Quantification of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat

ABSTRACT The pharmacodynamic (PD) interaction between the benzodiazepine agonist midazolam and the ␣ 2 -adrenergic agonist dexmedetomidine was characterized for defined measures of anesthetic action and cardiovascular and ventilatory side effects in 33 rats. For various combinations of constant plasma concentrations of midazolam (0.1-20 g/ml) and dexmedetomidine (0.3-19 ng/ml) obtained by target-controlled infusion, the whisker reflex (WR), righting reflex (RR), startle reflex to noise (SR), tail clamp response (TC), and corneal reflex (CR) were assessed. EEG (power in 0.5-3.5-Hz frequency band), mean arterial pressure, and heart rate were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The nature and extent of PD interaction was quantified by the model parameter synergy (SYN Ͻ 0, antagonism; SYN ϭ 0, additivity; and SYN Ͼ 0, synergy). With increasing drug concentrations WR was lost first, followed by RR, SR, TC, and CR. These effects were accompanied by an increase of the EEG measure. The drug interaction was synergistic for all stimulus-response measures and the degree of synergy increased with deeper levels of central nervous system depression (SYN was 7.3, 145, 560, 374, and 1490 for WR, RR, SR, TC, and CR, respectively). The cardiovascular side effects of dexmedetomidine, evaluated at similar PD endpoints, were reduced in the presence of midazolam. Ventilatory side effects were minor for all drug combinations. The nature and extent of the PD interactions were not reflected in the EEG measure. In clinical anesthetic practice adequate general anesthesia requires a minimum of two different classes of anesthetic drugs. A hypnotic (inhalational anesthetic, i.v. anesthetic) and an analgesic (opiate) drug are titrated to achieve adequate CNS depression. A muscle relaxant can be used to facilitate surgical procedures. This anesthetic combination is termed "balanced anesthesia" (Hug, 1990; Many variables influence the complex relationship between dosage, plasma concentration, and drug effect. To optimize the delivery of anesthetic drugs to individual patients, it is important to distinguish between pharmacokinetic (PK) and pharmacodynamic (PD) interactions. For example, Dexmedetomidine, a selective ␣ 2 -adrenergic agonist, is being studied for potential use in anesthetic practice because of its combined analgesic, sedative, hypnotic, and anxiolytic effect

Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m2 administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9–20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7–28.1 months; 95% CI: 3.9–7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B12 supplementation. © 2001 Cancer Research Campaign http://www.bjcancer.co

Habitat preference of geese is affected by livestock grazing:Seasonal variation in an experimental field evaluation

The number of staging geese in northwestern Europe has increased dramatically. Growing goose numbers put strong grazing pressure on agricultural pastures. Damage to agricultural land may be mitigated by managing nature reserves in order to optimally accommodate large numbers of grazing geese. Livestock grazing has been shown to facilitate foraging geese; we take the novel approach of determining the effects of four different livestock grazing treatments in a replicated experiment on the distribution of geese. We present experimental field evidence that livestock grazing of a salt marsh in summer affects the habitat preference of foraging geese during autumn and spring staging. In an experimental field set-up with four different livestock grazing treatments we assessed goose visitation through dropping counts, in both autumn and spring. Grazing treatments included 0.5 or 1 horse ha(-1) and 0.5 or 1 cattle ha(-1) during the summer season. The livestock grazing regime affected goose distribution in autumn, just after livestock had been removed from the salt marsh. In autumn, goose visitation was highest in the 1 head ha(-1) grazing treatments, where grazing intensity by livestock was also highest. In line with this result, goose visitation was lowest in the 0.5 head ha(-1) livestock grazing treatments, where the grazing intensity by livestock was lowest. The differences in goose visitation among the experimental treatments in autumn could not be explained by the canopy height. In spring we did not find any effect of livestock grazing treatment on goose visitation. Differences in the distribution of geese over the experiment between autumn and spring may be explained by changes in the availability of nutrient-rich vegetation. Livestock summer grazing with a high stocking density, especially with horses, can be used to attract geese to salt marshes in autumn and potentially reduces damage caused by geese to inland farmland. From a nature conservation interest point of view, however, variation in structure of the vegetation is a prerequisite for other groups of organisms. Hence, we recommend grazing of salt marshes with densities of 0.5 head ha(-1) of livestock when goose conservation is not the only management issue

The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child