Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches.

PURPOSE: A vancomycin population pharmacokinetic prediction model for adult and elderly patients was developed using NONMEM. The predictability of the model was studied and compared with ten other models. METHODS: Data were collected from routine care of 141 subjects. NONMEM was used to derive a population model. After internal evaluation using the bootstrap technique, external validation was studied using an independent dataset that consisted of 95 subjects; a statistical comparison of precision and bias was conducted. RESULTS: A two-compartment open model was derived with body weight, age, and CLcr as covariates. The bootstrap process showed stability of the model. A comparison of subjects older and younger than 65 years found that the older group had a mean clearance of 2.24 (+/- 1.2) l/h compared to 4.03 (+/- 1.7) l/h, and a peripheral volume of 43.7 (+/- 5.1) l compared to 28.4 (+/- 5.3) l compared to younger patients. These values were modeled using CLcr in the clearance equation and Vd as a function of age. The eleven models studied showed a bias in predicting serum concentrations from the test database that ranged from 0.35 mg/l to -5.93 mg/l. Precision ranged from 4.53 mg/l to 8.05 mg/l. Our method ranked in fourth place overall and when compared statistically its bias was different from the method that ranked in second place by -1.45 (95% CI -2.46, -0.42; p = 0.005), and different from all the methods that ranked worse. The only difference in precision was with the method that ranked in eleventh place with a relative precision of 0.49 (95% CI 0.27, 0.70; p < 0.001). CONCLUSIONS: A two-compartment open model fitted the data with weight, age, and CLcr as covariates. The derived method ranked in fourth place overall. The two-compartment nature of two of the equations studied did not provide an advantage. A future study with more data in the distribution phase could provide a model with better predictability.

Evaluation of the Safety of Drugs and Biological Products Used During Lactation: Workshop Summary.

This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants.

Modeling drug passage into human milk.

Breastfeeding has positive health consequences for both the breastfed infant and the nursing mother.(1,2) Although information on drug use during lactation is available through sites such as LactMed,(3) available information is often incomplete. Unlike pregnancy, in which large numbers of pregnant women need to be studied to assure safety, measurement of drug concentrations in breastmilk in a relatively few subjects can provide valuable information to assess drug safety. This article reviews methods of measuring and predicting drug passage into breastmilk.

Inhibition of the transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferator-activated receptor gamma ligands.

The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily, is essential for adipocyte differentiation and glucose homeostasis. PPARgamma has been found recently to regulate macrophage activation in response to mitogens and inflammation. Our study shows PPARgamma to be preferentially expressed in the nuclei of resting T cells and to increase upon activation of T cells by either anti-CD3 and anti-CD28 or phorbol myristyl acetate (PMA). We also found the PPARgamma ligand ciglitizone to attenuate the activation of T cells by inhibiting cytokine gene expression and anti-CD3 and anti-CD28 or PMA-induced proliferative responses. Inhibition of both the proliferative response and inflammatory cytokine expression in CD4 T cells was correlated with suppression of the activated transcription factors AP1 and NF-kappaB. PPARgamma ligands also strongly inhibited SEA-induced Vbeta3 T cell activation in vivo. These results, together with previous findings of the inhibitory effect of PPARgamma ligands on activated macrophages, provide clear evidence for PPARgamma as a negative regulator of the inflammatory activation of both macrophage and T cells. PPARgamma may thus be a potential therapeutic target for the treatment of autoimmunity.

Drugs and breast feeding.

PIP: This paper reviews: 1) the basic mechanisms of drug passage into milk; 2) clinical considerations in the use of drugs in lactating women; and 3) use of specific classes of drugs during lactation. Milk can be considered as an oil in H20 emulsion which is separated from the blood plasma by a semipermeable lipoid membrane; which consists of small pores which allow H20 and small H20-soluble molecules and electrolytes to pass from plasma to milk. Larger molecules, including most drugs, are diffused though the lipid portion of the membrane by diffusion. Physiochemical and pharmacokinetic factors affect the passage of drugs into milk. When drugs are prescribed to a breast-feeding mother (e.g., treatment of urinary tract and vaginal infections), the benefits of using drugs should be weighed against the potential hazards of the drug in the infant. Consideration should also be given to the fact that infants, especially the neonates and preterms, have immature excretory mechanisms which allow excessive accumulation of certain drugs. Effects of drugs in the milk could be beneficial, detrimental, and nonexistent on the breast-fed intake. So far, the only known beneficial effect of a drug in breast milk is that of pyrimethamine. Potentially hazardous drugs to lactation include: corticosteroids; sex hormones; major tranquilizers; tricyclic antidepressants; antihypertensives; and antituberculars. A series of guidelines for prescribing drugs from various classes of agents is also provided.^ieng

Meperidine: therapeutic use and toxicity.

Meperidine is a synthetic opioid analgesic frequently prescribed in the emergency department. Meperidine is most often administered intramuscularly or intravenously, due to its poor oral bioavailability, and is metabolized extensively by the liver. Analgesic effects usually last 3-4 hours with parenteral administration, and some adverse effects such as nausea may be reduced when meperidine is combined with antiemetic or antihistaminic medications. Although meperidine is often a preferred analgesic by both patients and physicians in the treatment of disorders such as migraine headaches, its analgesic efficacy has rarely proven superior to alternative parenteral pain medications in controlled trials. In addition, meperidine can precipitate monoamine oxidase inhibitor reactions, and during metabolism it is demethylated to normeperidine, a compound with significant central nervous system (CNS) toxicity. Meperidine should be considered a second line agent in the treatment of pain when opioid analgesics are required.

A close look at fenfluramine and dexfenfluramine.

In an effort to combat obesity, several medications have been developed. The nonamphetamine anorectics, such as phentermine, fenfluramine, and dexfenfluramine, have been recommended as first-line drug therapy for the treatment of obesity once diet and exercise alone have failed. Numerous studies have shown that these agents can promote weight loss when combined with diet restriction and exercise. Although fenfluramine and dexfenfluramine lack the abuse potential of amphetamine and its congeners, these agents are associated with drug interactions and adverse effects. Concomitant administration of fenfluramine or dexfenfluramine with medications that enhance serotonin levels (e.g., antidepressants, monoamine oxidase inhibitors, and migraine medications) can precipitate serotonin syndrome. Sudden discontinuation of fenfluramine or dexfenfluramine after prolonged administration can precipitate withdrawal depressive symptoms. Primary pulmonary hypertension, a potentially fatal disorder, has been reported to occur approximately 30 times more frequently in patients receiving anorectic agents for more than 3 months compared to the general population. More recently, the association of these popular anorectics with valvular heart disease has caused increased concerns about their use. The risks of primary pulmonary hypertension, valvular heart disease, and the occurrence of convulsions, coma, and death in overdose appear to be equally likely with dexfenfluramine and fenfluramine. In addition, many patients who lose weight while taking these anorectics rapidly regain it after the medication has been discontinued.

Clinical advances in the management of severe nausea and vomiting during pregnancy.

The nutritional status of the woman with hyperemesis of pregnancy has been compromised by decreased food intake and increased nutrient loss. Depending on the severity of symptoms, interventions may begin with dietary and life-style alterations, proceed to oral nutritional supplementation or pharmacologic preparations, and continue on to intravenous vitamin-mineral therapy and either enteral tube feedings, parenteral nutrition, or both. These therapies, and the role of the nurse in initiating or supporting them, are described.

Drug use during breast-feeding.

The physicochemical and pharmacokinetic factors involved in transfer of drugs into breast milk are reviewed. Passage of drugs into milk can best be viewed as a two-compartment system. Various ratios of the drug concentration values in the two compartments and ratios of maternal-to-infant intake have been described. Knowledge of the limitations of these methods is necessary to properly interpret and apply the literature on drug excretion into breast milk. Factors involved in choosing a drug for a nursing mother are listed, a stepwise approach to minimizing transfer of drug to the infant is presented, and the literature on the excretion of specific drugs into milk is reviewed. Generally, drugs given to nursing mothers reach infants in much smaller amounts than drugs given to pregnant women. Decisions about nursing during drug therapy and the choice of drug therapy in a nursing mother should be based on the dosage and duration of therapy, age of the infant, quantity of milk consumed, experience with the drug in infants, degree of oral absorption of the drug by the infant, potential long-term effects, possible interference with lactation, and non-dose-related toxicities (e.g., potential allergic reactions). Too often, the mother's need for a medication is perceived as a reason to discontinue nursing. By understanding the principles of drug passage into breast milk and systematically evaluating the mother's needs, infant factors, and the data on specific drugs, clinicians can usually devise treatment plans that allow nursing while minimizing the risks to the infant.

Establishment of a 900 telephone number at a university-based drug information service.

Effects of converting a free drug information service at a university medical center to a 900 telephone number are described. Calls to a university medical center drug information service had increased beyond the capacity of staff. A telephone survey to recent users of the service indicated that callers outside the institution would be willing to pay a fee for the service, so a 900 number was instituted for outside calls in January 1993. Staff recorded data on all questions they answered; data for 1993 were compared with those from 1992. Question volume decreased by 48% after the 900 number was instituted, with questions from outside the institution dropping by 55%, questions from outside health care professionals dropping by 72%, and questions from the lay public increasing slightly. One severe impediment to callers from local hospitals was that many hospitals block access to 900 numbers from their telephone systems. The average length of a call was three minutes and the average cost per call was $6. Net income during the first year of operation was $6698. The 900 number provided some income, but it did not completely offset operating costs. A 900 telephone number is a workable, but imperfect, method of providing drug information to outside callers. Early notification of users before implementing a 900 number is essential to allow time for them to arrange telephone access.

Delta-9-tetrahydrocannabinol as an antiemetic.

The use of delta-9-tetrahydrocannabinol (THC) as an antiemetic in patients undergoing cancer chemotherapy is reviewed. The pharmacokinetics of THC is discussed, and the agent's effects on the central nervous, cardiovascular, respiratory, gastrointestinal, immune, endocrine, and reproductive systems are presented. The toxicology, potential hazards, and adverse reactions of THC are reviewed. Also reviewed are studies of THC's use as an antiemetic. THC appears to be an effective antiemetic in cancer patients undergoing chemotherapy. The maximal antinauseant effects often correlate with the attainment of a "high". THC has been found consistently more effective than placebo and at least as effective as prochlorperazine. In phenothiazine-resistant patients, THC's effectiveness has exceeded that of the phenothiazines. Efficacy may depend on the chemotherapeutic agent causing emesis. Elderly patients do not tolerate the THC "high" well. Concurrent administration of phenothiazines with THC may block the "high" without reducing THC's antiemetic effectiveness. Because of variations in individual tolerance, absorption, and the form of chemotherapy, flexibility is necessary in establishing the correct dose of THC.

Evaluation of prenatal vitamin-mineral supplements.

Nutritional requirements of pregnancy are reviewed, and guidelines for evaluating prenatal vitamin-mineral supplements are provided. Daily antepartum supplementation of 0.4-0.8 mg of folic acid and 30-60 mg of elemental iron is currently recommended, although the lower ends of these ranges may be most appropriate. Dietary intake of these nutrients is likely to be inadequate without supplementation, and their importance is well established. Requirements for other minerals and vitamins are not well established, and there is no consensus on the need for supplementation. However, available data suggest that prenatal supplements should probably contain other nutrients; pyridoxine hydrochloride, cholecalciferol, vitamin E, pantothenic acid, calcium, magnesium, zinc, copper, and possibly selenium should be considered. Interactions among the minerals and vitamins commonly found in prenatal supplements may affect the absorption of various nutrient components. Thus, very high or low levels of certain nutrients should be avoided. The chemical form of minerals should also be considered. Products should have demonstrated bioavailability for iron, zinc, and other components that are subject to bioavailability problems. Use of low-potency product that contains a wide range of vitamins and minerals appears to be the most prudent approach to prenatal vitamin and mineral supplementation.