Search PubMed⌕ Search

Biomedical subjects

K Cox

Publications and source records attributed to K Cox.

At least 91 records · Page 5Linked to original sources
PubMed1995

Clinical sevoflurane metabolism and disposition. II. The role of cytochrome P450 2E1 in fluoride and hexafluoroisopropanol formation.

BACKGROUND: Sevoflurane is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Cytochrome P450 2E1 is the major isoform responsible for sevoflurane metabolism by human liver microsomes in vitro. This investigation tested the hypothesis that P450 2E1 is predominantly responsible for sevoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty-one patients within 30% of ideal body weight, who provided institutional review board-approved informed consent and were randomized to receive disulfiram (500 mg oral, n = 11) or nothing (control, n = 10) the night before surgery, were evaluated. All patients received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction. Thereafter, sevoflurane was discontinued, and anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Blood sevoflurane concentrations during anesthesia and for 8 h thereafter were measured by gas chromatography. Plasma and urine fluoride and total (unconjugated plus glucuronidated) HFIP concentrations were measured by an ion-selective electrode and by gas chromatography, respectively, during anesthesia and for 96 h postoperatively. RESULTS: Patient groups were similar with respect to age, weight, sex, case duration, and intraoperative blood loss. The total sevoflurane dose, measured by cumulative end-tidal sevoflurane concentrations (3.7 +/- 0.1 MAC-h; mean +/- SE), total pulmonary uptake, and blood sevoflurane concentrations, was similar in both groups. In control patients, plasma fluoride and HFIP concentrations were increased compared to baseline values intraoperatively and postoperatively for the first 48 and 60 h, respectively. Disulfiram treatment significantly diminished this increase. Plasma fluoride concentrations increased from 2.1 +/- 0.3 microM (baseline) to 36.2 +/- 3.9 microM (peak) in control patients, but only from 1.7 +/- 0.2 to 17.0 +/- 1.6 microM in disulfiram-treated patients (P < 0.05 compared with control patients). Peak plasma HFIP concentrations were 39.8 +/- 2.6 and 14.4 +/- 1.1 microM in control and disulfiram-treated patients (P < 0.05), respectively. Areas under the plasma fluoride- and HFIP-time curves also were diminished significantly to 22% and 20% of control patients, respectively, by disulfiram treatment. Urinary excretion of fluoride and HFIP was similarly significantly diminished in disulfiram-treated patients. Cumulative 96-h fluoride and HFIP excretion in disulfiram-treated patient was 1,080 +/- 210 and 960 +/- 240 mumol, respectively, compared to 3,950 +/- 560 and 4,300 +/- 540 mumol in control patients (P < 0.05). CONCLUSIONS: Disulfiram, an effective P450 2E1 inhibitor, substantially decreased fluoride ion and HFIP production during and after sevoflurane anesthesia. These results suggest that P450 2E1 is a predominant P450 isoform responsible for human sevoflurane metabolism in vivo.

1-Propanol↗
PubMed1995

Clinical practice is not applied scientific method.

Practice is often described as applied science, but real life is far too complex and interactive to be handled by analytical scientific methods. The limitations of usefulness of scientific method in clinical practice result from many factors. The complexity of the large number of ill-defined variables at many levels of the problem. Scientific method focuses on one variable at a time across a hundred identical animals to extract a single, generalizable 'proof' or piece of 'truth'. Clinical practice deals with a hundred variables at one time within one animal from among a clientele of non-identical animals in order to optimize a mix of outcomes intended to satisfy that particular animal's current needs and desires. Interdependence among the variables. Most factors in the illness, the disease, the patient and the setting are interdependent, and cannot be sufficiently isolated to allow their separate study. Practice as a human transaction involving at least two people is too complex to be analysed one factor at a time when the interaction stimulates unpredictable responses. Ambiguous data. Words have many usages. People not only assign different interpretations to the same words, they assign different 'meanings', especially according to the threat or hope they may imply. The perceptual data gleaned from physical examination may be difficult to specify exactly or to confirm objectively. The accuracy and precision of investigational data and their reporting can be low, and are frequently unknown. Differing goals between science and practice. Science strives for exact points of propositional knowledge, verifiable by logical argument using objective data and repetition of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Competence↗
PubMed1994

Depletion and recovery of the calcium-binding proteins calbindin and parvalbumin in the pigeon optic tectum following retinal lesions.

Retinal lesions in pigeons produced a marked depletion of somata and neuropil staining for both calbindin-D28k and parvalbumin immunoreactivities in the contralateral optic tectum. Calbindin-like immunoreactivity reappeared in some tectal layers by 6 weeks postlesion, whereas paravalbumin-like immunoreactivity recovered almost completely after 5 weeks. These data indicate that the retinal input may control the expression of calbindin and parvalbumin in the pigeon optic tectum.

Animals↗
PubMed1994

FK506 conversion therapy in pediatric liver transplantation.

The safety and efficacy of conversion to FK506 after failing immunosuppression with cyclosporine was prospectively evaluated in 31 pediatric liver transplant recipients between April 1991 and March 1993. The patients, who ranged in age from 40 days to 14 years, accounted for 28 primary transplantations and 3 retransplantations. The initial immunosuppression regimen consisted of cyclosporine in combination with prednisone. The indications for conversion were acute or chronic rejection refractory to OKT3, Minnesota antilymphocyte globulin, or steroids (13 patients); hypertension (8 patients); inability to reach a therapeutic level of cyclosporine (6 patients); hirsutism (3 patients); and growth retardation (1 patient). After an average follow-up of 10 months (range, 2 to 25 months), 27 (87%) of the patients are alive and have functioning grafts. Of the 13 patients who were converted for refractory rejection, 9 are alive. Six of these 9 patients experienced a complete biochemical reversal of the rejection process within 3 months of conversion; 2 had a partial response to conversion, and 1 patient failed but underwent successful retransplantation. Three of the 4 patients who died did so without showing any improvement. The remaining 18 patients who were converted for various other reasons are alive and have functioning grafts. Of the 8 patients who developed hypertension on cyclosporine and prednisone, 6 experienced a resolution of this problem within 3 months of conversion. Three of the 18 children who underwent rescue therapy for reasons other than refractory rejection experienced rejection episodes after conversion to FK506. Two of these 3 children achieved resolution with either steroid therapy or an increased dosage of FK506, while the third child developed chronic rejection. The side effects of FK506 were generally minor and resolved by lowering the dose. Lymphoproliferative disease developed in 2 patients (6%). The present study suggests that FK506 is a relatively safe and effective rescue therapy for pediatric liver transplant recipients who have failed immunosuppression with cyclosporine. Longer follow-up is needed to assess the effect of FK506 on growth.

Adolescent↗
PubMed1994

Responsiveness of clonal limb bud cell lines to bone morphogenetic protein 2 reveals a sequential relationship between cartilage and bone cell phenotypes.

There is growing evidence to suggest that BMPs are among the signals necessary to create the embryonic skeleton, but how these regulatory molecules enter the pathways of embryonic bone formation remains to be defined. The earliest steps of endochondral bone formation, consisting of mesenchymal condensation and chondrogenesis, have been shown to result directly from BMP-2 action. To determine whether the transition from chondrogenesis to osteogenesis occurring later in endochondral bone formation is also the result of BMP activity, we tested the effects of BMP-2 on immortalized endochondral skeletal progenitor cells derived from mouse limb bud. The cell lines established by this process were found to fall into three general categories: undifferentiated skeletal progenitor cells, which in the presence of BMP-2 first express cartilage matrix proteins and then switch to production of bone matrix proteins; prechondroblast-like cells that constitutively express a subset of markers associated with chondrogenesis and, in the presence of BMP-2, shut off synthesis of these molecules and are induced to produce bone matrix molecules; and osteoblast-like cells that are not significantly affected by BMP-2 treatment. These data suggest that BMP-2 initiates the differentiation of limb bud cells into cells of both the cartilage and bone lineages in a sequential manner, making BMP-2 a potent regulator of skeletal cell differentiation.

Aggrecans↗
PubMed1994

Angiotensin II metabolic clearance rate and pressor responses in nonpregnant and pregnant women.

OBJECTIVES: Normal pregnancy is associated with reduced pressor dose-responses to infused angiotensin II. We tested the hypotheses that alterations in the metabolic clearance rate and the half-life of angiotensin II account for reduced pressor dose-responses during gestation and that angiotensin II increases circulating levels of vasodilatory prostaglandins I2 and E2 relative to thromboxane A2. STUDY DESIGN: Eleven nonpregnant and 37 pregnant (30 +/- 0.3 weeks' gestation, mean +/- SE) women were infused with angiotensin II (3.11 to 22.36 ng/min.kg) for 15 minutes, and blood was obtained to evaluate steady-state immunoreactive plasma angiotensin II and eicosanoid concentrations. RESULTS: Angiotensin II pressor responses were dose dependent in all groups and reduced in pregnant women (p < 0.001). Basal immunoreactive plasma angiotensin II concentrations were 2.7-fold greater (p < 0.001) in pregnant versus nonpregnant women. Plasma levels reached steady state by 5 minutes of infusion, and at similar angiotensin II concentrations the increase in blood pressure was greater in nonpregnant versus pregnant women (p < 0.001). The angiotensin II metabolic clearance rate and half-life were similar in nonpregnant and pregnant women: metabolic clearance rate = 85 +/- 10 versus 68 +/- 3 ml/min.kg, respectively (p = 0.130), and half-life = 48 and 49 seconds, respectively. Plasma prostaglandin I2 (6-keto-prostaglandin F1 alpha) prostaglandin E2, and thromboxane B2 levels in pregnant women were unaffected by angiotensin II infusions. CONCLUSION: Neither changes in angiotensin II metabolism nor angiotensin II-induced increases in plasma levels of prostaglandin I2, prostaglandin E2, or the prostaglandin I2/thromboxane A2 ratio appear responsible for the decreased pressor response sensitivity to infused angiotensin II observed during normal human pregnancy.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Comparison of prophylactic angiotensin II versus ephedrine infusion for prevention of maternal hypotension during spinal anesthesia.

OBJECTIVE: Our purpose was to study the efficacy of ephedrine versus angiotensin II prophylactic infusions to counter maternal hypotension that occurs during spinal anesthesia at cesarean delivery. STUDY DESIGN: Healthy pregnant women undergoing elective repeat cesarean delivery at term with spinal anesthesia were randomized either to a control group (n = 10) or to one of two prophylactic infusion groups: angiotensin II (n = 10) or ephedrine (n = 10). Prophylactic infusions were titrated to a maternal diastolic blood pressure 0 to 10 mm Hg above baseline. Maternal and fetal blood samples for angiotensin II levels and acid-base status were obtained. Student's t test, chi 2, and analysis of variance were used. RESULTS: Mean arterial pressures were maintained after spinal anesthesia in the ephedrine and angiotensin II groups but decreased (p < 0.05) in the control group. Maternal angiotensin II levels rose with angiotensin II infusions but were unaltered in the other groups. Umbilical artery and vein angiotensin II levels were unaltered by angiotensin II infusions. Mean umbilical artery blood pH was lower (p < 0.05) in the ephedrine group than in the angiotensin II and control groups. CONCLUSIONS: In the healthy term fetus there is an advantage in using angiotensin II to maintain maternal blood pressure during regional anesthesia.

Adult↗
PubMed1994

Effect of the use of sleep medication in Dutch hospitals on the use of sleep medication at home.

Insomnia is an important nursing problem in hospitals. Although the use of sleep medication is often criticized, it is one of the commonest interventions with regard to sleep problems. In this study, the effect of the administration of sleep medication in Dutch hospitals on the use of sleep medication at home is investigated. Only patients were included who had never used sleep medication before admittance in hospital. Results show that patients who used sleep medication for at least 5 days in hospital (n = 233) used sleep medication more often at home after discharge than patients who did not use sleep medication in hospital (n = 55). Furthermore, the study showed that those patients who used at least 5 days' sleep medication, especially those patients who used sleep medication more often in hospital, also used sleep medication more often at home. This is in line with the addictive effects of sleep medication. From these results it can be concluded that the administration of sleep medication is not without danger. Therefore, it is recommended to search for alternative interventions, especially for patients who are in hospital for a longer period.

Adult↗