Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of glyburide and glipizide, two second-generation oral sulfonylurea hypoglycemic agents, are reviewed. Glyburide and glipizide are well absorbed after oral administration. The absorption of glipizide is delayed by food; in contrast, glyburide absorption does not seem to be affected by administration with meals. Both drugs are extensively metabolized by the liver. A two-compartment open model adequately describes the pharmacokinetics of these drugs. The apparent elimination half-life of glyburide in oral dosage forms available in the United States ranges from 7 to 10 hours. Glipizide has a terminal elimination half-life of 2-7 hours. The effects of renal and hepatic disease on the pharmacokinetics of glyburide and glipizide have not been well studied. Based on controlled, comparative studies in patients with new-onset, diet-failed, Type II diabetes, glyburide appears to be at least as effective as chlorpropamide and tolazamide in controlling blood glucose. Glipizide has shown efficacy comparable to or greater than that of chlorpropamide and tolbutamide. Glyburide and glipizide appear to be comparable in terms of their ability to control fasting blood glucose in Type II diabetics. The recommended initial dosage of glyburide in newly diagnosed Type II diabetics is 2.5-5 mg once daily. For glipizide, the initial dosage should be 5 mg once daily. Elderly or debilitated patients and those with renal or hepatic impairment should be started on lower dosages initially. Glyburide and glipizide have adverse effects that are similar to those observed with the first-generation oral hypoglycemic agents. Glyburide and glipizide do not appear to offer major therapeutic advantages over first-generation oral sulfonylurea hypoglycemic agents. However, they may represent therapeutic alternatives for some patients who do not respond satisfactorily to other sulfonylureas.     

Clinical pharmacokinetics of anti-parkinsonian drugs

Of the neurological disorders, none can claim a battery of therapeutic agents based upon as rational a pharmacology as can Parkinson's disease. In this review, the clinical pharmacokinetics of the major classes of anti-Parkinsonian drugs is discussed. Although they are the oldest drugs in the anti-Parkinsonian armamentarium, little pharmacokinetic data are available regarding the anticholinergic and antihistaminic agents. Based on elimination half-lives of 10 to 18 hours, most could probably be effectively given on a twice-daily schedule. Amantadine is unique among anti-Parkinsonian agents both in lacking a clearly defined mechanism of action and in being eliminated from the body exclusively by renal excretion of unchanged drug. Thus the normal decline of renal function in the elderly Parkinsonian population becomes an important factor in avoiding potential drug toxicity. The pharmacokinetics and pharmacodynamics of levodopa are complex. Since it is an amino acid, it follows metabolic pathways and must compete for absorption and brain uptake with a number of large neutral amino acids. It has a short elimination half-life and, as Parkinson's disease progresses, the brain loses its capacity to store the drug and becomes dependent in a moment-to-moment fashion on plasma levodopa concentrations, creating therapeutic response fluctuations in over 50% of patients. Pharmacokinetic considerations in the management of these response fluctuations are discussed. The newest class of anti-Parkinsonian agents are the direct acting dopamine receptor agonists. These drugs, all derivatives of ergot, have more prolonged durations of anti-Parkinsonian action than levodopa. However, other than bromocriptine, clinical experience with members of this class of drugs is still limited.     

Serum level monitoring of antibacterial drugs. A review

Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations. Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the aminoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring. Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the 'grey baby syndrome' and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients. Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function. The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.     

Pharmacokinetics of aminoglycosides in the newborn

Aminoglycosides have played a major role in antimicrobial therapy since their discovery in the 1940s. Their bactericidal efficacy in gram-negative infections, synergism with beta-lactam antibiotics, limited bacterial resistance, and low cost have given these agents a firm place in antimicrobial treatment. After penicillins, aminoglycosides are the most commonly used drugs in the neonatal intensive care unit. While the pharmacodynamic action on the bacterial target is obviously the same in neonates as compared to children and adults, dramatic differences exist in terms of pharmacokinetics. Renal function is the most important determinant in respect to the elimination of aminoglycosides and, depending on the age and development of the newborn infant, dramatic changes in renal clearing capacity have been documented. The incorporation of this knowledge about the developing kidney has, very recently, resulted in a revised aminoglycoside dosing guideline for use in newborn infants. This article will therefore address the rationale behind this new dosing regimen and also explain why this has resulted in clinically important changes in how to perform therapeutic drug monitoring of aminoglycosides in neonates to ensure safe and effective use of these frequently used medicines in this vulnerable population.     

Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials

A number of new fluoroquinolone antibacterials have been released for clinical use in recent years. These new agents exhibit enhanced activity against Gram-positive organisms while retaining much of the Gram-negative activity of the earlier agents within the same class. The pharmacokinetics of most of these agents are well described including serum pharmacokinetics, tissue and fluid distribution, and pharmacokinetics in renal and hepatic disease. When compared with earlier agents within this class (i.e. ciprofloxacin), the newer agents retain the wide distribution characteristics; however, they exhibit a more prolonged elimination, which, in part, supports single daily administration for these agents. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for ciprofloxacin, levofloxacin, gatifloxacin and sitafloxacin. Drug interactions, particularly with multivalent cations (calcium/aluminium-containing antacids and iron products), remain a problem for the newer agents, resulting in reduced absorption requiring separate administration times to maximise bioavailability. However, the newer agents do not appear to interfere significantly with the cytochrome P450 system, thus minimising the potential for interactions with other drugs metabolised by this system. The pharmacodynamic properties of the fluoroquinolones have been well described. The bactericidal activity is maximised when the ratios of peak plasma drug concentration (Cmax): minimum inhibitory concentrations (MIC) or area under the concentration-time curve (AUC): MIC exceed specific threshold values. Knowledge of the pharmacodynamic relationships allows for appropriate drug selection and enables design of dosage regimens to maximise the bactericidal activity. Therapeutic drug monitoring of the fluoroquinolones may provide a means of optimising the dosage regimen in certain clinical situations (that is, meningitis and hospitalised pneumonias) with the goals of achieving a more predictable therapeutic response and minimising the potential for the development of resistance.     

Population pharmacokinetics of flucytosine: comparison and validation of three models using STS, NPEM, and NONMEM

The objective of this study is to compare and validate three models of flucytosine (5-FC) population pharmacokinetics using three methods of analysis to elucidate which model describes 5-FC pharmacokinetics most accurately and which method is the most suitable for this purpose. Retrospectively, demographic and clinical data of two similar sets of a total of 88 intensive care unit (ICU) patients were gathered for calculation and validation of 5-FC pharmacokinetics respectively. Three pharmacokinetic models were analyzed: a one-compartment with renal elimination (renal model), a one-compartment with renal and metabolic elimination (mixed model), and a two-compartment with renal elimination (two-compartment model). Population pharmacokinetic parameters were calculated using the standard two-stage method (STS), NONMEM, and NPEM. Furthermore, a covariate model was built by NONMEM. Validation of the 10 calculated pharmacokinetic models showed that NONMEM is most suitable for predicting 5-FC population pharmacokinetics. Based upon AIC values, bias and precision, the best results are obtained using a two-compartment model with renal elimination (k(elr) = 0.000858 +/- 0.000143 l/h per mL per min, k12 = 0.0313 +/- 0.0168 h(-1), k21 = 0.0353 +/- 0.0145 h(-1), and Vd = 0.541 +/- 0.084 L/kg; bias = -13.16; 95% CI = -16.77; -9.55; precision = 30.50; 95% CI = 27.47; 33.26) or a two-compartment covariate model as built by NONMEM [Vd (L) = 0.572 x WT, Cl(5FC) (L/h) = 1.69 + 0.0273 x (Cl(cr) (mL/min) - 52.5), k12 = 0.0235 +/- 0.0107 h(-1), and k21 = 0.0375 +/- 0.0147 h(-1); bias = -8.29; 95% CI = -11.63; -4.95; precision = 26.77; 95% CI = 24.24; 29.07]. In conclusion, this study shows that a two-compartment model with renal elimination best describes 5-FC population pharmacokinetics and NONMEM is able to build a two-compartment covariate model that predicts 5-FC levels equally well in our population of ICU patients. Furthermore, NONMEM appeared to be the most suitable method of population pharmacokinetics in our population and for this purpose it offers more reliable and accurate results than NPEM or the STS method.     

Single-dose and steady-state pharmacokinetics of piroxicam in elderly vs young adults

Summary Age-dependent changes in pharmacokinetics are considered a possible factor contributing to a higher risk of side-effects from drug treatment in the elderly. However, very little is known about the kinetics and metabolism of most NSAI agents in geriatric subjects. In a prospective age-comparison study, the single dose and steady-state pharmacokinetics of piroxicam 20 mg once daily were determined in 44 subjects ranging in age from 30 to 80 years. Plasma concentrations, elimination half-life, AUC, and volume of distribution were not influenced by age or sex and were in agreement with previously reported results in young adults. Pharmacokinetic parameters in 18 patients with evidence of mild or moderate renal impairment at study entry were not different from those in patients without impairment. Based on this and other studies, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations.     

Pharmacokinetics of Calcium Channel Blocking Agents

Abstract: Verapamil and nifedipine are the most frequently used calcium channel blocking agents in Sweden at present time. The pharmacokinetics of verapamil has been described both in healthy volunteers as well as in patients with supraventricular arrythmias, angina pectoris, liver cirrhosis, hypertrophic cardiomyopathy or hypertension. Intravenous pharmacokinetics of nifedipine has been investigated in healthy volunteers and oral pharmacokinetics in healthy volunteers as well as in patients with hypertension. The pharmacokinetics of verapamil and of one of its metabolites, norverapamil, is changed after multiple oral dosing as has been described in patients with supraventricular tachyarrythmias, angina pectoris or in patients with essential hypertension. Plasma concentration-effect relationships have been established for verapamil in different clinical situations and in a few cases also for nifedipine. An update of the pharmacokinetics of these two important calcium channel blocking agents is presented.     

Pharmacokinetics of newer drugs in patients with renal impairment (Part II)

Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.     

Encainide hydrochloride and flecainide acetate: two class 1c antiarrhythmic agents

The chemistry, electrophysiology, pharmacokinetics, clinical use and efficacy, adverse effects, drug interactions, and dosage of encainide hydrochloride and flecainide acetate are reviewed. Encainide and flecainide are class 1c antiarrhythmic agents that slow myocardial conduction and mildly prolong the duration of repolarization. Both agents block anterograde conduction over accessory pathways and prolong the effective refractory period of the accessory pathway. Bioavailability of encainide ranges from 7% to 82%, whereas that of flecainide is 90% to 95%. Encainide is metabolized by the liver to two major active metabolites that are slowly eliminated in the urine. About 23% of flecainide's total body clearance is dependent on renal elimination, and drug excretion is slowed in patients with renal dysfunction, requiring dosage adjustments. Both agents are effective in the suppression and prevention of ventricular arrhythmias, including premature ventricular contractions and sustained and nonsustained ventricular tachycardia. These agents may also be valuable in controlling supraventricular arrhythmias. The most common adverse effects of both agents involve the central nervous system and include dizziness, blurred vision, and headache. The potential for proarrhythmic effects is a concern with these agents. The risk is greater in patients with more severe arrhythmias, poor ventricular function, or high serum concentrations of drug. The usual initial oral dosage of encainide hydrochloride is 25 mg three times a day, with a usual dosage range of 100-200 mg/day. Flecainide acetate should be initiated at 100 mg every 12 hours and may be increased up to 400 mg/day. Encainide and flecainide could become useful therapeutic options in the treatment of a variety of arrhythmias.     

Use of cephalosporins with enhanced anti-anaerobic activity for treatment and prevention of anaerobic and mixed infections

The microbiology, adverse-effect profiles, pharmacokinetics, published results of comparative clinical trials, and costs of cephalosporins with enhanced antianaerobic activity are reviewed. Cefoxitin, ceftizoxime, cefotetan, and moxalactam have been used as single agents in the treatment or prophylaxis of anaerobic or mixed aerobic and anaerobic infections, including intra-abdominal, female genital tract, and soft-tissue infections. None of these agents is as active against Bacteroides species as is clindamycin or metronidazole, but differences among the four cephalosporins do not appear to be clinically important. These agents differ somewhat in their activity against gram-positive and gram-negative bacteria. The majority of adverse reactions to these agents are immunological; disulfiram-like reactions and alterations in normal hemostasis have also been observed with cefotetan and moxalactam. All of these agents are well absorbed after intramuscular injection and produce serum concentrations adequate to treat most infections. Only ceftizoxime and moxalactam produce cerebrospinal fluid concentrations adequate for treatment of gram-negative meningitis. The primary route of elimination is renal, and each agent requires dosage adjustments in patients with renal impairment. Major differences exist among the elimination half-lives of the agents in patients with normal renal function. The decision to use a cephalosporin for treatment of anaerobic infections should be based on the results of clinical trials that have demonstrated the efficacy of the agent. Data are available to support the use of cefoxitin, ceftizoxime, and moxalactam in the treatment of intra-abdominal infections; cefoxitin and moxalactam to prevent infection of traumatic injury to the abdomen; all four agents in the treatment of female genital tract infections; and all four agents for prophylactic use in surgical procedures that may involve enteric anaerobes, especially B. fragilis. Cephalosporins with enhanced antianaerobic activity appear to have similar in vitro microbiological activity and have efficacy similar to that of combination regimens for the treatment and prophylaxis of intra-abdominal infections, abdominal contamination, obstetric and gynecological infections, and soft-tissue infections.     

Hematological effects associated with beta-lactam use

Beta-lactam antibiotics have continued to be the mainstay of antiinfective treatment. Newer agents, such as the third-generation cephalosporins or ureidopenicillins, have the advantage of a broader antimicrobial spectrum and improved pharmacokinetics. The beta-lactams are often promoted as alternatives to more toxic antibiotic regimens. However, several of the beta-lactams have been shown to produce hematological effects, some of which can be life threatening. The primary hematological effects appear to be inhibition of normal platelet function and the coagulation cascade, which is reflected by changes in bleeding times and increases in prothrombin time and activated partial thromboplastin time, respectively. Although not all patients will develop bleeding problems associated with these agents, close monitoring of patients with risk factors for bleeding and dosage adjustments may help to avert these drug-induced hematological problems.     

Prediction of pharmacokinetics of antibiotics in patients with end-stage renal disease

A novel and convenient method to predict the pharmacokinetics of several kinds of antibiotic agents in patients with end-stage renal disease (ESRD) was examined based on the in vitro extraction ratios and pharmacokinetic parameters in healthy volunteers. The dializability of 17 antibiotic agents in 4% human serum albumin solution were determined using a high-performance hemodialytic membrane for clinical use. We assumed that the off-hemodialysis clearance approximated the non-renal clearance, while the on-hemodialysis clearance was considered to be sum of the off-hemodialysis clearance and the hemodialytic clearance. The estimated on- and off-hemodialysis clearances were compared with the ones observed in ESRD patients. In order to confirm the method prospectively, an in vivo pharmacokinetic study was performed in dogs with mercury chloride-induced experimental renal failure. The in vitro extraction ratios of 9 beta-lactams were broadly ranged from 10.9 to 75.6% depending on their physicochemical properties. In contrast, those of the other antibiotics were consistent with their chemical classes: 60.5-63.2% for fluoroquinolone, 48.8-51.1% for aminoglycoside and 18.7-25.6% for glycopeptide. Both the estimated on- and off-hemodialysis clearances of the 17 antibiotics coincided well with the observed values in the literature, regardless of their physicochemical and pharmacokinetic properties. The validity and applicability of this method to three cefems, cefmetazole, cefotaxime and cefoperazone, was prospectively confirmed in the animal study. In conclusion, this new method enables the prediction of the on- and off-hemodialysis clearances of several kinds of antibiotics in ESRD patients from minimal information of their pharmacokinetics in healthy subjects and their in vitro dializability.     

Olanzapine pharmacokinetics in pediatric and adolescent inpatients with childhood-onset schizophrenia

Well-designed studies investigating how pediatric or adolescent patients with mental disorders respond to and metabolize the newer antipsychotic drugs are practically nonexistent. Without such data, clinicians have difficulty designing appropriate dosage regimens for patients in these age groups. The results from a study of olanzapine pharmacokinetics in children and adolescents are described. Eight inpatients (ages 10-18 years) with treatment-resistant childhood-onset schizophrenia received olanzapine (2.5-20 mg/day) over 8 weeks. Blood samples, collected during dose titration and at a steady state provided pharmacokinetic data. The final evaluation (week 8) included extensive sampling for 36 hours after a 20-mg dose. Olanzapine concentrations in these eight pediatric patients were of the same magnitude as those for nonsmoking adult patients with schizophrenia but may be as much as twice the typical olanzapine concentrations in patients with schizophrenia who smoke. Olanzapine pharmacokinetic evaluation gave an apparent mean oral clearance of 9.6 +/- 2.4 L/hr and a mean elimination half-life of 37.2 +/- 5.1 hours in these young patients. The determination of the initial olanzapine dose for adolescent patients should take into consideration factors such as the patient's size. In general, however, the usual dose recommendation of 5 to 10 mg once daily with a target dose of 10 mg/day is likely a good clinical guideline for most adolescent patients on the basis of our pharmacokinetics results.     

Third-generation cephalosporins: a critical evaluation

Six third-generation cephalosporins--cefotaxime, moxalactam, cefoperazone, ceftizoxime, ceftriaxone, and cefmenoxime--are reviewed; covered are chemistry and structure-activity relationships, mechanism of action, spectra of activity, pharmacokinetics, clinical utility, adverse effects, and cost effectiveness. The third-generation cephalosporins have a similar mechanism of action to that of other beta-lactam antibiotics. None of the agents is particularly active against certain gram-positive bacteria, including methicillin-resistant Staphylococcus aureus; the drugs are effective against gonococci, Haemophilus influenzae, and Neisseria meningitidis. Several common gram-negative pathogens are susceptible to the third-generation cephalosporins, including Escherichia coli, Klebsiella, Citrobacter diversus, Proteus, and Morganella. About 50% of Pseudomonas aeruginosa isolates are susceptible. Only moxalactam has good activity against Bacteriodes fragilis. The pharmacokinetic profiles of the six agents reveal some important differences. The half-life of ceftriaxone allows once-daily dosing in many patients; the half-lives of ceftizoxime and cefoperazone permit dosing every 8-12 hours. Cefoperazone and ceftriaxone are highly protein bound, but the clinical relevance of this is unknown. Generally, the agents penetrate most body tissues and fluids well. Moxalactam and cefotaxime and possibly ceftriaxone effectively penetrate into the cerebrospinal fluid well. The third-generation cephalosporins have become the accepted drugs of choice for the treatment of adult gram-negative bacillary meningitis; as more experience is gained, they are likely to become the drugs of first choice for neonatal (with ampicillin) and childhood (except for moxalactam) meningitis. Serious infections of Enterobacteriaceae can be treated with these agents, thereby avoiding use of the aminoglycosides. Moxalactam is comparable with combination therapy in treating intra-abdominal infections. Adverse effects associated with use of the third-generation cephalosporins are generally similar to those that occur with other beta-lactam antibiotics with the exception of coagulopathies and the disulfiram reaction seen with moxalactam and cefoperazone. Despite the relatively high cost of the third-generation cephalosporins, they are often cost effective because of their reduced dosing frequencies, broad spectra of activity, and effectiveness in serious infections for which more toxic antibiotics have been required in the past.     

Protein binding of glycopeptide antibiotics with diverse physical-chemical properties in mouse, rat, and human serum

In previous studies of the pharmacokinetics and urinary excretion of nine glycopeptides with diverse isoelectric points (pI), as pI decreases, the total systemic and renal clearance, urinary recovery, and volume of distribution decrease, whereas the half-life increases. With glycopeptides of similar pI, clearance decreases and half-life increases with increasing lipophilicity. The present study examines the serum protein binding of these glycopeptide antibiotics in mouse, rat, and human serum and calculates the previously reported pharmacokinetic parameters for these drugs based on unbound concentration. Increased negative charge and lipophilicity increase serum protein binding (90-fold, fu 83% to 0.96%), which decreases the renal clearance and total systemic clearance (90-fold, 16.4 to 0.18 ml/min/kg) of these drugs. Increased serum protein binding also decreases the volume of distribution of these compounds, but this change is relatively small (sixfold, 755 to 131 ml/kg) compared with the change in total systemic clearance causing an increase in elimination half-life (25-fold, 20 to 492 min). The results demonstrate that the large differences in the total systemic clearance and half-life of these glycopeptide antibiotics are primarily due to dramatic differences in serum protein binding and not to differences in the intrinsic elimination processes (enzymes or transport proteins). It appears that the same physical-chemical properties that govern the protein binding and pharmacokinetics of small organic molecules govern the disposition of these high-molecular weight glycopeptide antibiotics.     

Target site bacterial killing of cefpirome and fosfomycin in critically ill patients

We employed an in-vivo pharmacokinetic/in-vitro pharmacodynamic method to simulate bacterial killing in plasma and the interstitium of skeletal muscle tissue after intravenous administration of 2 g of cefpirome and 8 g of fosfomycin alone and in combination to patients with sepsis. Interstitial antimicrobial concentrations were determined by use of in-vivo microdialysis. CFU/ml of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (clinical isolate) decreased by approximately 2 log₁₀ for plasma and muscle tissue 6 h after cefpirome and fosfomycin administration compared with the baseline, respectively. The simulation of plasma and tissue pharmacokinetics for the combined administration of these antibiotics resulted in complete eradication of S. aureus within 5 h after drug exposure. No bacterial re-growth occurred in any of the simulations within 6 h. The in-vitro simulation of in-vivo plasma and tissue pharmacokinetics of cefpirome and fosfomycin has shown that both antimicrobial agents kill S. aureus and P. aeruginosa strains effectively after single dose administration. This effect was most pronounced by the combined use of these antimicrobial agents. Therefore, this data corroborates antimicrobial strategies of simultaneous administration of cefpirome and fosfomycin in patients with severe soft tissue infection.     

Pharmacokinetics of ranitidine after intravenous administration in hemodialysis patients

The pharmacokinetics of ranitidine and its removal by hemodialysis were determined in 9 patients with chronic renal failure requiring hemodialysis. Ranitidine (50 mg) was administered as an intravenous bolus at the beginning of the dialysis procedure, which lasted for 4 h. The elimination half-life, plasma clearance and volume of distribution (VD area) of ranitidine in these patients were 9.0 +/- 2.6 h (mean +/- SD), 305 +/- 152 ml/min and 3.5 +/- 1.9 liters/kg, respectively. About 8% of the administered dose was removed during a single dialysis procedure. The elimination of ranitidine is appreciably reduced in these patients. These results suggest that the dose of ranitidine should be adjusted in patients with severe renal failure who are undergoing hemodialysis, and a suitable schedule for dosing such patients is suggested.     

Differences in kinetic properties of drugs: implications as to the selection of a particular drug for use in patients with renal failure with special emphasis on antibiotics and beta-adrenoceptor blocking agents

Adjustment of dosage of a renally excreted drug (or active metabolite) for patients with severe renal failure still causes some difficulties. It is therefore helpful to select, within a given therapeutic group of drugs, a compound that is particularly safe and easy to use and, if possible, does not require adjustment of dosage. This is 'the drug of choice for renal patients'. Such a drug would ideally meet the following pharmacokinetic criteria: normal urinary excretion less than 30% of the administered dose, predominant biliary and intestinal removal, disposition essentially unaffected by parameters likely to be modified in renal failure (e.g. changes in serum proteins or fluid compartments: receptor sensitivity, etc), and pharmacokinetics not complicated by the formation of active or toxic metabolites that depend on urinary elimination. Above all, the drug should have a wide therapeutic margin and must be free of nephrotoxicity. Examples of drugs of choice for patients with impaired renal function are given for some important therapeutic groups and special emphasis is placed on antibiotics and beta-adrenoceptor blocking agents.     

稳态时加替沙星对茶碱在家兔体内药动学的影响

目的 :研究稳态时加替沙星对茶碱在家兔体内药动学的影响。方法 :采用自身对照法 ,HPLC法平行监测合用药前后茶碱的血药浓度 ,通过PKBP N1软件拟合茶碱的药动学参数 ,并做统计学比较。结果 :合并用药前后茶碱的血药浓度AUC差异有显著性 (P <0 .0 5 ) ,合用后茶碱的血药浓度显著提高 ,峰时Tmax提前 ,吸收速率Ka 变大 ,消除半衰期T1 / 2 β相应延长 ,消除率相应减少。结论 :加替沙星能延缓茶碱在体内的代谢 ,提示合并用药时应对茶碱进行血药浓度监测 ,防止因茶碱代谢减慢而引起蓄积中毒。