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Biomedical subjects

H F Hill

Publications and source records attributed to H F Hill.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1986

Developmental alterations in maturing rats caused by chronic prenatal and postnatal diazepam treatments.

The post treatment effects of early prenatal, late prenatal, early postnatal or combined prenatal and neonatal treatment with diazepam on the development of pain sensitivity, acoustic startle responsiveness, and benzodiazepine receptors in the cerebral cortex were investigated in rats between 14 and 90 days of age. Tail-flick latency was significantly decreased by combined prenatal and neonatal and by early prenatal diazepam treatment, but not by diazepam during the last half of gestation or during the neonatal period alone. Acoustic startle response was decreased by either late prenatal or neonatal diazepam treatment, but not by early prenatal treatment alone. Density of benzodiazepine receptors in the cortex was increased from postnatal day 1 to 21 by either early or late prenatal diazepam treatment. Neonatal diazepam treatment suppressed cortical benzodiazepine receptor or development until postnatal day 21; thereafter, receptor density increased to significantly higher values than in controls at 90 days of age. The results demonstrate that diazepam can alter development of pain sensitivity by actions during early gestation, startle responsiveness by actions late in pregnancy, and cortical benzodiazepine receptors by actions throughout gestation and the early postnatal period.

Acoustic Stimulation↗
PubMed1984

Effects of pre- and postnatal haloperidol administrations to pregnant and nursing rats on brain catecholamine levels in their offspring.

Effects of perinatal, maternal treatments with haloperidol on brain catecholamine and serotonin concentrations in maturing offspring were examined. The drug was administered orally, at three different dosages, each day from the 14th gestational day to postnatal day 12. At 14, 22, 53 and 90 days of age offspring were selected for regional assays of amine neurotransmitter concentrations. The results indicate that haloperidol can alter the developmental accumulation of central catecholaminergic neurotransmitters. The drug-induced decreases in cortical and spinal norepinephrine levels and in striatal dopamine content in the offspring persisted into adulthood. Regional serotonin concentrations in offspring were not affected by the maternal haloperidol treatments. These findings suggest that central catecholamine receptors are necessary for normal development of dopaminergic and noradrenergic innervation in the central nervous system.

Aging↗
PubMed1984

Differential, postnatal ontogeny of opiate and benzodiazepine receptor subtypes in rat cerebral cortex: binding characteristics of tifluadom and brotizolam.

The postnatal development of 3[H] ethylketocyclazocine (EKC) binding characteristics was examined using membranes from the cerebral cortex of rats at various ages. Binding site affinity did not vary significantly between postnatal days 1 and 90. However, the apparent density of cortical binding sites increased fivefold between birth and adulthood. These results were similar to another ontogenic study of brain opiate receptor binding. Whereas EKC was equally potent as a competitor for 3[H] EKC binding in cortex from neonatal and adult rats, tifluadom was three times more potent in neonatal cortex than in adult cortex as a displacer of specific EKC binding. Brotizolam, a new thienodiazepine and a potent sedative hypnotic, also was distinctly more potent as an inhibitor of 3H-diazepam binding in neonatal rat brain cortex than in adult rat brain cortex. These results suggest that subtypes of benzodiazepine receptors, as well as some opiate receptor subtypes, exhibit different rates of postnatal development.

Animals↗
PubMed1983

Prenatal and postnatal exposure to diazepam: effects on opioid receptor binding in rat brain cortex.

The effects of chronic perinatal or postnatal administrations of diazepam on opiate receptor development in cerebral cortex and striatum were studied at two different post-treatment ages, using tritiated ethylketocyclazocine, the prototypic kappa-opiate, for measurements of opiate binding site ontogeny. Prenatal plus postnatal exposure to diazepam markedly decreased the total number of binding sites for [3H]ethylketocyclazocine in the rat cerebral cortex and striatum at 14 days of age. Postnatal diazepam treatment alone did not alter [3H]ethylketocyclazocine binding site development in cortex or striatum. These results suggest that development of opiate receptors in rat brain can be altered by prenatal exposure to diazepam.

Animals↗
PubMed1979

Maintenance dose of penicillamine in rheumatoid arthritis: a comparison between a standard and a response-related flexible regimen.

There is much individual variation in the response of rheumatoid arthritis (RA) to penicillamine, some patients deriving benefit from very small doses. A dose of 750 mg daily is widely regarded as standard, and, while their RA commonly responds, many patients discontinue treatment because of adverse reactions to penicillamine. A more flexible prescribing policy might be more successful in the long term and was tested in 1 group of 20 patients, another receiving a 'standard' regimen, each beginning treatment at a low dose level. Of those who were given increases of dose only if response was poor 17 completed 1 year of treatment on an average maintenance dose of 308 mg daily, but only 11 of the other group on an average dose 613 mg daily. Proteinuria, which was found only in the latter group accounted for 6 withdrawals, all at doses of 625 mg daily or above. The reduction in rheumatoid activity appeared to be of about the same degree among the members of both groups who completed 12 months of treatment. Penicillamine should be given initially in a low dose and this should be raised only if there is lack of response after at least 4 weeks.

Adult↗
PubMed1979

Penicillamine in rheumatoid arthritis: adverse effects.

The use of penicillamine in rheumatoid arthritis (RA) is limited by the incidence of adverse effects, some of which are potentially hazardous. However, adverse effects are dose-related and the advantages and disadvantages of different fixed and flexible dose regimes are discussed. The incidence of adverse effects is significantly greater in patients previously treated with gold who developed toxicity to that drug--no such increase being found in gold treated patients whose only reason for stopping gold was ineffectiveness. Rashes which develop after several months of treatment are variants of pemphigus and their various presentations are described. Fatal reactions, fortunately rare, are predominantly associated with aplasia of the bone marrow. Monthly haematological checks coupled with meticulous charting of the results may reveal trends as well as numerical changes and serve as an early warning of marrow damage.

Anemia, Aplastic↗
PubMed1979

Penicillamine in rheumatoid arthritis.

Perhaps the most important conclusion is that much remains to be learnt about how to use penicillamine in clinical practice. The results described have been obtained by observing groups of patients on various fixed schedules of dosage. There may be a case for using a more flexible system but this makes comparisons difficult and at this stage predetermined fixed schedules have been preferred. A total daily dose of 1500 mg is clearly excessive and probably unnecessary. There is some suggestion that administration between meals produces better and perhaps more predictable absorption. If used in this way the total daily dose should be lower than the one found most suitable when the drug is given with food. Experience to date favours a daily total of 375 mg given between meals. The late onset of some adverse reactions in patients on low doses suggest that the total cumulative dose may be relevant and that some toxic reactions are liable to occur when a certain total intake has been reached. No mention has been made in this survey of comparisons with other drugs. The main task has been seen to be the exploration of various dosage schedules in the hope of finding an effective dose which does not produce a high incidence of adverse effect. Only when this information has been obtained will it once again become relevant to test the drug under control conditions either against an inactive placebo or some other anti-rheumatoid drug.

Arthritis, Rheumatoid↗