Pharmacological and Host Considerations Surrounding Dose Selection and Duration of Therapy with Echinocandins

Caspofungin, micafungin and anidulafungin are antifungal drugs with excellent safety profiles. Dosing regimens and treatment durations must be appropriate for optimal patient outcomes. Overall, factors that affect dosing of all three drugs are similar. Drug-specific properties, including in vitro concentration-dependent antifungal activity, activity against fungal biofilms, and pharmacokinetic and pharmacodynamic parameters influence dose selection and duration of therapy. Dosing strategies that provide “unbound” plasma drug concentrations exceeding the minimum inhibitory concentration (or minimum effective concentration) of the fungus are essential. Patient weight, age and illness severity are also important considerations for adequate exposure to drug: individuals >66 kg, pediatric patients and the critically-ill clear drug at higher rates although drug product information guidelines do not recommend for these populations to receive doses higher than those currently used. Clinical studies of treatment of, and prophylaxis against, Candida and Aspergillus infection indicate that currently recommended dosing regimens are adequate in most instances.     

Pefloxacin pharmacokinetics in pyo-inflammatory diseases of the kidneys and urinary tract]

The factors defining the therapy efficacy were studied in 15 patients with purulent inflammatory diseases of the kidneys and urinary tract. It was found that after the use of pefloxacin, urine bactericidal properties against a pathogen was pH-dependent due to high urinary norfloxacin levels. To predict the efficacy of pefloxacin therapy in renal and urinary diseases, the pathogen should be tested for sensitivity to pefloxacin and norfloxacin within a wide range of pH values. Pefloxacin concentrations correlated with plasma bactericidal properties with respect to the pathogen and was applicable in defining the optimal treatment schemes and doses based on the data of individual drug pharmacokinetics. Monitoring of plasma and urine bactericidal properties in regard to the pathogen proved to be useful in estimating the therapy efficacy.     

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.     

Recent advances in drug therapy for epilepsy.

Recent advances in drug therapy for epilepsy have contributed to the reduction in the proportion of persons whose epilepsy is uncontrolled. New knowledge of the pharmacokinetics of phenytoin has led to a better understanding of the drug''s bioavailability and uses. Carbamazepine has recently been introduced for the treatment of generalized tonic-clonic and partial seizures. Clonazepam has been found of particular benefit in the treatment of absence and myoclonic seizures. Valproic acid is a promising antiepileptic drug with broad-spectrum activity, and is particularly useful in the treatment of absence and myoclonic seizures, although further clinical experience is required before it can supplant ethosuximide as the preferred drug for the treatment of absence seizures. Monitoring of the plasma concentration of antiepileptic drugs has added greatly to the achievement of optimal drug therapy and the prevention of toxic effects.     

Molecular aspects of extracorporeal photochemotherapy

8-methoxypsoralen (8-MOP), activated upon exposure to long-wavelength ultraviolet radiation, is used therapeutically to treat the diseased blood cells of cutaneous T-cell lymphoma patients. The factors responsible for the efficacy of this therapy are reviewed. Primary among these are the plasma level of 8-MOP at the time of irradiation and the effective dose of UVA. 8-MOP plasma levels determined in a series of six patients demonstrated that the drug is absorbed at a highly variable rate (122 ng/ml +/- 67). A new liquid form of 8-MOP is absorbed with a modest increase in plasma levels (170 ng/ml) but with no improvement in the variability (+/- 163). An examination of the dose-response relationship between 8-MOP concentration and UVA dose indicated that properties such as 8-MOP photoadduct formation and PHA response are proportional to the combined doses of these two factors. A new molecular target for 8-MOP photomodification, cell membrane DNA, is described.     

Parameter optimisation in clinical pharmacokinetics

This paper describes a package of computer program designed to be used in Clinical Pharmacokinetics or Clinical Chemistry Laboratories to assist in the interpretation of plasma drug concentration measurements. A simple pharmacokinetic model is utilised, and values of the necessary parameters for the general population determined using standard nomograms. Parameter estimates for individual patients are obtained by a feedback process using Bayes' theorem and the principle of maximum likelihood. Thus optimal dosage regimes can be obtained for individual patients. The package can be used with a series of drugs.     

Pharmacokinetics of meloxicam in rabbits after single and repeat oral dosing

We evaluated the pharmacokinetic profile of meloxicam (0.3 and 1.5 mg/kg) given as single and repeated (once daily for 5 d) oral doses to female rabbits (n = 5/group) to define the optimal dose and dosing interval for clinical use. Clinical signs, body weight, and serum chemistry parameters (sodium, potassium, chloride, total protein, urea, creatinine, glucose, alkaline phosphatase, gamma glutamyl transferase, and alanine aminotransferase) were evaluated before and 5 d after dosing to monitor safety at the 2 dose levels in both studies. Plasma samples were collected serially, and concentrations were determined by high performance liquid chromatography. After single oral dosing at 0.3 or 1.5 mg/kg, maximal plasma concentrations of meloxicam were achieved at 6 to 8 h and were 0.14 and 0.3 microg/ml, respectively. Plasma drug levels decreased rapidly to near-undetectable levels by 24 h. There was moderate interindividual variability in plasma meloxicam concentrations with less than proportional increases in peak plasma concentration and area under the concentration curve values at the higher dose after the single and repeat dosing. The elimination half-life was approximately 8 h at both dose levels, suggesting that metabolism was not saturated. Oral clearance of meloxicam is high in rabbits, indicating rapid metabolism and elimination. There was no accumulation of meloxicam when given at 0.3 or 1.5 mg/kg for 5 d, and meloxicam was rapidly eliminated after discontinuation of dosing. Rabbits may require a dose exceeding 0.3 mg/kg given once daily to achieve optimal plasma levels of meloxicam over a 24-h interval.     

Optimal controls for a model with pharmacokinetics maximizing bone marrow in cancer chemotherapy

A mathematical model for the depletion of bone marrow under cancer chemotherapy is analyzed as an optimal control problem. The control represents the drug dosage of a single chemotherapeutic agent and pharmacokinetic equations which model its plasma concentration are included. The drug dosages enter the objective linearly. It is shown that optimal controls are bang-bang, i.e. alternate the drug dosages at full dose with rest-periods in between, and that singular controls which correspond to treatment schedules with varying dosages at less than maximum rate are not optimal. Numerical simulations are given to illustrate the effect of the pharmacokinetic equations on the dosages.     

Pharmacokinetic analysis and calculations using a program for the minicalculator TI-59

The described pharmacokinetic program for TI-59 is in clinical practice applicable in analyses of plasma concentration profiles established after single-dose, intravenous or oral administration of drugs showing one- or two-compartment first-order pharmacokinetics. Analysis of multiple dose, steady state plasma concentration data may also be carried out. Predictions of mean steady state plasma concentrations related to multiple dose drug administration are obtainable on the basis of a preceding single-dose pharmacokinetic analysis. The program contains routines for: exponential regression analysis, determination of and treatment of residuals, simulation of plasma concentration curves, corrections for time-defined intravenous infusion substituting for bolus injection, determination of and correction for lag-time and routines for calculation of fitted and derived pharmacokinetic parameters. Naproxen and theophylline plasma concentration data were used to demonstrate the practical applications of the program.     

Slow intravenous administration of low dose aspirin inhibits both vascular and platelet cyclooxygenase activity: an experimental study in the rat

Aspirin irreversibly inhibits cyclooxygenase, thus preventing thromboxane (Tx)A2 production in platelets and prostacyclin in vascular cells. While it is generally accepted that the inhibitory effect of low dose aspirin is cumulative on platelet cyclooxygenase, it is still a matter of debate whether a similar phenomenon also occurs on vascular cyclooxygenase. We have measured in anesthetized rats the inhibitory effect of two doses of aspirin (2.5 and 5.0 mg/kg), given intravenously either as a bolus or as a continuous infusion (for 30 min), on platelet TxB2 and 6-ketoprostaglandin F1 alpha generation by different vascular segments. Aspirin significantly inhibited both platelet and vascular cyclooxygenase independently of the rate of drug administration. The aspirin peak plasma levels at the end of bolus injection was about 170 times higher than the average level measured during the slow infusion (1.21 +/- 0.15 micrograms/ml). At this concentration aspirin did not affect in vitro either platelet or vascular cyclooxygenase activity. Thus the inhibitory effect of aspirin on both platelet and vascular cyclooxygenase seems to be related to total exposure of the enzyme to the drug rather than to the maximal drug concentration attainable in the systemic circulation. These findings may be relevant to the current debate on optimal conditions for the biochemical selectivity of aspirin as an antithrombotic drug.     

阿奇霉素治疗支原体肺炎的序贯疗法定量分析

利用室分析方法,建立了药物动力学模型,给出了静脉、口服多次用药后血药浓度,并绘制出药时曲线,分析了所给的阿奇霉素治疗支原体肺炎的序贯疗法用药方案可行性,提高了用药的依从性。     

A mathematical model of cancer chemotherapy with an optimal selection of parameters

An optimal parameter selection model of cancer chemotherapy is presented which describes the treatment of a tumor over a fixed period of time by the repeated administration of a single drug. The drug is delivered at evenly spaced intervals over the treatment period at doses to be selected by the model. The model constructs a regimen that both minimizes the tumor population at the end of the treatment and satisfies constraints on the drug toxicity and intermediate tumor size. Numerical solutions show that an optimal regimen withholds the bulk of the doses until the end of the treatment period. When a drug used is of either moderate or low effectiveness, an optimal regimen is superior to a schedule that delivers all of the drug at the beginning of the treatment. This study questions whether the current method for the administration of chemotherapy is optimal and suggests that alternative regimens should be considered.     

Variability in Response to Drugs

Variability in the response to drugs is due to three principal components—the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.     

The effect of desmethylimipramine on the metabolism of norepinephrine

Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.     

Modulatory effects of one polysaccharide from Acanthopanax senticosus in alloxan-induced diabetic mice

One water-soluble polysaccharide ASP was purified from Acanthopanax senticosus and its physicochemical properties were confirmed by the combination of chemical and instrumental analysis. ASP administered orally at three doses (100, 200 and 400 mg/kg body weight) could significantly decrease the concentration of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) cholesterol levels except for high density lipoprotein (HDL) cholesterol level and the relative ratio (HDL/TC) in alloxan-induced diabetic mice, compared with the diabetic controls without drug treatment, comparable with that of diabetic mice treated with metformin. Furthermore, ASP could obviously increase the body weight and serum insulin level and reduce the fasting blood glucose (FBG) levels, especially at dose of 200 mg/kg. The data demonstrated ASP at the certain did often exhibit the optimal protective effect in alloxan-induced diabetic mice. It is promising that ASP may serve as a drug candidate or a healthcare food for diabetic therapy or protection.     

Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy.     

Pharmacokinetic monitoring of aminoglycoside therapy: an optimal method of administration of individualized doses of gentamicin and sisomicin]

One of the most promising approaches to design the optimal schedule for TDM provides a single determination of a drug content in the blood specimen being collected at the "ideal" sampling time equaled to the inverse value of the elimination rate constant. Three versions of the one-point method when the specimen was collected at the "ideal" time point (3 h after a single i.m. drug administration), as well as at the times of "maximum" (1 h after injection) and "minimum" (6 h after injection) concentrations were compared by the retrospective analysis of the routine TDM data obtained with HPLC-techniques in 47 patients treated with gentamicin or sisomicin. As optimal individualized doses were considered ones calculated on the base of three subsequent determinations of the aminoglycoside concentrations, i.e. 1, 3 and 6 h after injection, and the estimation of individual clearance values (Cli). The optimal doses (DCl) were calculated according to equation DCl = Dp.Cli/Clp, where Dp and Clp are population values of the dose (1 mg/kg) and Cl 72.4 ml/(h.kg), respectively. The approximate values of the individual doses (D) were calculated according to equation D = Dp.Cp/Ci, where Ci is the individual drug serum concentration 1, 3 or 6 h after administration and Cp is the corresponded population value (4.8, 1.9 and 0.8 mg/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of the antispasmodic agent ethaverine in human plasma by high-performance liquid chromatography

Ethaverine can be measured in the plasma of human subjects by reversed-phase high-performance liquid chromatography employing UV detection. The limit of detection was 2 ng/ml, and the precision was ± 14, ± 6 and ± 2% at concentrations of 5, 25 and 50 ng/ml respectively. A peak mean plasma drug concentration of 20 ng/ml occurred at 1.5 h after single oral doses of a capsule formulation to human subjects, and declined with a half-life of 2.9 h.     

Treatment of Severe Diabetes Mellitus by Insulin Infusion

A new and simple form of insulin therapy for diabetic hyperglycaemia and ketoacidosis has been developed using a continuous intravenous infusion of insulin at a rate of 2·4 U/hr to maintain serum insulin concentration at physiological levels. This rate raises the mean serum insulin to 83 μU/ml and has a therapeutic effect which is not augmented by higher infusion rates. The response to such low doses of insulin indicates a need for a reappraisal of currently held theories about insulin resistance in diabetic ketoacidosis. In 11 diabetic patients with a mean plasma glucose of 514 mg/100 ml this therapy produced continuous falls in plasma glucose at a mean rate of 75 mg/100 ml/hr, and 10 out of 11 patients recovered within eight hours. This form of therapy is simple to institute, not complicated by hypoglycaemia, and avoids the confusion and empiricism of previously described forms of therapy.     

Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues

The distribution of the antiarrhythmic drug amiodarone and its principal lipophilic metabolite, desethylamiodarone, was determined in postmortem tissues of six patients who received amiodarone therapy (treatment period, 6-189 days; total dose, 4.8-127.0 g). Amiodarone concentration was highest in liver, lung, adipose tissue, and pancreas, followed by kidney, heart (left ventricle), and thyroid gland, and lowest in antemortem plasma. There was no measurable amiodarone in brain (less than 1.0 microgram/g). Desethylamiodarone concentration was highest in liver and lung, followed by pancreas, adipose tissue, kidney, heart, thyroid gland, and brain, and lowest in plasma. For most patients, the desethylamiodarone concentration was higher than the amiodarone concentration in liver, lung, kidney, heart, thyroid gland, and brain, whereas the parent drug concentration was higher than the metabolite concentration in adipose tissue, pancreas, and plasma. Tissue amiodarone and desethylamiodarone concentrations appeared to be related more closely to the total dose of amiodarone than to their respective plasma concentrations. One patient died of apparent amiodarone-induced pulmonary toxicity after an 18-day period of pharmacotherapy. Clinical evidence of pulmonary dysfunction appeared at 15 days after the initiation of amiodarone therapy, and the patient died at 23 days. Histologic assessment of a lung necropsy specimen revealed acute alveolar interstitial damage. This case represents the earliest reported incident of amiodarone-induced pulmonary toxicity.