among other factors, food-drug interactions. Acenocoumarol is an oral anticoagulant with a narrow therapeutic range. The aim of the present research is to evaluate, in vitro, the effect of bifidobacteria on acenocoumarol. The drug was incubated with Bifidobacterium bifidum CIDCA 5310 or Bifidobacterium adolescentis CIDCA 5317 in MRS broth at 37°C for 24 h in anaerobic conditions. The effect of incubation with sterilized spent culture supernatants (SSCS) was also evaluated. Analysis by RP-HPLC showed that both bifidobacterial strains reduced the area of the acenocoumarol peak and two new peaks were evidenced. In addition, a decrease in the intensity of the bands at 1650, 1390 and 1110/cm was observed in the FTIR spectroscopic determinations. Moreover, a new band appeared at 1720/cm. No effect on the drug was observed when incubation was performed with SSCS. The present study showed a significant change in the concentration of the anticoagulant after incubation with bifidobacteria and results are compatible with biomodification of the drug due to enzymatic activity of bifidobacteria.

Therapeutic Drug Monitoring: Fundamentals, And Optimization

Therapeutic drug monitoring (TDM) is a teamwork clinical pharmacokinetic services aimed to optimize pharmacotherapy of certain drugs such as those with a narrow therapeutic range, complicated pharmacokinetics. It involves the determination of drug level in blood samples taken at the appropriate time. Interpretation of results requires integration of pharmacokinetics, the pharmacodynamics of the drug and the patient’s clinical profile. To be cost-effective the service should be optimized. This review was written by experts from different developing countries to highlight the fundamentals of the service and provide suggestions for its optimization. These cover the rationale of requesting drug level, design of request form, optimal sampling, and analytical tools. guidelines for appropriate interpretation of drug levels; completeness of the roles of the qualified medical team; continuing education and skills development; involve the patients in improving the service, conducting relevant research; use PK software and integration of TDM with pharmacogenomics

Relevant Issues of Planning Bioequivalence Studies of Drugs with a Narrow Therapeutic Range

In order to be registered, generic drugs with a narrow therapeutic range have to undergo bioequivalence or therapeutic equivalence studies. In most cases, comparative pharmacokinetic studies and demonstration of bioequivalence between the test and the reference products are sufficient for this group of drugs. However, there is no established official definition in Russia for the group of drugs that are regarded as having a narrow therapeutic range. Evaluation of bioequivalence of such drugs has to be performed providing for narrower confidence intervals, which entails certain problems at the stage of bioequivalence study planning. Finding solutions to the problems stated above is of great importance. The aim of the study was to develop approaches to planning bioequivalence studies of drugs with a narrow therapeutic range. Materials and methods: the paper analyses the results of 33 bioequivalence studies of drugs with a narrow therapeutic range, in which Cmax, AUC0-t, and tmax were calculated. Intra-individual variation and weighted mean intra-individual variation of Cmax and AUC0-t were estimated in the study. Statistical processing was performed using IBM SSPS Statistics v.25. and Microsoft Office Excel 2016. Results: the paper summarises criteria for categorising drugs as having a narrow therapeutic range and describes general requirements for assessing their bioequivalence. A number of bioequivalence studies of generic valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine products which meet the criteria for drugs with a narrow therapeutic range, were analysed retrospectively. The data on their pharmacokinetics and intra-individual variation were calculated. It also summarises requirements for bioequivalence evaluation of drugs with a narrow therapeutic range. The paper gives product-specific recommendations for performing bioequivalence studies. Conclusion: the study helped to formulate approaches to the planning of bioequivalence studies of generic drugs with a narrow therapeutic range using the examples of valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine.

Dosage of phenytoin in neurocritical patients using Bayesian algorithms: a pilot study

Phenytoin is widely used in neurocritical patients. Owing to its high pharmacokinetic variability and narrow therapeutic range, plasma level-guided dosing has become the standard. Bayesian prediction (BP) is considered the most flexible and precise pharmacokinetic strategy among several options. A retrospective study of BP dosage adjustment in 20 patients (35 plasma measures) was developed. Results indicated that 70% of phenytoin plasma levels of first plasma samples were beyond the therapeutic range. Phenytoin doses were also estimated according to BP for all patients. The measurements confirmed the ability of the strategy to lead to optimal dosage in 80% of patients, thus indicating a three-fold improvement over the basing dosage adjustment recommended in the literature.

How does the mood stabilizer lithium bind ATP, the energy currency of the cell

Lithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.We determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3-5.5 Å from Li, and coordinate the first phosphate and two terminal phosphates.In conclusion, solid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate. The methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.

Preparasi Teofilin dalam Pembawa Vesikular Etosom untuk Penggunaan Transdermal

Theophylline is a methyl xanthine of alkaloid derivative compound has been used as a bronchodilator in the treatment of chronic lung disorders, especially asthma. Oral administration of theophylline causes inconvenient for patients including bitter taste, narrow therapeutic range, and indigestion due to increased of gastric acid secretion. Therefore, other administration of theophylline has been developed as transdermal delivery system. This study disscused about preparation of theophylline in ethosome as vesicular carrier. Preparation of ethosome was used hot method (40oC) and cool method (30oC). Characterization of ethosomes includes observation of shape and size of vesicles by microscopic method and the vesicles were fractionated by centrifugation then entrapment efficiency (% EE) were measured by spectrophotometric method. Then optimazed theophylline that entrapped in ethosome. Based on the results, ethosomes preparation by hot method were produced Small Unilamellar Vesicle (SUV), the size were 0,0522-0,100 µm, and the highest value of % EE was 98.95%, while ethosomes preparation by cold method were produced Small Unilamellar Vesicle (SUV), the size were 0.0522-0.100 μm, and the highest value of % EE was 99.80%. The optimum concentration of theophylline was entrapped in etosom was 0.1%. It was concluded that cold method was the appropriate method for preparation of theophylline in ethosome as vesicular carrier.Keywords: Etosome, theophylline, vesicular, transdermal

High-Resolution Melting Assay for Genotyping Variants of the CYP2C19 Enzyme and Predicting Voriconazole Effectiveness

ABSTRACT Voriconazole is a triazole antifungal agent recommended as primary treatment for invasive aspergillosis, as well as some other mold infections. However, it presents some pharmacokinetic singularities that lead to a great variability intra- and interindividually, nonlinear pharmacokinetics, and a narrow therapeutic range. Most experts have recommended tracing the levels of voriconazole in patients when receiving treatment. This azole is metabolized through the hepatic enzyme complex cytochrome P450 (CYPP450), with the isoenzyme CYP2C19 being principally involved. Allelic variations (polymorphisms) of the gene that encodes this enzyme are known to contribute to variability in voriconazole exposure. Three different allelic variants, CYP2C19*17, CYP2C19*2, and CYP2C19*3, could explain most of the phenotypes related to the voriconazole metabolism and some of its pharmacokinetic singularities. We designed a rapid molecular method based on high-resolution melting to characterize these polymorphisms in a total of 142 samples, avoiding sequencing. Three PCRs were designed with similar cycling conditions to run simultaneously. The results showed that our method represents a fast, accurate, and inexpensive means to study these variants related to voriconazole metabolism. In clinical practice, this could offer a useful tool to individually optimize therapy and reduce expenses in patients with fungal infections.

A CASE REPORT ON DIGOXIN INTOXICATION IN A CLINICAL PHARMACIST’S PERSPECTIVE

Context: Digoxin is a commonly used inotropic drug that has a narrow therapeutic range and is monitored poorly for its plasma concentration. It is commonly used in the management of cardiovascular disorders for its inotropic effects. Increased risk of chronic digoxin toxicity among the patients receiving digoxin pharmacotherapy is related to its narrow therapeutic range. Apart from its inotropic properties, it can also produce chronotropic and dromotropic effect. Its serum levels vary due to changes in body weight, age, renal function, hepatic impairment, and concomitant drug administrations. Patients receiving digoxin should be monitored periodically for potential drug interactions, adverse effects, toxicity, and other drug-related problems. Symptoms of digoxin-induced cardiotoxicity are difficult to be identified and may become fatal too. Therapeutic drug monitoring will play a significant role in reducing such drug therapy problems and will ensure safety and efficacy of the given drug. Case Report: We report a case of chronic digoxin toxicity in a 22-year-old male with congestive cardiac failure - Class IV and atrial fibrillation with ventricular bigeminy. Results: Patient’s renal parameters were elevated and among electrolytes, sodium level was decreased and potassium level was increased. A reduction in the volume of the distribution of digoxin, due to impairment of renal function or congestive cardiac failure, might be one of the reasons for digoxin toxicity. Drug therapy problems (DTPs) such as untreated indication, inappropriate drug therapy, potential major drug-drug interactions, and drugs prescribed when contraindicated were observed. Conclusion: Monitoring digoxin drug therapy can bring down the risk of digoxin intoxication.

Cross sectional study on different doses of acenocoumarol with INR in a tertiary care hospital

Background: It is of high value to be assess the relationship between doses of Acenocoumarol and the INR values to offer better patient care. Since Acenocoumarol is a commonly used drug with a narrow therapeutic range it is essential to monitor the variations encountered in response to it to avoid drastic complications and to provide better health care. Aim: The aim of this study is to compare the INR values with different doses of Acenocoumarol, to compare the association of dose of Acenocoumarol with their respective INR and to find out the occurrence of bleeding with different doses of Acenocoumarol.Methods: The study was conducted in a Tertiary care hospital. 40 patients taking Acenocoumarol were recruited in the study. Relevant details like age, weight, dose of Acenocoumarol, INR and other concomitant drugs were obtained in a prospective manner. Correlation of dose of Acenocoumarol with respective INR was done by simple linear regression.Results: The relationship between dose and INR was analyzed using Simple linear regression and the scatter plot revealed no significant correlation between the dose and INR values. There is a lot of inter-individual variability in the dose response and thereafter the INR values.Conclusions: The dose of Acenocoumarol cannot predict INR values. Patient can ideally be started treatment on a low dose of Acenocoumarol and based on the INR values, dose can be titrated. There is a need for consideration of other factors which influence the dose and INR values.

Prognostic impact of digoxin use for rate control of atrial fibrillation in patients ≥75 years of age

Digoxin use remains a common therapeutic option in the pharmacological control of heart rate in patients with atrial fibrillation, endorsed in current guidelines with the same level of evidence than beta-blockers in patients with and without heart failure. Digoxin has a narrow therapeutic range and is influenced by drug‐to‐drug interactions, serum electrolyte concentrations, and renal function. Conflicting data exist regarding adverse outcomes that are associated with digoxin use in patients with atrial fibrillation. It remains unclear whether the association between digoxin use and worse clinical outcome is causal or may be the result of confounding by differences in the characteristics of patents including age, comorbidities and treatment. Particularly in older patients with atrial fibrillation, who are frequently prescribed a multitude of agents for stroke prevention, treatment of cardiovascular disease and other comorbidities, use of digoxin should be cautious and instituted with assessment of drug concentrations.