Pharmacodynamic Factors Research Articles

Opioid action: Analysis of the impact of ovarian steroids on pharmacokinetics of morphine using population pharmacokinetics

Gender related differences have been documented in the analgesic effect received from morphine in both human and animal studies. Pharmacodynamic factors have been investigated to explain these differences, but pharmacokinetic factors could also differ between males and females. Morphine and steroid hormones are both metabolized by a similar pathway and different levels of steroid hormones have been shown to alter the metabolism of morphine. This study investigates the effect of covariates such as subject demographics and biochemical data, including steroid hormone level, on the pharmacokinetics of oral morphine in post-menopausal women. Plasma concentration levels of morphine were modeled using a population pharmacokinetic approach (WinNonMix, Pharsight Corp, Mountain View CA) after a standardized dose. The data was initially modeled with a one-compartment, first order pharmacokinetic model with no lag time and with no covariates. Systematically, the covariates were added to the model. Adjusting the model for the individual covariates of age or endogenous steroid levels reduced the error in the pharmacokinetic model. The covariate adjustments that provided the largest error reduction were estrogen and progesterone. The greatest error reduction was found using progesterone alone as a covariate for V/F, volume of distribution divided by bioavailability. The results showed that systemic levels of progesterone affect the pharmacokinetics of oral morphine in post-menopausal women. If this correlation applies also to the level of analgesia experienced in elderly women, dosing regimen of morphine may need to be adjusted in respect to the women's progesterone level. Supported by NIH R03AG16509-01. Gender related differences have been documented in the analgesic effect received from morphine in both human and animal studies. Pharmacodynamic factors have been investigated to explain these differences, but pharmacokinetic factors could also differ between males and females. Morphine and steroid hormones are both metabolized by a similar pathway and different levels of steroid hormones have been shown to alter the metabolism of morphine. This study investigates the effect of covariates such as subject demographics and biochemical data, including steroid hormone level, on the pharmacokinetics of oral morphine in post-menopausal women. Plasma concentration levels of morphine were modeled using a population pharmacokinetic approach (WinNonMix, Pharsight Corp, Mountain View CA) after a standardized dose. The data was initially modeled with a one-compartment, first order pharmacokinetic model with no lag time and with no covariates. Systematically, the covariates were added to the model. Adjusting the model for the individual covariates of age or endogenous steroid levels reduced the error in the pharmacokinetic model. The covariate adjustments that provided the largest error reduction were estrogen and progesterone. The greatest error reduction was found using progesterone alone as a covariate for V/F, volume of distribution divided by bioavailability. The results showed that systemic levels of progesterone affect the pharmacokinetics of oral morphine in post-menopausal women. If this correlation applies also to the level of analgesia experienced in elderly women, dosing regimen of morphine may need to be adjusted in respect to the women's progesterone level. Supported by NIH R03AG16509-01.

Pharmacogenetic and Pharmacogenomic Research in Psychiatry: Current Advances and Clinical Applications

After more than 50 years of investigations, pharmacogenetic efforts have crystallized in several findings relating genetically determined pharmacokinetic and pharmacodynamic factors to treatment response. Metabolic enzymes and neurotransmitter proteins contain genetic polymorphisms that alter their interaction with psychotropic drugs and contribute to response variability. This knowledge can be used to predict clinical results and adverse reactions. Current clinical applications include rapid methods for the characterisation of metabolic status that is used in clinical trials for the identification of individuals susceptible to side-effects. This practice is being extended to clinical laboratories to avoid toxic reactions to specific treatments. Pharmacogenetics methods for the pre-treatment prediction of clinical response to the antipsychotic drugs clozapine, risperidone, olanzapine and haloperidol are in development and expected to be available for clinical use in the next decade. However, much is still expected from the wealth of information produced by pharmacogenomic research. Pharmacogenomic strategies, including large scale functional studies in brain areas related to the aetiology of mental disorders, will increase the knowledge on therapeutic mechanisms and identify novel targets. Pharmacogenomic advances will be translated into more specific and safer drugs and tailoring of drug prescription according to the patient ’ s genetic susceptibilities. Pharmacogenetic and pharmacogenomic investigations have the potential to transform psychiatric treatment in the next decades. Keywords: pharmacogenetics, pharmacogenomics, antipsychotic drugs, genetic prediction of response

Sex Differences in Opioid Analgesia: “From Mouse to Man”

Numerous experimental studies, conducted primarily over the past 10 years, show that there are sex differences in opioid analgesia. This review summarizes the published literature on sex differences in analgesia produced by acute administration of drugs acting at mu-, kappa-, and delta-opioid receptors, in animals and humans. Additionally, methodological issues in research into opioid sex differences are discussed. Procedural variables that may influence the outcome of studies examining sex differences in opioid analgesia include modality and intensity of the noxious stimulus used in the pain test, opioid type (efficacy and selectivity), and experimental design and data analytic techniques. Subject variables that may be important to consider include subject genotype and gonadal steroid hormone state of the subject at the time of analgesia testing. Evidence is provided for multiple mechanisms underlying sex differences in opioid analgesia, including both pharmacokinetic and pharmacodynamic factors. Future research directions are suggested, such as examining sex differences in opioid tolerance development, sex differences in opioid analgesia using models of acute inflammatory pain and chronic pain, and sex differences in effects of opioids other than analgesia, which may limit their therapeutic use.

Long-acting injectable antipsychotics in the elderly: guidelines for effective use.

The elderly are at increased risk for psychosis because of age-related deterioration of cortical areas and neurochemical changes, comorbid physical illnesses, social isolation, sensory deficits and polypharmacy. The prevalence of psychiatric and neuropsychiatric disorders requiring treatment with an antipsychotic agent is expected to increase dramatically among people aged >64 years. Antipsychotic agents are effective in the treatment of schizophrenia, schizoaffective disorder, behavioural symptoms in patients with dementia, and mood disorders with psychosis. However, failure to adhere to a prescribed medication regimen by patients with psychosis is one of the most frustrating problems faced by mental healthcare providers, because of the high risk of relapse associated with partial compliance. For patients with psychosis who will not or cannot take oral medications on a regular daily basis or have other characteristics, such as memory, vision or auditory impairment, which contribute to partial compliance, long-acting injectable antipsychotic medication offers a solution. Older patients are especially at risk of adverse effects associated with traditional antipsychotic agents, such as motor effects, postural hypotension, excessive sedation, and anticholinergic effects because of age-related pharmacokinetic and pharmacodynamic factors, coexisting medical illnesses and concomitant medications. Therefore, drug dosage recommendations in the elderly are much more conservative than in younger patients. The appropriate starting dose of an antipsychotic in older individuals is 25% of the usual adult dose; total daily maintenance doses ranges from 25-50% of the adult dose. There are few studies regarding the use of depot antipsychotics in elderly patients. Studies that are available indicate that traditional antipsychotic agents given as depot injections are associated with positive outcomes in the elderly. Because the risks for extrapyramidal symptoms and tardive dyskinesia are reduced dramatically with atypical antipsychotics compared with traditional agents, the development of long-acting atypical antipsychotic formulations has been pursued. Of the atypical antipsychotics, risperidone is the first agent to be approved in a long-acting injectable formulation. Unpublished clinical data have revealed that patients treated with long-acting injectable risperidone (25mg, 50mg or 75mg) are more likely to show significant clinical improvement than placebo. In addition, hospitalisation rates decreased continuously and significantly during 1 year of treatment for patients who received long-acting injectable risperidone.Long-acting injectable antipsychotic medication should be considered for older patients for whom long-term treatment is indicated. The choice of which drug to use should be based on patients' history of response and personal preference, clinician's previous experience and pharmacokinetic properties.

Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions : implications for management.

Cutaneous drug eruptions are among the most common adverse reactions to drug therapy. The etiology may reflect immunologic or nonimmunologic mechanisms, the former encompassing all of the classic Gell and Combs immune mechanisms. Cumulative and synergistic effects of drugs include those interactions of pharmacokinetic and pharmacodynamic factors reflecting the alteration by one drug of the effective serum concentration of another and the functions of drugs and their metabolites that interact to evoke cutaneous and systemic adverse reactions. Recent observations include the role of concurrent infection with lymphotropic viruses and drug effects that, through the enhancement of lymphoid blast transformation and/or lymphocyte survival and the contribution of intercurrent systemic connective tissue disease syndromes, promote enhanced lymphocyte longevity and the acquisition of progressively broadening autoantibody specificities. The latter are particularly opposite to drug-induced lupus erythematosus and to drug reactions in the setting of HIV infection. Specific common types of cutaneous drug eruptions will be discussed in this review. Successful management of cutaneous drug eruptions relies upon the prompt discontinuation of the causative medication; most drug eruptions have a good prognosis after this is accomplished. Oral or topical corticosteroids can be administered to aid in the resolution of some types of eruptions. Antihistamines or anti-inflammatory agents may also be administered for some eruptions.

Nasopharyngeal carriage of Streptococcus pneumoniae: a review of the potential role of pharmacokinetics and pharmacodynamics

Much antibiotic prescribing is based upon irrational practice rather than scientific principles. The advent and the better understanding of the pharmacokinetics and pharmacodynamics of antimicrobials are slowly leading to a change whereby antibiotics are prescribed with a better rationale. The fundamental understanding of the pharmacokinetics of the antimicrobial, for example how well it is absorbed, metabolized, distributed and eliminated from the body, should lead to an appreciation of the correct dosing interval. Pharmacodynamic factors, in particular, appreciation of the MIC of an antimicrobial for an infecting pathogen and whether time-independent or -dependent killing occurs, will also have a profound influence upon how an antimicrobial is used. This review attempts to consider these features as they apply to nasopharyngeal carriage of Streptococcus pneumoniae. The reason for the dosing and dosing frequency of a number of agents is discussed and an attempt is made to point the way to more judicious antibiotic prescribing so as to maximize clinical efficacy yet minimize the possibility of resistance emerging during therapy.

Effect of Soy Milk on Warfarin Efficacy

To describe the effect of soy milk on the international normalized ratio (INR) in a patient treated with warfarin. A 70-year-old white man who was stable on warfarin therapy developed subtherapeutic INR values after ingesting soy protein in the form of soy milk. The subtherapeutic INR values could not be explained by factors known to reduce the INR such as noncompliance, new medications, other alternative therapies, increased physical activity, changes in medication storage, or increased consumption of vitamin K. INR values returned to therapeutic concentrations within 2 weeks after discontinuation of the soy milk. Repeated coagulation test results during the next 2 months remained within the normal range. Impaired warfarin metabolism may be ascribed to various pharmacodynamic and pathologic factors. Subtherapeutic INR values may also be the result of concomitant administration of metabolic inducers resulting in drug-drug, drug-herb, or drug-food interactions. An objective causality assessment in this case revealed that INR decline in a warfarin-treated patient as a result of soy milk ingestion was in the range of possible to probable. Speculative mechanisms of soy milk-induced INR decline such as changes in warfarin absorption or metabolism resulting from alterations in the P-glycoprotein efflux system or organic anion-transporting polypeptides are discussed. The temporal relationship between the start of soy milk and subtherapeutic INR values in 1 patient suggests that soy milk may have possibly or probably caused a decline in INR. Soy protein food-drug interactions with warfarin may be more common than the literature suggests, and further studies are needed to determine the exact mechanism. Healthcare professionals should be alerted to the potential implications of this food-drug interaction.

The dermatopathology of drug eruptions

Cutaneous drug eruptions are among the most common adverse reactions to drug therapy, the etiology of which reflects immunologic and/or nonimmunologic mechanisms, the former encompassing all of the classic immune mechanisms of Gell and Combs. The latter reflect cumulative and synergistic effects of drugs including interactions of pharmacokinetic and pharmacodynamic factors such as the alteration by one agent of the effective serum concentration of another and the molecular interactions of drugs and their metabolites. It has recently been observed that concurrent infection with lymphotropic viruses may enhance drug effects by promoting lymphoid blast transformation and lymphocyte survival. Drug reactions may also be dramatically affected by intercurrent systemic connective tissue disease syndromes that promote enhanced lymphocyte longevity and the acquisition of progressively broadening autoantibody specificities, a phenomenon that is also of import in drug-induced lupus erythematosus. To confirm the relationship between drug intake and the provocation of a cutaneous eruption in any given patient, ideally one should establish that (1) the onset of the eruption correlates temporally with drug ingestion, resolves with discontinuation of the suspect agent, and recurs following rechallenge; (2) the suspect drug is established to provoke the adverse effect seen in the patient; and (3) an alternate explanation is unlikely. (Curr Probl Dermatol 2002;14:117-146)

Risks associated with herbal medicinal products.

Health risks associated with the use of herbal medicinal products (HMPs) are often an emotionally discussed issue. The topic is, however, important not least because of the present popularity of HMPs. This article aims to provide a factual overview of this complex subject. The evidence relating to the toxicity, interactions and quality of a number of HMPs is reviewed. Toxicity data indicate that some HMPs have the potential to cause serious adverse events and fatalities. HMPs affect pharmacokinetic and pharmacodynamic factors and thus cause herb-drug interactions. Reports of HMPs affected by contamination, adulteration or substitution of botanical material have repeatedly caused concern. Asian HMPs are most often implicated. It is concluded that HMPs are not free of risk. More research and more information are required in order to maximize consumers' safety.

Strategies for minimizing antimicrobial resistance

Various interventions for reducing antimicrobial resistance are described. Prudent and appropriate use of antimicrobials may help reduce the selective pressure that promotes the emergence of resistance. Limiting antimicrobial use for the promotion of growth in animals may also decrease the potential for transmission of resistant microorganisms to humans through the food supply. Clinical practice guidelines provide a standard of care for the use of antimicrobials in specific infectious syndromes, promoting appropriate antimicrobial use. Excluding certain antimicrobials from institutional formularies and restricting prescribing of some agents or classes of agents included in the formulary may reduce the emergence of resistance. Therapeutic failure can be avoided by considering pharmacokinetic and pharmacodynamic factors when selecting an antimicrobial regimen. A sufficient dose and an appropriate administration interval are necessary to ensure that the antimicrobial concentration at the site of infection is high enough to kill or inhibit the growth of the pathogen. Routine antimicrobial susceptibility surveillance can detect the emergence of resistant pathogens and allow for prompt intervention. Implementation of infection control practices can prevent or stem outbreaks of infection caused by resistant microorganisms. Vaccinations may reduce antimicrobial resistance indirectly by decreasing the need for antimicrobial therapy. Antimicrobial resistance can be reduced through a combination of interventions. The management of antimicrobial resistance requires a multidisciplinary approach, including participation from physicians, nurses, pharmacists, and infection control and housekeeping staff.

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF STYRENE AND STYRENE OXIDE RESPIRATORY-TRACT DOSIMETRY IN RODENTS AND HUMANS

Styrene (ST) is widely used to manufacture resins, glass-reinforced plastics, and a number of commercially important polymers (Miller et al., 1994). Chronic ST inhalation studies in rodents have demonstrated unique species specificity in the resulting pulmonary toxicity and carcinogenicity. Increased incidences of pulmonary bronchioloalveolar tumors have been observed in mice, but not in rats. No other tumor type was increased significantly in either species. Clara cells lining the respiratory epithelium metabolize ST to styrene 7,8-oxide (SO), which is cytotoxic and weakly genotoxic. Rodent species show marked differences in the distribution and regional density of Clara cells within the respiratory tract, as well as in their capacity to produce and eliminate SO. A mode of action-based physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of ST and SO in blood, liver, and the respiratory-tract tissues, particularly in terminal bronchioles (target tisue), in order to conduct interspecies extrapolations and determine the extent to which there is a pharmacokinetic basis for the observed species specificity. This PBPK model has a multicompartment description of the respiratory tract and incorporates species-specific quantitative information on respiratory-tract physiology, cellular composition, and metabolic capacity. The model is validated against multiple data sets, including blood, liver, and whole lung tissue concentration of ST and SO following multiple routes of exposure. The trend in neoplastic incidences in mice correlated well with model-estimated SO concentration in the terminal bronchioles. The PBPK model predicts a 10-fold lower SO concentration in the terminal bronchioles in rats compared to mice, which is consistent with the observed species sensitivity to the development of respiratory-tract neoplasms. The model-based analysis suggests that humans would be expected to be 100-fold less sensitive to ST-inducted lung tumors than mice, based on pharmacokinetic differences. Pharmacodynamic factors are also expected to contribute to species sensitivity, potentially augmenting pharmacokinetics-based differences.

Intra- and interstrain differences in models of “behavioral despair”

In the present studies, base line and drug-induced performance of two mouse strains (C57Bl/6 and NIH-Swiss) was evaluated in the forced swim test (FST) and tail suspension test (TST). Intra- and interstrain comparisons indicate that the biological substrates mediating performance in these behavioral procedures are not identical. For example, in NIH-Swiss mice, a sevenfold difference in base line immobility was observed between the FST and TST. By contrast, the base line immobility in C57Bl/6 mice was similar in both procedures. Further, in C57Bl/6 mice, imipramine produced a “U-shaped” dose–response curve in the FST, whilst no evidence of a biphasic response was present in the TST at doses up to 45 mg/kg. In the FST, the AMPA receptor potentiator LY451646 produced a similar dose–response relationship in C57Bl/6 and NIH-Swiss mice, but the minimum effect dose (MED) was fivefold higher in NIH-Swiss mice. This potency difference appears due to both pharmacokinetic and pharmacodynamic factors. These intra- and interstrain differences in performance indicate that despite a face value similarity, the neurochemical pathways involved in mediating performance in these two widely used tests are not identical.

Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it?

The camptothecins provide a novel class of effective anticancer agents that exert their action against DNA topoisomerase I. Members of the camptothecins include topotecan, irinotecan, 9-aminocamptothecin, and 9-nitrocamptothecin, which are analogs of the plant alkaloid 20(S)-camptothecin. These agents vary in their antitumor efficacy and toxicity. Several pharmacokinetic and pharmacodynamic factors including cellular efflux, modulation of topoisomerases I and II, lactone stability, alterations in metabolism, and drug-drug interactions, influence the antitumor response and toxicity of these agents. Preclinical studies suggest that protracted schedules of administration produce greater antitumor effect than bolus administration. However, the optimal treatment regimens and administration schedules of these agents have yet to be established in clinical studies.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Genotypes of catechol- O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease

A single nucleotide polymorphism at the nucleotide 1947 in the catechol- O-methyltransferase (COMT) gene encodes the high and low activity forms of the enzyme. We investigated COMT genotypes of 73 Korean patients with Parkinson's disease (PD), 29 with multiple system atrophy (MSA), and 49 controls, and analyzed the response to levodopa challenge in the PD patients. We found no significant difference in the distribution of the COMT genotypes among the three groups. The frequencies of the G- and A-alleles in the total population were 75 and 25%, respectively. The levodopa response was determined by a single oral levodopa challenge test with Sinemet ® (25/250 mg) in the patients with PD. The motor response evaluated by the time to peak response, the duration and magnitude of the response in the motor part of the Unified Parkinson's Disease Rating Scale; tapping or walking times showed no significant difference between the genotypes. Thus, pharmacokinetic or pharmacodynamic factors other than the investigated genetic variant of the COMT enzyme seem to determine the response to levodopa in PD.

Data-Derived Uncertainty Factors: Boric Acid (BA) as a Case Study

There is growing support for the use of data-derived uncertainty factors. In recent years, risk assessments of boric acid have been performed by several well-respected organizations, including IEHR, ECETOC, IPCS, and WHO. For each, the pivotal study was a developmental toxicity study in rats with a no-observed-adverse-effect level (NOAEL) of 55 mg BA/kg/day. These risk assessments employed reduced uncertainty factors in the range of 25 to 60 for boric acid, because available pharmacokinetic data for boric acid reduced uncertainty in evaluating the overall data base with this compound. However, a limitation of previous risk assessments was the absence of specific data on the renal clearance of boric acid in pregnant rats and pregnant women. New data has demonstrated that when renal clearance was normalized to body weight (ml/min/kg), pregnant rats cleared boric acid at a rate roughly three times greater than pregnant women. In addition, the boric acid specific allometric relationship was determined from the log-log plot of clearance vs. body weight. Based on the new renal clearance data, it was estimated that pregnant women and rats would have the same AUC when pregnant women are given 30% of the boric acid dose given to pregnant rats. In addition, the renal clearance of boric acid among pregnant women varied by a factor of about 2. Therefore, boric acid-specific data on renal clearance in pregnant women and rats supports reduced interspecies and intraspecies pharmacokinetic uncertainty factors of approximately 3 and 2, respectively. Further, growing evidence of the essentiality in animals, combined with consistency of effects among species in toxicity studies, suggests a reduced pharmacodynamic uncertainty factor is appropriate for boric acid. Total uncertainty factors in the range of 22 to 44 are scientifically justified for this compound. An acceptable daily intake of 1.25 to 2.5 mg BA/kg/day is estimated by applying an uncertainty factor of 22 to 44 to the NOAEL of 55 mg BA/kg/day. Data-derived uncertainty factors should be used whenever possible, and they should be determined and applied in a consistent manner. Ultimately, estimates based on target tissue dose-adjusted relationships should offer a better approach to risk assessment.

Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease.

According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo on the cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus; a 7-point global scale), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea based on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors are the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1% with eptastigmine 60 mg/day to 53% with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.

Anticonvulsant Blood Levels: Historical Review With a Pediatric Focus

Epilepsy is heterogeneous and its treatment is often complicated by variable drug responses. Buchtal et al reported a close correlation between serum phenytoin levels, electroencephalographic findings, and clinical status in 1960. They suggested that physicians adjust dosage to attain a "therapeutic level." The concept was enthusiastically received. "Therapeutic serum levels" were proposed for most anticonvulsant drugs, and by 1975, most authorities believed that pharmacokinetic factors explained individual differences in drug response. However, Froscher found that measuring levels did not improve patient outcome. More recently, Schumacher's double-blind study found no correlation between phenytoin levels and seizure control or adverse effects. Pharmacodynamic variables (differences in drug responsiveness) are more important than pharmacokinetic factors for many drugs, especially receptor-active drugs. Pharmacokinetic variables were studied first, and led to a simplistic model. They are less significant than pharmacodynamic factors in the case of warfarin anticoagulation. Anticonvulsant levels can reveal noncompliance and pharmacokinetic differences. They say nothing about pharmacodynamics. Reports of "subtherapeutic levels" imply a need to increase dosage, but this is not supported by outcome data. We still lack evidence that specific drug levels are a valid intermediate target 40 years after Buchtal's paper. Responses to some anticonvulsants could depend primarily on pharmacokinetic factors, while pharmacodynamic factors could be supreme for others.

Microbiological and Pharmacodynamic Considerations in the Treatment of Infection Due to Antimicrobial-Resistant Streptococcus pneumoniae

The incidence of antimicrobial-resistant strains of Streptococcus pneumoniae has increased alarmingly in recent years. The problem is exacerbated by the global spread of resistant organisms. Currently, the incidence of penicillin-resistant pneumococci isolated from clinical specimens in the United States is > or = 35%. For empirical oral treatment of community-acquired respiratory infections, 3 choices are available: beta-lactam agents, macrolides, and fluoroquinolones. In considering the therapeutic efficacy of these agents, it is essential to also take pharmacokinetic and pharmacodynamic (PK/PD) factors into account. Many drugs are effective against penicillin-susceptible strains. However, the higher the minimum inhibitory concentration of penicillin, the more likely that cross-resistance to beta-lactam agents and macrolides will occur. Currently, the incidence of fluoroquinolone-resistant pneumococci is low; it is proposed that adequate dosing based on the PK/PD properties of fluoroquinolones may help reduce the emergence of resistant organisms. Prudent use of all antimicrobials is essential to decrease the emergence of strains resistant to these agents.

Cigarette Smoking Decreases the Prolactin Response to Serotonergic Stimulation in Subgroups of Alcoholics and Controls

The prolactin response to serotonergic stimulation has been used as an index of central nervous system serotonin function. We evaluated the prolactin response to d,l-fenfluramine to determine whether subtypes of alcoholics differed in prolactin responsivity compared with nonalcoholics and whether cigarette smoking affected prolactin response. One hundred ten healthy, abstinent men across four groups (controls [23% smokers]; alcoholics [72% smokers]; alcoholics with antisocial personality disorder [94% smokers]; nonalcoholic antisocials [88% smokers]) received d,l-fenfluramine (100 mg orally) in a randomized, double-blind, placebo-controlled study. Plasma prolactin levels were obtained at baseline and at half-hour intervals for 5 hr after fenfluramine/placebo administration. Plasma fenfluramine and norfenfluramine levels were obtained hourly. Smokers had a blunted prolactin response to fenfluramine compared with nonsmokers without any alcoholism or antisocial personality effects. Using a cutoff point of delta peak prolactin < 10 ng/ml, more smokers (41/76, 54%) had a dampened response to fenfluramine than did nonsmokers (7/34, 21%) [chi2(1) = 10.6, p < 0.003]. The percentage of low responders was greatest among smokers regardless of whether they were healthy controls, alcoholics, or antisocial. Multiple regression revealed that three variables--(1) number of pack-years of smoking, (2) actual dosage of fenfluramine received, and (3) plasma norfenfluramine level obtained--explained 43% of the variance (R2 = 0.43) in delta prolactin area under the curve. Variables that included alcoholism diagnostic status, antisocial personality diagnostic status, and impulsive aggressive personality, depressive, and suicidal traits failed to explain any additional unique variance. Cigarette smoking blunted the prolactin response to a pharmacological challenge with d,l-fenfluramine. Pharmacodynamic and pharmacokinetic factors related to smoking both appear to influence fenfluramine-induced prolactin secretion. Phenotypes of alcoholics did not differ in their prolactin response to this serotonergic probe.