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Biomedical subjects

H F Hill

Publications and source records attributed to H F Hill.

At least 19 recordsLinked to original sources
PubMed1992

Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat.

The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.

Alfentanil↗
PubMed1992

Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges.

Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules' permeability measurements are new. The measured permeability coefficient was then correlated with the drugs' molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs' permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs' measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.

Animals↗
PubMed1992

Treatment of acute graft-versus-host disease with a nonmitogenic anti-CD3 monoclonal antibody.

Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.

Adult↗
PubMed1992

Can midazolam diminish sufentanil analgesia in patients with major trauma? A retrospective study with 43 patients.

Benzodiazepine agonists in combination with opioid analgesics are commonly used for combined analgesia and sedation in intensive care patients as well as for anesthesia. In animals, studies indicate either agonistic or antagonistic interactions of benzodiazepine agonists and opioids. This retrospective study of 43 patients evaluated the possible clinical relevance of benzodiazepine-opioid interactions related to pain management. We observed an increase of greater than 50% of the maximal sufentanil infusion rate in significantly more patients in group 2 (13 patients vs 6 patients; chi 2: p = 0.04) and a decrease of the sufentanil infusion rate in eight group 1 patients, but only in one patient in group 2 (chi 2: p = 0.03). We believe that an interaction between midazolam and sufentanil on nociceptive transmission and/or a rapid development of tolerance to sufentanil may be responsible for the observed difference. Contrary to the common clinical impression that midazolam potentiates opioid analgesia, these results indicate that systemic co-administration of midazolam over a period of more than three days can diminish sufentanil efficacy.

Adult↗
PubMed1992

Use of 2-hydroxypropyl-beta-cyclodextrin as an intrathecal drug vehicle with opioids.

2-Hydroxypropyl-beta-cyclodextrin (CDEX), a seven-membered glucose pyranose structure, forms reversible inclusion complexes with the lipophilic portion of a drug molecule by noncovalent bonding. This can increase the water solubility of lipid-soluble drugs and reduce the rate of clearance of such agents from the spinal cord into the vasculature after i.t. administration. In this study, opioids (morphine, lofentanil, alfentanil and sufentanil) with and without CDEX (20, 2, 0.2 and 0.02% w/v in sterile water) were administered spinally in rats prepared with chronic i.t. catheters. CDEX prolonged the duration of analgesia (52.5 degrees C hot plate) and reduced the incidence of catalepsy otherwise produced by a supermaximal i.t. dose of each of the opioids. The magnitude of the potentiating effect of CDEX on opioids was dependent upon concentration of the CDEX and varied with drug lipid partition coefficients. The highest concentration of CDEX alone (20%) had no effect upon the volume-evoked micturition reflex, blood pressure, heart rate, or spinal reflexes. Our data indicate that CDEX may be a useful i.t. vehicle for modifying the redistribution characteristics of highly diffusible molecules after their i.t. administration, and that for each drug there is an optimal CDEX concentration. In the present case, CDEX prolongs the spinal analgesic action and reduces the supraspinal actions of i.t. drugs.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

Patient-controlled analgesic administration. A comparison of steady-state morphine infusions with bolus doses.

The authors have shown previously that bone marrow transplant (BMT) patients who self-administered bolus doses of morphine gained equal oral mucositis pain relief while using less drug compared with similar patients receiving morphine by staff-controlled continuous infusion. In a follow-up study they compared the efficacy and side effects of morphine in two groups of marrow transplant patients who controlled their own analgesic administration either by conventional bolus-dose, patient-controlled analgesia (PCA) or by adjusting the rate of continuous morphine infusion to increase or decrease their plasma morphine concentration. Patients controlling their morphine infusion rates (pharmacokinetically based patient-controlled analgesia [PKPCA] group) obtained more relief from oral mucositis pain than did patients using conventional PCA. Patients in the PKPCA group used more morphine than PCA patients and achieved superior pain relief without significant increases in side effects (e.g., nausea, mood changes, sedation). The authors conclude that PKPCA improves the management of prolonged, severe pain in marrow transplant patients and that this approach to patient-controlled analgesia may be useful in other types of persistent pain.

Adult↗
PubMed1991

Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism.

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

The spinal nerve root sleeve is not a preferred route for redistribution of drugs from the epidural space to the spinal cord.

It has been frequently suggested that the spinal nerve root sleeve is a preferred route for redistribution of drugs from the epidural space to the spinal cord. To determine if this supposition is true, the authors measured the rate at which morphine, fentanyl, and lidocaine diffuse through dog and monkey meningeal specimens with and without a root sleeve. Two meningeal specimens of intact dura-arachnoid-pia mater were removed from each animal and placed in separate temperature-controlled diffusion cells. One specimen included a spinal nerve root sleeve; the other did not. The permeability of the tissues to each drug was then determined by placing the study drug in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and accumulated in the second reservoir. There was no difference in permeability between specimens with and without a nerve root sleeve for any drug in either species. Lidocaine was found to diffuse through the tissue significantly faster than fentanyl in both the dog and monkey even though fentanyl is nearly 48 times more lipid soluble than lidocaine. Morphine diffused through the tissue significantly slower than both lidocaine and fentanyl. The authors conclude that the spinal nerve root sleeve is not a preferred route of entry for drugs moving from the epidural space to the spinal cord. In addition, despite hypotheses to the contrary, lipid solubility does not appear to be the overriding determinant of meningeal permeability.

Animals↗
PubMed1991

Multiple-dose evaluation of intravenous hydromorphone pharmacokinetics in normal human subjects.

We measured the pharmacokinetics of hydromorphone in normal volunteers given three doses of the drug (10, 20, and 40 micrograms/kg) as intravenous 45-s injections on different days. Concentrations of hydromorphone in plasma from serial blood samples were measured by a high-performance liquid chromatography method specific for hydromorphone with a detection limit of 0.1 ng/mL. In all cases, plasma hydromorphone concentration versus time data for individual subjects were best described by a triexponential (instead of mono- or biexponential) function. Furthermore, we found that the pharmacokinetics of hydromorphone was independent of dose across the range studied. Averaged across doses, the distribution and terminal elimination half-lives were 1.27 min (t1/2 pi), 14.7 min (t1/2 alpha), and 184 min (t1/2 beta), respectively. Average values for systemic clearance, initial dilution volume, and steady-state volume of distribution were 1.66 L/min (Cl), 24.4 L (Vc), and 295 L (Vdss). Our results indicate that hydromorphone pharmacokinetic parameters are linear across a fourfold range of doses that are usually employed clinically and that previously reported pharmacokinetic values for hydromorphone (based on radioimmunoassay measurements) deserve reconsideration.

Adult↗
PubMed1991

A computer-based system for controlling plasma opioid concentration according to patient need for analgesia.

Microprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.

Analgesia, Patient-Controlled↗
PubMed1990

Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain.

This report examines the relationship of plasma drug concentration to analgesic effect following bolus doses of alfentanil, fentanyl and morphine and assesses individual differences in analgesic response among volunteers. We predicted that the 3 opioids would yield disparate analgesic profiles because their physicochemical and pharmacokinetic characteristics differ. Ten healthy volunteers received intravenous bolus doses of either alfentanil, fentanyl, morphine or normal saline on different days. We stimulated their teeth electrically and measured brain evoked potential (EP) and pain report (PR) repeatedly over 2 h to assess analgesic effect. Concurrently, we drew 18 blood samples to assess opioid plasma concentrations during the test period. The relationship between opioid plasma concentration and analgesic effect was well defined for alfentanil but ambiguous for morphine. Fentanyl exhibited a marked hysteresis. We observed noteworthy individual differences in analgesic response with all 3 drugs but these differences were greatest for morphine and least for alfentanil. Inter- and intrasubject variability in analgesic response across drugs is related to the physicochemical properties of the drugs tested.

Adult↗
PubMed1990

Steady-state infusions of opioids in human volunteers. I. Pharmacokinetic tailoring.

We report a method for controlling and adjusting plasma opioid concentration to preselected target values in individual human subjects in order to study analgesic and other effects of opioids at steady state. The method employs a computer-controlled infusion pump and an algorithm that utilizes individual subject pharmacokinetic parameters predetermined with tailoring bolus opioid doses. We used this approach to produce 3-step increases in plasma concentrations of alfentanil, fentanyl and morphine in each of 15 subjects. We maintained each plasma concentration plateau for 70 min, measured plasma opioid concentrations achieved during the infusions and analyzed the results for bias and precision of the individually tailored infusions. Our results show that pharmacokinetically tailored opioid infusions produce stable plasma opioid concentrations within 10 min for alfentanil and morphine; with each drug overall prediction error was 20% or less. Fentanyl was somewhat more difficult to control by this method than were the other 2 opioids. We conclude that individual tailoring of opioid infusions minimizes the impact of individual pharmacokinetic differences on achieving preselected plasma opioid concentrations and provides an accurate means of controlling steady-state drug concentrations for studies of concentration-effect relationships and comparisons of side-effect intensities produced by equianalgesic plasma opioid concentrations.

Adult↗
PubMed1990

Steady-state infusions of opioids in human. II. Concentration-effect relationships and therapeutic margins.

We used computer-controlled individually tailored infusions to study relationships between plasma drug concentration and opioid effects, and to evaluate the therapeutic margins of alfentanil, fentanyl and morphine in human subjects. In order to compare the 3 drugs, we infused each opioid to 3 different steady-state target plasma concentrations during separate 8 h test periods so that concentration-effect curves could be defined for each opioid and subject. Dental electrical stimulation produced a consistent degree of baseline experimental pain, and we measured the influence of increasing plasma opioid concentrations on pain intensity and the magnitude of pain-related evoked potentials. We also quantified ventilatory function and subjective side-effects during baseline (no drug), at the 3 target plasma concentrations with each drug. Finally, we measured actual plasma opioid concentrations during each phase of the infusion period. This procedure allowed us to calculate for each opioid the plasma concentration required to produce a 50% decrease in reported pain intensity and evoked potential amplitude (IC50). Subsequent calculation of side-effect magnitudes at the analgesic IC50s permitted direct comparisons of therapeutic margins between alfentanil, fentanyl and morphine. We found a robust relationship between plasma drug concentration and analgesic, ventilatory, and subjective-effect magnitudes for each opioid in this study. We conclude that the magnitudes of individual side-effects associated with equianalgesic, steady-state plasma concentrations of these 3 mu receptor-selective opioids do not differ across drugs.

Adult↗
PubMed1990

Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and monkeys.

Little information exists about which spinal meninx is the principal permeability barrier between the epidural space and the spinal cord or about what physicochemical properties of drug molecules govern their meningeal permeability. To better understand these aspects of epidural pharmacokinetics, the authors measured the permeability of morphine and alfentanil through the different components of the spinal meninges-dura mater, arachnoid mater, and pia mater-of dogs and monkeys in vitro. Live meningeal tissue from either species (dura mater alone, pia mater alone, or intact dura-arachnoid-pia) was placed between two fluid reservoirs of a temperature-controlled diffusion cell. The permeability of the tissues to each opioid was determined by placing the opioid in one of the reservoirs of the diffusion cell and measuring the rate at which the drug diffused through the tissue and appeared in the second reservoir. The arachnoid mater was found to be the major meningeal diffusion barrier between the epidural space and the spinal cord. Alfentanil was 3.7 times more permeable than morphine through all three meninges, suggesting that increased lipid solubility increases meningeal permeability. However, neither lipid solubility nor molecular weight adequately explained the difference in permeability between morphine and alfentanil. The authors conclude that this in vitro model has significant utility for studies aimed at predicting in vivo meningeal permeability and hence the potency and rapidity of action of any opioid administered by the epidural route.

Alfentanil↗
PubMed1989

Prolonged morphine self-administration and addiction liability. Evaluation of two theories in a bone marrow transplant unit.

The technology for patient intravenous self-administration of morphine has been successfully implemented in postoperative and other clinical settings and can be used with terminal patients who experience pain. The question of whether patients who use such instrumentation will be vulnerable to over-medication or development of addiction has not been addressed. This report reviews two competing theories that bear upon this question and tests their predictions about self-administration of morphine for pain relief using data obtained from patients in a bone marrow transplant unit. The first, Opponent Process Theory, predicts escalating drug use and the development of addictive behavior in patients who self-administer morphine. The second, Control Theory, predicts that patients will self-regulate pain effectively by administering morphine without developing problems of medication abuse or addiction. Patients self-administering morphine for 2 weeks were compared to controls who received the drug via routine staff-controlled continuous infusion procedures. Self-administering patients used significantly less morphine than controls and still achieved the same amount of pain control; moreover, they terminated drug use sooner than controls. The predictions based upon Opponent Process Theory were not supported in these marrow transplant patients, but Control Theory accounted well for the outcomes. These results support the assumption that self-administration of opioids in a medical setting does not put patients at risk for over-medication or addiction.

Adult↗
PubMed1989

Assessment and management of donor pain following marrow harvest for allogeneic bone marrow transplantation.

We studied the time course and intensity of pain of multiple bone marrow aspirations in 30 healthy adult marrow donors receiving acetaminophen with codeine for analgesia immediately after marrow harvesting for allogeneic bone marrow transplantation. Upon discharge, donors were supplied with acetaminophen (315 mg) plus codeine (30 mg) tablets and instructed to use one or two tablets up to every 4 h as needed for pain control. Donors used analgesic medication for a mean (+/- SE) of 3.3 +/- 0.5 days (range = 1-13 days) and reported less than complete pain relief. Subjects reported more pain at time of medication than between doses, indicating that the analgesic was at least partially effective. Male donors tended to report more pain and use more analgesic than did females. We conclude that donors self-regulate their analgesic usage to achieve maximal relief and that incomplete relief with acetaminophen plus codeine may be due to limited efficacy of this analgesic preparation. Our findings suggest that donor pain management may be improved by use of more powerful analgesics.

Acetaminophen↗