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Biomedical subjects

A Dahan

Publications and source records attributed to A Dahan.

At least 19 recordsLinked to original sources
PubMed2007

Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two- and three-compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E(max) pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).

Adult↗
PubMed2006

A novel phospholipid derivative of indomethacin, DP-155 [mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl [corrected] choline], shows superior safety and similar efficacy in reducing brain amyloid beta in an Alzheimer's disease model.

Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.

Alzheimer Disease↗
PubMed2006

Buprenorphine induces ceiling in respiratory depression but not in analgesia.

BACKGROUND: We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects. METHODS: Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. RESULTS: After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). CONCLUSIONS: While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Adult↗
PubMed2005

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

BACKGROUND: There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. METHODS: In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). RESULTS: In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). CONCLUSIONS: Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Adult↗
PubMed2005

Transient neurological symptoms with subarachnoid lidocaine: effect of early mobilization.

BACKGROUND AND OBJECTIVE: Although lidocaine has been used extensively for spinal anaesthesia since 1949, it has been associated with transient neurological symptoms only in the past 10 yr. It has been suggested that early ambulation after spinal anaesthesia, as opposed to traditional 24 h recumbency, might be the causative factor for the development of transient neurological symptoms. The purpose of this study was to examine the effect of early ambulation on the incidence of transient neurological symptoms after single injection spinal anaesthesia with lidocaine 2%. METHODS: Sixty patients undergoing minor surgery under spinal anaesthesia were included. All patients received lidocaine 60 mg. After the establishment of successful subarachnoid block, patients were randomly allocated to two groups of 30 patients. Patients in Group 1 were ambulated as soon as possible, whereas patients in Group 2 were kept recumbent until 6 h after subarachnoid injection. Two days after surgery patients were contacted by a blinded observer and interviewed of transient neurological symptoms using a standardized questionnaire. Patients were asked to express the intensity of pain/discomfort on a verbal rating scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: There was no significant difference in the incidence of transient neurological symptoms (23% vs. 27%). In all patients, symptoms resolved completely within 6-24 h. The median pain score was 5 (range 2-8) in Group 1 and 7 (range 1-8) in Group 2. CONCLUSIONS: Under the conditions of this study, there is no correlation between the time of ambulation after spinal anaesthesia with lidocaine and the incidence of transient neurological symptoms.

Adult↗
PubMed2005

Lumbar epidural catheter insertion: the midline vs. the paramedian approach.

BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the characteristics of epidural catheter insertion via the midline or the paramedian approach with regard to ease of catheter insertion, incidence of paraesthesias and efficacy of epidural block. In addition to the type of approach, the prognostic value of Patients characteristics variables with regard to the incidence of paraesthesias was assessed. METHODS: Thirty patients scheduled for surgery under epidural anaesthesia were randomly assigned to one of two groups of 15 patients each. Epidural anaesthesia was performed via a midline or paramedian approach using loss of resistance to saline. Variables measured were: time needed to identify the epidural space, time needed for and ease of epidural catheter insertion and the incidence of paraesthesias. After completion of these observations, epidural anaesthesia was established with 150 mg ropivacaine 1%. Efficacy of the epidural block was assessed by the need for intraoperative analgesics and by the patient on a three-point scale (good/fair/poor). RESULTS: Quality of sensory blockade was adequate in both groups. Catheter insertion was significantly faster using the paramedian approach. The difference between the two approaches with regard to the incidence of paraesthesias was not significant, however, there was a trend towards more paraesthesias in the midline group. In the multivariate analysis, type of approach was an independent significant predictor of paraesthesias and we found a trend towards a higher incidence of paraesthesias in female patients. CONCLUSIONS: Catheter insertion was faster in the paramedian group and we found a trend towards a higher incidence of paraesthesias with the midline approach.

Anesthesia, Epidural↗
PubMed2005

Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.

BACKGROUND: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor. OBJECTIVE: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. METHODS: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. RESULTS: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. CONCLUSIONS: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

Adolescent↗
PubMed2004

Food-drug interaction: grapefruit juice augments drug bioavailability--mechanism, extent and relevance.

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Perioperative infusions in paediatric patients: rationale for using Ringer-lactate solution with low dextrose concentration.

To assess the usefulness of Ringer-lactate solution with 0.9% dextrose, fluid therapy during surgery in paediatric patients was reviewed. From the literature, the need for intravenous (i.v.) infusion and water could be established. The need for sodium was also evident and use of normonatraemic i.v. solutions should be recommended to avoid hyponatraemia. Little data were found about the value of the other electrolytes. Dextrose requirements have been the subject of debate for the last two decades. The choice of dextrose concentration is a compromise between avoiding hypoglycaemia and hyperglycaemia. Four clinical trials assessing the use of Ringer-lactate solution with 0.9 or 1% dextrose in paediatric patients suggest that it is appropriate for routine infusion in paediatric patients during the perioperative period. However, fluid therapy during surgery has rarely been studied, probably because it is inexpensive, rarely leads to problems and is used in very different clinical settings. Development of consensus clinical guidelines on the use of electrolyte infusions in paediatric surgery would be helpful.

Blood Glucose↗
PubMed2003

Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice.

BACKGROUND: Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine. METHODS: Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The influence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail flick and hotplate tests. RESULTS: In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration. CONCLUSIONS: The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid- and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our findings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.

Analgesics, Opioid↗
PubMed2002

[The effect of anesthetics on control of respiration].

Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control. Perioperative respiratory depression remains a serious clinical problem in perioperative medicine. This review will give an overview of ventilatory control and discuss the most relevant responses, describe the effects of pain, anaesthetics and opioids on ventilatory control and their interaction. The current body of knowledge is put into perspective to identify patients at risk for perioperative respiratory depression.

Analgesics, Opioid↗
PubMed2001

Low-dose acetazolamide reduces CO(2)-O(2) stimulus interaction within the peripheral chemoreceptors in the anaesthetised cat.

1. Using the technique of end-tidal CO(2) forcing, we measured the effect of the carbonic anhydrase inhibitor acetazolamide (4 mg kg(-1), I.V.) on the CO(2) sensitivities of the peripheral and central chemoreflex loops both during hyperoxia and hypoxia in 10 cats anaesthetised with alpha-chloralose-urethane. 2. In the control situation, going from hyperoxia (arterial P(O2) (P(a,O2)) 47.40 +/- 3.62 kPa, mean +/- S.D.) into moderate hypoxia (P(a,O2) 8.02 +/- 0.30 kPa) led to an almost doubling of the peripheral CO(2) sensitivity (S(P)): a rise from 0.09 +/- 0.07 to 0.16 +/- 0.06 l min(-1) kPa(-1). After acetazolamide, however, lowering the P(a,O2) from 46.95 +/- 5.19 to 8.02 +/- 0.66 kPa did not result in a rise in S(P), indicating the absence of a CO(2)-O(2) stimulus interaction. 3. In hypoxia, acetazolamide reduced S(P) from 0.16 +/- 0.06 to 0.07 +/- 0.05 l min(-1) kPa(-1). In hyperoxia, however, the effect on S(P) was much smaller (an insignificant reduction from 0.09 +/- 0.07 to 0.06 +/- 0.05 l min(-1) kPa(-1)). 4. Acetazolamide reduced both the hyperoxic and hypoxic sensitivities (S(C)) of the central chemoreflex loop: from 0.45 +/- 0.16 to 0.27 +/- 0.13 l min(-1) kPa(-1) and from 0.40 +/- 0.16 to 0.26 +/- 0.13 l min(-1) kPa(-1), respectively. In hyperoxia, the apnoeic threshold B (X-intercept of the ventilatory CO(2) response curve) decreased from 2.91 +/- 0.57 to 0.78 +/- 1.9 kPa (P = 0.005). In hypoxia, B decreased from 1.59 +/- 1.22 to -0.70 +/- 2.99 kPa (P = 0.03). 5. Because acetazolamide abolished the CO(2)-O(2) interaction, i.e. the expected increase in S(P) when going from hyperoxia into hypoxia, we conclude that the agent has a direct inhibitory effect on the carotid bodies. The exact mechanism by which the agent exerts this effect will remain unclear until more detailed information becomes available on the identity of the carbonic anhydrase iso-enzymes within the carotid bodies and their precise subcellular distribution.

Acetazolamide↗
PubMed2001

Transcription, beta-like DNA polymerases and hypermutation.

This paper discusses two aspects of immunoglobulin (Ig) gene hypermutation. In the first approach, a transcription termination signal is introduced in an Ig light chain transgene acting as a mutation substrate, and transgenic lines are generated with control and mutant transgenes integrated in tandem. Analysis of transcription levels and mutation frequencies between mutant and control transgenes clearly dissociates transcription elongation and mutation, and therefore argues against models whereby specific pausing of the RNA polymerase during V gene transcription would trigger an error-prone repair process. The second part reports the identification of two novel beta-like DNA polymerases named Pol lambda and Pol mu, one of which (Pol mu) represents a good candidate for the Ig mutase due to its higher lymphoid expression and its similarity with the lymphoid enzyme terminal deoxynucleotidyl transferase. Peculiar features of the expression of this gene, including an unusual splicing variability and a splicing inhibition in response to DNA-damaging agents, are discussed.

Animals↗