Analysis of the Pharmacokinetic Interaction between Cephalexin and Quinapril by a Nonlinear Mixed-Effect Model

Oligopeptidic drugs such as β-lactams and angiotensin-converting enzyme inhibitors share the same carriers in humans and animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method and by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. Five groups of eight rats were examined. In the first three groups, cephalexin elimination kinetics after intra-arterial administration alone or in combination with quinapril given by the parenteral or the oral route were studied, and the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral administration might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concentrations of cephalexin than those of quinapril. In the last two groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concentration-time curve (AUC) for cephalexin was increased by ca. 30% by coadministration of quinapril (40.1 versus 31.4 mg · h/liter; P = 0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/h/kg of body weight (P < 0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 h⁻¹; P < 0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level.     

Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man.

The pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 x 400 mg doses of Nurofen were determined in 12 healthy volunteers. Terminal half-lives were similar for both enantiomers, but plasma levels of S-ibuprofen were higher than those of R-ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time-dependency. A large inter-individual variability in the ratio of S- to R-ibuprofen average concentrations at steady-state was observed (mean +/- SD 1.89 +/- 0.89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.     

Exploring the contribution of the Clinical Librarian to facilitating evidence-based nursing

Aim. To examine the potential role of the Clinical Librarian in facilitating evidence‐based practice of nurses in acute hospital settings and develop a model for the role. Background. There is a growing policy and professional expectation that nurses will seek out and apply evidence in their clinical practice. Studies have demonstrated that nurses experience barriers in working with an evidence‐based approach. The role of Clinical Librarian has been used in other countries and within medicine to overcome some of the barriers to evidence‐based practice. There are limitations in the previous work in terms of rigour of evaluation, scope of the Clinical Librarian role and application to nursing in a UK setting. Design. A qualitative consultation of 72 nurses in acute care settings. Methods. Six consultation group interviews of between 4–19 participants. Written records were recorded by the scribe. Content analysis was undertaken to identify the range and frequency of comments. Results. Clinical questions currently go unanswered because of barriers of time, skills deficits and access to resources. Literature searching, skills training and evidence dissemination were the main areas of work the staff requested that a Clinical Librarian should undertake. It was anticipated that the Clinical Librarian could interact and work productively with nursing staff with a limited but regular presence on the ward. Interim communication could be via e‐mail, phone and written suggestions and requests for work. It was seen to be vital that the Clinical Librarian worked in partnership with staff to build evidence‐based practice capacity and ensure clinical relevance of the work. Conclusions. This study has generated the first model for the Clinical Librarian role with an emphasis on nursing. It is derived from the views of clinical nurses. Recommendations are made for the implementation and evaluation of such a role. Relevance to clinical practice. The Clinical Librarian could be an invaluable support to promoting evidence‐based nursing.     

Medical Oversight,Educational Core Content,and Proposed Scopes of Practice of Wilderness EMS Providers: A Joint Project Developed by Wilderness EMS Educators,Medical Directors,and Regulators Using a Delphi Approach

Introduction: A disparity exists between the skills needed to manage patients in wilderness EMS environments and the scopes of practice that are traditionally approved by state EMS regulators. In response, the National Association of EMS Physicians Wilderness EMS Committee led a project to define the educational core content supporting scopes of practice of wilderness EMS providers and the conditions when wilderness EMS providers should be required to have medical oversight. Methods: Using a Delphi process, a group of experts in wilderness EMS, representing educators, medical directors, and regulators, developed model educational core content. This core content is a foundation for wilderness EMS provider scopes of practice and builds on both the National EMS Education Standards and the National EMS Scope of Practice Model. These experts also identified the conditions when oversight is needed for wilderness EMS providers. Results: By consensus, this group of experts identified the educational core content for four unique levels of wilderness EMS providers: Wilderness Emergency Medical Responder (WEMR), Wilderness Emergency Medical Technician (WEMT), Wilderness Advanced Emergency Medical Technician (WAEMT), and Wilderness Paramedic (WParamedic). These levels include specialized skills and techniques pertinent to the operational environment. The skills and techniques increase in complexity with more advanced certification levels, and address the unique circumstances of providing care to patients in the wilderness environment. Furthermore, this group identified that providers having a defined duty to act should be functioning with medical oversight. Conclusion: This group of experts defined the educational core content supporting the specific scopes of practice that each certification level of wilderness EMS provider should have when providing patient care in the wilderness setting. Wilderness EMS providers are, indeed, providing health care and should thus function within defined scopes of practice and with physician medical director oversight.     

Female offspring sired by diet induced obese male mice display impaired blastocyst development with molecular alterations to their ovaries,oocytes and cumulus cells

Purpose

To investigate the impacts that a paternal high fat diet (HFD) has on embryology, ovarian/cumulus cell gene expression and COC metabolism from female offspring, using a mouse model.

Methods

Founder male mice were either fed a control diet (CD) or a HFD for 12 weeks. The HFD induced obesity but not diabetes, and founder males were then mated to normal weight CD fed female mice. Female offspring were maintained on a CD, super-ovulated, mated and the resultant zygotes were cultured to the blastocyst stage for embryo morphology, blastocyst cell number and apoptosis assessment. Ovaries and cumulus cells from offspring were collected for gene expression analysis of selected genes that maintain chromatin remodeling and endoplasmic reticulum (ER), metabolic and inflammatory homeostasis. Cumulus/oocyte complexes were also investigated for glucose uptake and lipid accumulation.

Results

Female offspring sired by obese fathers produced embryos with delayed development and impaired quality, displayed increases in ovarian expression of Glut1, Glut3 and Glut4, and an increase in cumulus cell expression of Glut4. Interestingly their COCs did take up more glucose, but did accumulate more lipid.

Conclusions

A paternal HFD is associated with subfertility in female offspring despite the offspring being fed a CD and this subfertility is concomitant with ovarian/cumulus cell molecular alterations and increased lipid accumulation.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-015-0470-x) contains supplementary material, which is available to authorized users.     

NO hyperpolarizes pulmonary artery smooth muscle cells and decreases the intracellular Ca2+ concentration by activating voltage-gated K+ channels.

NO causes pulmonary vasodilation in patients with pulmonary hypertension. In pulmonary arterial smooth muscle cells, the activity of voltage-gated K+ (Kv) channels controls resting membrane potential. In turn, membrane potential is an important regulator of the intracellular free calcium concentration ([Ca2+]i) and pulmonary vascular tone. We used patch clamp methods to determine whether the NO-induced pulmonary vasodilation is mediated by activation of Kv channels. Quantitative fluorescence microscopy was employed to test the effect of NO on the depolarization-induced rise in [Ca2+]i. Blockade of Kv channels by 4-aminopyridine (5 mM) depolarized pulmonary artery myocytes to threshold for initiation of Ca2+ action potentials, and thereby increased [Ca2+]i. NO (approximately 3 microM) and the NO-generating compound sodium nitroprusside (5-10 microM) opened Kv channels in rat pulmonary artery smooth muscle cells. The enhanced K+ currents then hyperpolarized the cells, and blocked Ca(2+)-dependent action potentials, thereby preventing the evoked increases in [Ca2+]i. Nitroprusside also increased the probability of Kv channel opening in excised, outside-out membrane patches. This raises the possibility that NO may act either directly on the channel protein or on a closely associated molecule rather than via soluble guanylate cyclase. In isolated pulmonary arteries, 4-aminopyridine significantly inhibited NO-induced relaxation. We conclude that NO promotes the opening of Kv channels in pulmonary arterial smooth muscle cells. The resulting membrane hyperpolarization, which lowers [Ca2+]i, is apparently one of the mechanisms by which NO induces pulmonary vasodilation.     

Eye pain: 5 cases to test your skill

The ability to distinguish between ophthalmic emergencies and benign eye conditions is crucial for a family physician. Find out how your skills stack up.