Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men

Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/pharmacodynamic parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/pharmacodynamic parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility breakpoints, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.     

Comparative study of three routes of administration of sisomicin

A comparative study was performed using three routes of administration of sisomicin (1 mg/kg as single dose): intramuscular injection, intravenous rapid injection, and 1-hour infusion. Intravenous administration resulted in higher blood levels immediately after the injections than by the intramuscular route; however, later, the intramuscular injection resulted in optimal blood levels. High levels of sisomicin which were bactericidal for most Gram-negative bacilli were found in the urine of the treated patients. The antimicrobial activity of the serum obtained 1 hour after administration of sisomicin, as determined against 20 strains of Gram-negative microorganisms isolated from blood cultures, was identical with all three routes of administration of sisomicin.     

Clinical pharmacokinetics of sisomicin: dosage schedules in renal-impaired patients

The pharmacokinetics of intravenously administered sisomicin were studied in 33 patients with normal renal function and different degrees of renal impairment. In all patients, the serum disappearance of sisomicin, once distribution equilibrium had been achieved, followed first-order kinetics and percentage of hourly loss from serum decreased proportionally with decreasing renal function. Half-lives averaged 2.06 h in normal subjects (endogenous creatinine clearance greater than 80 ml/min per 1.73 m(2)) and reached 35.3 h in a virtually anephric subject. Linear relationships were defined between sisomicin serum half-life and the reciprocal of the endogenous creatinine clearance and serum creatinine concentration. The latter relationship indicates that the half-life of sisomicin may be approximated as twice the serum creatinine concentration and may be used for dosage adjustment in renal-impaired patients. Prediction of the extent of sisomicin removal by hemodialysis may be made from the relationship between the dialyzate of sisomicin and that of creatinine and blood urea nitrogen. Dosage schedules and methods of administration compatible with the pharmacokinetic properties of the antibiotic are finally proposed.     

Comparison of activity of sisomicin and gentamicin in mouse protection tests with gram-negative bacilli

The efficacy of sisomicin and gentamicin was compared in mouse protection studies against strains of Escherichia coli, Klebsiella sp., Enterobacter aerogenes, Serratia marcescens, Proteus mirabilis, and Pseudomonas aeruginosa. There was no significant difference in mortality of the mice in any of the protocol groups when five different dosages of sisomicin and gentamicin given by three separate schedules were compared for each bacterial inoculum in each antibiotic protocol. The mean protective dose values of sisomicin were at least one-half those of gentamicin for each protocol against Pseudomonas aeruginosa.     

Neuromuscular blocking actions of the aminoglycoside antibiotics sisomicin and micronomicin in the rabbit

In children with immune thrombocytopenic purpura (ITP), bone marrow lymphocytes can express the common acute lymphoblastic leukemia antigen (CALLA) pattern with no evidence of leukemia or lymphoma. Bone marrow lymphocytes from 23 children and 20 adults affected with ITP were studied to determine the incidence and the clinical impact of lymphocytes with the immature B-cell phenotype and CD34+ cell expression. In this investigation we identified a group consisting of 52% of the children who showed the immature B phenotype, while the remaining 48%, similarly to adult ITP displayed an increase of T-cell antigens. CD34 was positive in 53% of children, but it was present in only half of the patients with the immature B phenotype and it was always absent in adults. IgH genes disclosed a germline configuration in all six patients in the immature B phenotype group. No difference was found in the two groups of children in terms of age, presentation of the disease or final outcome. Finally, no patient in either children's group has developed an acute lymphoproliferative disorder.     

Pharmacokinetic parameters of genotoxic activity inferred from the comparison of the kinetics of MN-PCE induced by chemical agents and ionizing radiation

Some kinetic parameters of clastogenic activity of cyclophosphamide were inferred by means of the comparison of its kinetics of micronucleated polychromatic erythrocytes (MN-PCE) formation with the kinetics induced by radiation. The same reasoning was also applied to the kinetics obtained by treatment with mitomycin C (MMC), arabinocyl cytosine (Ara-C) and 6-mercaptopurine (6-MOP), based on previously reported data from the literature. The results indicate that the latency period (LP) and half-lives (HL) vary from one mutagen to another. For MMC, they are very similar to radiation indicating a rapid distribution and reaction. CP presents very long LP and HL which agree with the requirement of mutagen activation. Ara-C showed a very short LP which suggests a rapid activation and fast induction of damage in DNA. 6-MOP presented a very long LP which agreed with the requirement of its incorporation into DNA to cause micronucleus (MN). From the data obtained in the present work, it can be concluded that the comparison of the kinetics of MN-PCE formation induced by chemical agents with that obtained by the exposure to an acute dose of radiation permits one to estimate some parameters of the kinetics of clastogenic activity of chemical agents, like the LP and the HL. This seems to be valid for agents that act through the induction of DNA lesions; in the case of agents whose clastogenic activity is through other mechanisms, such as the inhibition or alteration of the process of duplication of the DNA, the kinetic parameters are not equivalent to the LP and HL; however, they could provide information on their possible mechanism of action.     

Pharmacokinetic studies of pentylenetetrazol in dogs

Pharmacokinetic profiles of pentylenetetrazol in the dog were studied following rapid intravenous and oral administrations of a convulsant dose (15-20 mg/kg). Plasma level-time curves after a rapid intravenous injection showed biexponential decline, indicating that the disposition of this drug in the dog follows a two-compartment body model. Pharmacokinetic parameters were calculated from the intravenous data. After oral administration of the solution dose, the peak plasma level appeared at about 30 min postdose, indicating that the absorption occurs rapidly. Areas under the oral plasma level-time curves s howed that the drug was absorbed completely and that the first-pass metabolism effect was minimal. The ligation studies of the kidney and the liver suggested that the main elimination pathway of this drug was biotransformation in the liver. The average plasma half-life was 1.4 hr. At steady state, the volume of distribution was approximately equivalent to the volume of the total body water.     

Pharmacokinetic study of bisaramil in man

Six healthy volunteers received an oral dose of 100 mg and an intravenous dose of 35 mg of bisaramil in a cross over study. Plasma concentrations were measured by HPLC. Bisaramil was eliminated from the plasma with a half life of 8.6 +/- 1.8 h and 9.0 +/- 4.1 h after iv. and oral administration, respectively. The mean total plasma clearance and volume of distribution were found to be 70 +/- 13.1 l/h and 864 +/- 204 l, respectively. The calculated oral bioavailability of bisaramil in tablets amounted to 56 +/- 20%.     

Pharmacokinetic profile of perphenazine enanthate]

The authors report of sex chromosome aberration screenings among the patients of the male psychiatric department, University Medical School, Pecs. 310 patients were investigated. The X-chromatin was detected in buccal smears with thionin-staining and the Y-chromatin in peripheric blood smears with quinacrin-staining by the help of fluorescentoptical technique. Two Klinefelter-patients and one YY-patient were diagnostized. The Klinefelter-patients were psychopaths and mentally subnormal, the YY-patient was a paranoid schizophrenic. The incidence of Klinefelter syndrome is 0.64%, that of the YY syndrome is 0.32%. Mental relations of sex chromosome aberrations are discussed in detail.     

Neuronal degeneration of primary cochlear and vestibular innervations after local injection of sisomicin in the guinea pig

This paper reports on a dynamic study of the morphological changes within the cochlear and vestibular ganglia of the guinea pig after local application of Sisomicin in the inner ear. The treatment leads to a rapid, complete and irreversible destruction of the sensory cells in the cochlear and vestibular neuroepithelia. A progressive degeneration of the type I and type II afferent neurons, presenting a decreasing gradient from the base towards the apex of the cochlea, is rapidly observed and becomes almost complete as early as 15 days after the peripheral injury. Five months after the treatment the spiral ganglion cells have almost completely disappeared. At this time the vestibular ganglion cell density appears normal but the neurons exhibit important signs of alteration. Such damage to the cochlear and vestibular afferent neurons may result from either retrograde neuronal degeneration and/or direct neurotoxic effect of the drug. Thus the combination of the two mechanisms could lead to neuronal losses in spiral and Scarpa's ganglia after the local aminoglycoside intoxication of the inner ear. The difference in the time course of degeneration for these two afferent ganglia could be due to their specific susceptibilities or to their different anatomical locations.     

Pharmacokinetic parameters and killing rates in serum of volunteers receiving amoxicillin, cefadroxil or cefixime alone or associated with niflumic acid or paracetamol

1. The effects of antimalarial drugs on the intracellular signaling leading to activation of the phospholipase C and phospholipase A2 pathways and the induction of proinflammatory cytokines have been studied in mouse macrophages. 2. Both chloroquine and quinacrine, and to a lesser extent hydroxychloroquine, inhibited arachidonate release and eicosanoid formation induced by phorbol diester. This inhibition was due to that of the activation of the arachidonate-mobilizing phospholipase A2. 3. All three antimalarials potently inhibited arachidonate release induced by zymosan. They also inhibited the zymosan-induced formation of inositol phosphates, which hints that an inhibitory effect at the phospholipase C level might explain the inhibition of the response to zymosan. 4. Quinacrine, and to a lesser extent chloroquine, has an inhibitory effect on the lipopolysaccharide- or zymosan-induced expression of interleukin 1beta and tumor necrosis factor alpha, both at the mRNA and protein levels. This, in particular, has important implications for the mode of action of these compounds in rheumatoid arthritis.     

Pharmacokinetic optimisation of the treatment of neurocysticercosis

Neurocysticercosis is the most important parasitic infection of the nervous system. It is common in communities living in conditions with poor hygiene. Until the last 2 decades, there was no specific pharmacological treatment: surgery and corticosteroids were the only medical alternatives. The recent introduction of anticysticercal drugs, an isoquinoline (praziquantel) and a benzimidazole (albendazole), has dramatically changed the medical management of neurocysticercosis. Praziquantel is taken orally and undergoes extensive first pass hepatic biotransformation. Peak concentration in serum is reached after 1 to 2 hours and the elimination half-life is between 1 and 3 hours. Praziquantel permeates the blood-brain barrier, thus explaining its effectiveness on parenchymal brain cysticercosis. Plasma concentrations of the drug are increased when a high carbohydrate diet is administered. Cimetidine also increases the plasma concentration of praziquantel by inhibition of cytochrome P450. Bioavailability of the drug is markedly reduced when given jointly with antiepileptics or corticosteroids, specially carbamazepine, phenytoin or dexamethasone. The current schedule for neurocysticercosis treatment lasts 2 weeks at daily doses of 50 mg/kg. Recently, a new therapeutic scheme has been proposed that considers the pharmacokinetics of the drug. This regime lasts only 1 day and includes 3 dosages of 25 mg/kg at 2-hour intervals. This increases the time that the parasite is exposed to high drug concentrations. This therapeutic scheme has produced similar results to longer schemes, with the additional advantages of cost, length of usual treatments and reduction in total dose received (being one-tenth of the total dosage). Albendazole is considered by many as the drug of choice for treatment of neurocysticercosis. It is given orally and is rapidly and extensively metabolised to albendazole sulfoxide (ALBSO), which is considered to be the metabolite directly or indirectly responsible for both toxicity and efficacy outside the gastrointestinal tract. Concentrations of ALBSO are highly variable between individuals and it has a half-life of between 6 and 15 hours. It also crosses the blood-brain barrier. In patients with extrahepatic obstruction, the elimination process is prolonged and plasma concentration is increased. Fatty meals improve absorption. Concomitant administration of albendazole with dexamethasone or with praziquantel increases plasma concentration of ALBSO. Albendazole is administered in an 8 day course of 15 mg/kg per day in 2 divided doses 12 hours apart. This scheme, based on drug pharmacokinetics, has proven to be highly effective. Inflammation is a common accompaniment of neurocysticercosis; in many cases it is the aetiopathogen responsible for histological damage. Corticosteroid therapy is useful for preventing further tissue injury. Long term corticosteroid therapy can be accomplished with 50 mg of oral prednisone 3 times a week. Acute corticosteroid therapy includes brief courses with high dosages of intramuscular dexamethasone or intravenous methylprednisolone. Clinical decisions on cysticidal and anti-inflammatory treatments must be made with the information gathered by neuroimaging studies, either computed tomography or magnetic resonance, and by the analysis of cerebrospinal fluid.     

Pharmacokinetic analysis of low-dose intra-peritoneal cis-platinum administration

Pharmacokinetic parameters after intra-peritoneal administration of low-dose cis-platinum (CDDP) were analysed in order to evaluate the possibility of applying low-dose 5-FU/CDDP therapy (1-FP) for outpatients. Four patients with advanced gastric cancer were the subjects of this study. CDDP at a dose of 20 mg/body was administered intra-peritoneally, and peripheral venous blood was collected at 30 min, 4, 8, 24, 48, 72, 96 and 120 hr after drug administration. The plasma platinum (Pt) concentration was determined by atomic absorption spectrometry. Pharmacokinetic parameters were calculated using a two-compartment open model. C max, AUC, t1/2 alpha and t1/2 beta of total-Pt were 1. 27 +/- 0.21 micrograms/ml, 95.28 +/- 16.93 micrograms.hr/ml, 1.91 +/- 0.76 hr and 190.2 +/- 125.6 hr, respectively. Total-Pt concentration at 120 hr, after administration was 0.54 +/- 0.14 microgram/ml. This result suggests that intraperitoneal low-dose CDDP administration is a promising method for 1-FP therapy for outpatients, because the plasma total-Pt level is maintained at a sufficiently high level for a long period.     

Pharmacokinetic/pharmacodynamic consequences of space flight

As astronauts prepare for long-term space missions, the question arises of whether drug medication in a zero gravity environment will have the same effects as under normal gravity. There are two potential kinds of changes that must be evaluated: alterations of pharmacokinetics and pharmacodynamics. Pharmacokinetic changes will affect the drug concentrations produced by a certain dosage regimen. They can be caused by changes in: (1) intrinsic clearance (e.g., enzyme activity and renal function), (2) drug binding (e.g., protein binding and tissue binding), (3) blood flow (e.g., liver blood flow and renal blood flow), and (4) bioavailability (e.g., rate and extent of absorption). Pharmacodynamic changes will affect the response that is produced by a given drug concentration. They can be caused by changes in drug-receptor interaction or changes in disease characteristics. Studies of pharmacokinetic and pharmacodynamic changes in microgravity are limited, and predictions of any alterations are mainly extrapolated from known relationships between certain physiologic parameters and their effects on pharmacokinetics in normal gravity. Almost no data is available on changes in pharmacodynamics. Also, no information is available on the relationship between pharmacokinetics and pharmacodynamics. More studies are needed to elucidate the changes in pharmacokinetics and pharmacodynamics in microgravity to ensure the optimum use of drug therapy during space flight.     

Pharmacokinetic analysis of intra-peritoneal administration of cisplatin]

OBJECTIVE: To compare the 1997 American Diabetes Association (ADA) and the 1980-1985 World Health Organization (WHO) diagnostic criteria in categorization of the diabetes diagnostic status of adults in the U.S. RESEARCH DESIGN AND METHODS: Analyses are based on a probability sample of the U.S. population age 40-74 years in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III). People with diabetes diagnosed before the survey were identified by questionnaire. For 2,844 people without diagnosed diabetes, fasting plasma glucose was obtained after an overnight 9 to < 24-h fast, HbA1c was measured, and a 2-h oral glucose tolerance test was administered. RESULTS: Prevalence of diagnosed diabetes in this age-group is 7.9%. Prevalence of undiagnosed diabetes is 4.4% by ADA criteria and 6.4% by WHO criteria. The net change of -2.0% occurs because 1.0% are classified as having undiagnosed diabetes by ADA criteria but have impaired or normal glucose tolerance by WHO criteria, and 3.0% are classified as having impaired fasting glucose or normal fasting glucose by ADA criteria but have undiagnosed diabetes by WHO criteria. Prevalence of impaired fasting glucose is 10.1% (ADA), compared with 15.6% for impaired glucose tolerance (WHO). For those with undiagnosed diabetes by ADA criteria, 62.1% are above the normal range for HbA1c compared with 47.1% by WHO criteria. Mean HbA1c is 7.07% for undiagnosed diabetes by ADA criteria and 6.58% by WHO criteria. CONCLUSIONS: The number of people with undiagnosed diabetes by ADA criteria is lower than that by WHO criteria. However, those individuals classified by ADA criteria are more hyperglycemic, with higher HbA1c values and a greater proportion of values above the normal range. This fact, together with the simplicity of obtaining a fasting plasma glucose value, may result in the detection of a greater proportion of people with undiagnosed diabetes in clinical practice using the new ADA diagnostic criteria.