A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-levels study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of > or = 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of > or = 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied.     

Time of peak drug concentration after a single dose and a dose at steady state

The time of peak concentration after administration of oral drug is an often quoted and used pharmacokinetic parameter. It is not well appreciated, however, that the peak times after a single dose and a dose at steady state during a multiple administration regimen can differ significantly. This article derives the mathematical relationships that determine how a peak time at steady state differs from that after a single or first dose. These relationships are then evaluated using three different approaches: 1) graphic simulations of time courses of drug concentration for three hypothetical drugs; 2) comparisons of predicted and observed peak times using examples from the literature; and 3) comparisons of predicted and simulated peak times based on different sampling schedules for three hypothetical drugs. The key finding is that peak times after a dose at steady state can occur considerably earlier after administration than after a single dose. However, the manner by which peak times are usually determined, that is, the sampling time corresponding to the highest measured drug concentration, imposes significant limitations on the usefulness of this parameter.     

Expanding clinical applications of population pharmacodynamic modelling

Population pharmacokinetics or pharmacodynamics is the study of the variability in drug concentration or pharmacological effect between individuals when standard dosage regimens are administered. We provide an overview of pharmacokinetic models, pharmacodynamic models, population models and residual error models. We outline how population modelling approaches seek to explain interpatient variability with covariate analysis, and, in some approaches, to characterize the unexplained interindividual variability. The interpretation of the results of population modelling approaches is facilitated by shifting the emphasis from the perspective of the modeller to the perspective of the clinician. Both the explained and unexplained interpatient variability should be presented in terms of their impact on the dose-response relationship. Clinically relevant questions relating to the explained and unexplained variability in the population can be posed to the model, and confidence intervals can be obtained for the fraction of the population that is estimated to fall within a specific therapeutic range given a certain dosing regimen. Such forecasting can be used to develop optimal initial dosing guidelines. The development of population models (with random effects) permits the application of Bayes's formula to obtain improved estimates of an individual's pharmacokinetic and pharmacodynamic parameters in the light of observed responses. An important challenge to clinical pharmacology is to identify the drugs that might benefit from such adaptive-control-with-feedback dosing strategies. Drugs used for life threatening diseases with a proven pharmacokinetic-pharmacodynamic relationship, a small therapeutic range, large interindividual variability, small interoccasion variability and severe adverse effects are likely to be good candidates. Rapidly evolving changes in health care economics and consumer expectations make it unlikely that traditional drug development approaches will succeed in the future. A shift away from the narrow focus on rejecting the null hypothesis towards a broader focus on seeking to understand the factors that influence the dose-response relationship--together with the development of the next generation of software based on population models--should permit a more efficient and rational drug development programme.     

Cable grafting of the spinal accessory nerve after radical neck dissection

AIMS: To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10 mg) and after 28 days therapy with imidapril 10 mg once daily. METHODS: Cmax, tmax, t1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation. RESULTS: The AUC of imidapril was 140 (43 s.d.) ng ml(-1) h after the first dose and 123 (34 s.d.) ng ml(-1) h at steady state. AUC of the active moiety imidaprilat averaged 211 (101 s.d.) ng ml(-1) h after the first dose and 240 (55 s.d.) ng ml(-1) h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22 mm Hg after the first dose and 25 mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an Emax-curve, whereas the plateau around Emax is maintained at steady state. CONCLUSIONS: In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

Crossover comparison of the pharmacokinetics of amlodipine and felodipine ER in hypertensive patients

The pharmacokinetics of amlodipine 5 mg and felodipine ER (extended release) 5 mg o.d. after single and 2 weeks of repeated oral doses, were compared in 28 essential hypertensive patients using a crossover design. As a secondary parameter the effects of the drugs on blood pressure were assessed. Significant differences were found between all principal pharmacokinetic variables, when comparing the 2 treatments after both single and repeated dosing. The coefficients of variation of maximal drug concentration and AUC after single dosing and at steady-state were significantly higher for felodipine ER than for amlodipine. After repeated dosing the peak-to-trough plasma concentration ratio were 1.58 and 4.43 (p < 0.001) for amlodipine and felodipine ER, respectively. Both drugs lowered systolic and diastolic blood pressure to the same extent after 2 weeks of repeated dosing. No significant differences between the blood pressure lowering vs time profile of the 2 drugs were encountered. In conclusion, the interpatient drug concentration variability and the peak-to-trough plasma concentration ratio were more favorable for amlodipine compared to felodipine ER. It remains to be established whether these characteristics are also reflected in a more smooth and consistent blood pressure control.     

Methylprednisolone and cortisol metabolism during the early post-renal transplant period

Despite the widespread use of methylprednisolone and the well-appreciated effects of this drug on HPA suppression, little data is available which describes individual patient exposure to both methylprednisolone and cortisol following renal allograft placement. The clinical utilization of methylprednisolone during the early post-transplant period is based upon standardized dosing protocols that do not consider factors which may influence the pharmacokinetics of this drug during the post-transplant period. Therefore, this study was designed to examine the pharmacokinetics of methylprednisolone (mean dose: 28 mg) and cortisol pharmacodynamics in 9 renal transplant recipients (4 females; 5 males) who were studied during the early post-transplant period (5 to 12 days after surgery). All patients (mean serum creatinine: 1.4 +/- 0.3 mg/dl) had serial blood samples collected over a 12- to 24-hour period (depending upon the dosing schedule) which were analyzed concurrently for methylprednisolone and cortisol. A three-fold variation in drug clearance ranging from 174 to 638 ml/h/kg with a range in the volume of distribution of 0.83 to 2.24 l/kg and resultant half-lives ranging from 1.20 to 3.02 hours was noted. The cortisol response was quantitated by a 12-hour cortisol area under the curve (C-AUC12) to examine the interpatient cortisol patterns during the early post-transplant period. C-AUC12 ranged from 44.0 to 636 ng.h/ml. Significant correlations were noted between the cortisol plasma concentration at 12 hours and methylprednisolone clearance and area under the concentration versus time curve (AUC). Interpatient variability in the disposition of methylprednisolone and cortisol response noted during the early post-transplant period contradict the clinical assumptions which underlie the fixed dosing protocols currently utilized for methylprednisolone.     

Dose optimization in clinical oncology: pharmacokinetic-pharmacodynamic relationship

The establishment of relationships between pharmacokinetics and pharmacodynamics of anticancer drugs might allow to individualize the dosing of these drugs. Our knowledge of this kind of relationship has grown markedly in recent years. After a review of the different causes of variability in pharmacokinetics and pharmacodynamics of these drugs, the different models used for establishing these correlations were analyzed and criticized. Finally, the three methods for adapting drug dosing based on pharmacokinetic data were proposed and the main applications of these concepts were reviewed.     

Healing of adult male survivors of childhood sexual abuse

1. Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication. 2. This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively. 3. Thirty-one children aged 6 months to 5 years were included and received a 2 mg kg-1 single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half-lives (mean +/- s.d.) were: 7.7 +/- 1.8 h, 21.9 +/- 6.8 h, 44.7 +/- 10.2 h in the "inducer', "other' and "inhibitor' groups respectively. 4. Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3 mg l-1. The mean minimum plasma concentration for the three groups was 2.54 +/- 1.28 mg l-1 at steady state. 5. Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.     

Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse

Rapamycin-28-N,N-dimethylglycinate methanesulfonate salt (RG), synthesized as a potential water-soluble prodrug to facilitate parenteral administration of the antineoplastic macrolide rapamycin (RA), is active against intracranially implanted human glioma in mice. Preclinical pharmacokinetic studies to evaluate the prodrug were conducted in male CD2F1 mice treated with 10, 25, 50 and 100 mg/kg doses of RG by rapid i.v. injection. The plasma concentration of RG decayed in a distinctly triphasic manner following treatment with the 100 mg/kg dose; however, prodrug disposition was apparent biexponential at each of the lower doses. RG exhibited dose-dependent pharmacokinetics, characterized by an increase in the total plasma clearance from 12.5 to 39.3 ml.min-1.kg-1 for dosage escalations in the range 10-50 mg/kg, while clearance values at doses of 50 and 100 mg/kg were similar. The terminal rate constants decreased linearly as the dose was increased from 10 to 100 mg/kg, eliciting an apparent prolongation of the biological half-life from 2.1 to 4.8 h. There was also a sequential increase in the steady state apparent volume of distribution from 1.73 to 8.75 l/kg. These observations are consistent with saturable binding of RG to plasma proteins while binding to tissue remains linear. Nevertheless, conversion to RA appeared to represent a prominent route of RG elimination. The molar plasma concentration of RA exceeded that of the prodrug within 30-90 min after i.v. treatment and declined very slowly thereafter, with plasma levels sustained between 0.1 and 10 microM for 48 h at each of the doses evaluated. Thus, RG effectively served as a slow release delivery system for RA, implying the possibility of maintaining therapeutic plasma levels of the drug from a more convenient dosing regimen than a continuous infusion schedule. The present findings, coupled with the demonstrated in vivo activity of RG against human brain tumor models, warrant its continued development as a much needed chemotherapeutic agent for the treatment of brain neoplasms.     

Compartmental pharmacokinetics and tissue drug distribution of the pradimicin derivative BMS 181184 in rabbits

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (Cmax) ranged from 120 microg/ml at 10 mg/kg to 648 microg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0-24) ranged from 726 to 2,130 microg . h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0-24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.     

Treatment of concomitant illnesses in patients receiving anticonvulsants: drug interactions of clinical significance

As epilepsy often is a chronic condition requiring prolonged therapy with anticonvulsants, patients being treated for epilepsy can be at risk when they are prescribed other drugs for concomitant diseases. Pharmacokinetic interactions can occur at each step of drug disposition (absorption, distribution, metabolism and elimination). Although such interactions may occur frequently with some drugs, only some will be clinically relevant. Alterations in the hepatic biotransformation of metabolised drugs due to hepatic isoenzyme induction or inhibition is of particular concern. The consequences of pharmacokinetic interactions are either accumulation of the drug leading to toxicity, or lowering of plasma concentrations resulting in reduced efficacy. Clinically relevant interactions depend on the structure, dosage and duration of administration of interacting agents, and on the individual's genetic make-up. In the past, drug interactions have been analysed empirically. At present, at least for interactions between drugs that are biotransformed in the liver, the risk should be predicted by considering the individual cytochrome P450 isoforms involved in the metabolism of coadministered drugs. Although drug-drug interactions can be predicted, their extent cannot be due to large interindividual variability. Even if nearly all drug combinations could be used with close clinical surveillance and blood concentration determinations, drugs that are not metabolised and are not highly protein bound, as are several of the new anticonvulsants, such as gabapentin, lamotrigine and vigabatrin, have a clear advantage in terms of a lower interaction potential.     

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.     

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.     

The role of positron emission tomography in pharmacokinetic analysis

The physiological and biochemical measurements that can be performed noninvasively in humans with modern imaging techniques offer great promise for defining the precise state of a patient's disease and its response to therapy. In general, there are two critical points in drug development when PET measurements are likely to be particularly useful: (1) In preclinical studies, a new drug can be precisely compared to standard therapies or a series of analogs can be screened for further development on the basis of performance in appropriate animal models. (2) In phase I-II human studies, classic pharmacokinetic measurements can be coupled with imaging measurements (a) to define optimal dosing schedule; (b) to define the potential utility of interventions in particular clinical situations; and (c) to formulate the design of phase III studies that are crucial for drug licensure. In general, the types of measurements that are possible can be grouped into the following categories: 1. In those situations in which the drug can be radiolabeled, the time course of tissue delivery can be determined noninvasively in vivo in health and disease. Such information should be useful for determining dosing schedules, establishing efficacy, and predicting possible toxicity. 2. Ligand-receptor binding can be assessed in vivo in two ways. The ability of the drug to displace standard radiolabeled ligands from their receptors can be determined; alternatively, labeled drug can be used to more directly assess the distribution and time course of binding. These measurements are particularly useful for studying drugs that are active in the central nervous and cardiovascular systems. 3. Measurements of tissue metabolism will be useful in determining the effects of therapies aimed at particular metabolic abnormalities. In addition, these measurements may be useful in defining viability and function of tissues in such widely disparate clinical situations as cancer chemotherapy and cardiology. For example, effects of CNS or cardiovascular drugs can be monitored by observing 18FDG metabolism in brain and heart. We suggest that the joining of classic clinical pharmacology to exquisite imaging measurements will help form the basis for 21st-century clinical drug development.     

Biochemical evaluation of digoxin dosage in patients with heart failure

The investigations were carried out in 56 patients aged 54 to 84 years, treated with a supporting dosage 0.25 mg of digoxin because of chronical insufficiency of the heart, according to the NYHA classification II and III degree, in whom the functions of liver and kidneys have not been ascertained. A fourfold determination of digoxin concentrations in the blood was established in the time of distribution balance. From among the examined patients three groups were separated: receiving the drug chronically at 8.00 a.m. (group A), receiving it at 8.00 p.m. (group B) and group C, for which the sacral method was used. Depending on medical indications the patients received during the examination other drugs. In group C the therapy was limited to diuretic drugs. In no clinical symptoms of digitalism could be observed. Subtherapeutic levels of digoxin (< 0.8 ng/ml) were found in the three groups on an average in 50% of the patients. The high percentage of patients with nontherapeutic concentration in blood serum confirms once more, that treatment with digoxin without checking their concentration in the serum does not give the certainty of suitable dosage. The results of the studies show that the optimalization of digoxin therapy from the point of pharmacological view should be based on a penetrating estimation of the whole of the clinical image, the checking of the image with the help of the concentration determinations of the drug.     

A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels

Phenytoin, carbamazepine, and lamotrigine are anticonvulsants frequently prescribed in seizure clinics. These drugs all show voltage-dependent inhibition of Na+ currents, which has been implicated as the major mechanism underlying the antiepileptic effect. In this study, I examine the inhibition of Na+ currents by mixtures of different anticonvulsants. Quantitative analysis of the shift of steady state inactivation curve in the presence of multiple drugs argues that one channel can be occupied by only one drug molecule. Moreover, the recovery from inhibition by a mixture of two drugs (a fast-unbinding drug plus a slow-unbinding drug) is faster, or at least not slower, than the recovery from inhibition by the slow-unbinding drug alone. Such kinetic characteristics further strengthen the argument that binding of one anticonvulsant to the Na+ channel precludes binding of the other. It also is found that these anticonvulsants are effective inhibitors of Na+ currents only when applied externally, not internally. Altogether these findings suggest that phenytoin, carbamazepine, and lamotrigine bind to a common receptor located on the extracellular side of the Na+ channel. Because these anticonvulsants all have much higher affinity to the inactivated state than to the resting state of the Na+ channel, the anticonvulsant receptor probably does not exist in the resting state. Thus, there may be correlative conformational changes for the making of the receptor on the extracellular side of the channel during the gating process.     

Practical treatment guide for dose individualisation in cancer chemotherapy

Dosages of anticancer drugs are usually calculated on the basis of a uniform standard, the body surface area (BSA). Although many physiological functions are proportionate to BSA, overall drug clearance is only partially related to this parameter. Consequently, following administration of equivalent drug dosages based on BSA, a wide variability in plasma drug concentrations can be found between patients, as a result of which some patients experience little toxicity while others may show severe toxic symptoms. A clear pharmacokinetic/pharmacodynamic correlation has been demonstrated for some anticancer drugs, and this relationship provides a background against which rational dose optimisation can be implemented for individual patients. The 3 strategies that can be employed for optimising dosage regimens, none based on BSA, are described and criticised. A priori adaptive dosage determination is based on the relative contribution of identifiable characteristics of patient, drug therapy and disease state that influence plasma drug concentrations; the dosage regimen is based on each patient's profile with regard to these characteristics. Although this approach is most successful with drugs whose clearance is closely tied to renal function, patient characteristics such age, obesity, serum albumin or hepatic function may be useful. The anticancer drug most closely identified with this approach is carboplatin, although dosage reduction strategies for etoposide, taxanes, anthracyclines, topotecan, oxazaphosphorines, vinca alkaloids or melphalan are advocated for patients with renal or hepatic dysfunction. The importance of pharmacogenetics for fluorouracil and mercaptopurine is also briefly discussed. The second approach consists of adaptive dosage adjustments during repetitive or continuous administration of a drug. It has been used for several years to administer methotrexate therapy and, more recently, it has been developed more fully and applied to continuous infusion of fluorouracil or etoposide. It was based, after determination of a target plasma concentration or area under the plasma drug concentration-time curve (AUC), on modification of the drug dosage during the cycle of chemotherapy or for the next cycle. Finally, the third approach of adaptive dosage adjustment with feedback control, based on population pharmacokinetics, with limited sampling strategy, may allow a feedback revision of the dosage following measurement of plasma drug concentration and comparison with the population previously studied. This approach is a theoretical strategy which has not, until now, been used prospectively in clinical oncology. For drugs such as anticancer agents with a very narrow therapeutic index, every effort should be made to minimise interpatient variability in drug exposure in order to maximise the benefit while keeping the risk of serious adverse effects at an acceptable level. This is particularly important when treatment is being given with curative intent.     

Single point estimation of phenytoin dosing: a reappraisal

A previously proposed method for estimation of phenytoin dosing requirement using a single serum sample obtained 24 hours after intravenous loading dose (18 mg/Kg) has been re-evaluated. Using more realistic values for the volume of distribution of phenytoin (0.4 to 1.2 L/Kg), simulations indicate that the proposed method will fail to consistently predict dosage requirements. Additional simulations indicate that two samples obtained during the 24 hour interval following the iv loading dose could be used to more reliably predict phenytoin dose requirement. Because of the nonlinear relationship which exists between phenytoin dose administration rate (RO) and the mean steady state serum concentration (CSS), small errors in prediction of the required RO result in much larger errors in CSS.     

A multiple-pathway model for the diffusion of drugs in skin

A mathematical model for the diffusion of drugs in skin is presented. The penetration of the drug by both transcellular and intercellular pathways, as well as its interchange between these pathways, is considered. A pharmacologically motivated asymptotic limit is identified and analysed to obtain, in particular, an analytical expression for the flux of drug to the blood at steady state. Relevant model data is discussed, and some numerical results are also presented.     

Food-deprivation level alters the effects of morphine on pigeons' key pecking

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.