Bruno Oertel - Academia.edu (original) (raw)
Papers by Bruno Oertel
Der Schmerz, 2015
Pain is one of the most common reasons for consulting a physician. Chronic pain patients often su... more Pain is one of the most common reasons for consulting a physician. Chronic pain patients often suffer from a variety of comorbidities, such as depression and anxiety and they are therefore often simultaneously treated with more than one drug. The probability of drug interactions increases with every additional drug. A systematic internet and literature search up to February 2015 was carried out. Systematic lists were included. In addition, the drug prescription information sheets were used and an internet search via Pubmed and google.com was carried out for drugs alone and in combination in order to find substance-specific interactions. A differentiation is made between pharmaceutical, pharmacodynamic and pharmacokinetic drug interactions. Pharmaceutical interactions are caused by chemical, physical or physicochemical incompatibility of drugs or adjuvants used. These can even occur outside the body and during concomitant administration via the same route. A pharmacodynamic interaction in pain management is for example the additive sedative effect of opioids and benzodiazepines when taken together. Pharmacokinetic interactions occur during the absorption, distribution, metabolism and in the elimination phases. Many drug interactions can be avoided by careful and continuous evaluation of pharmacotherapy and if necessary its adaptation; however, a sound knowledge of the underlying pharmacological mechanisms and the properties of currently used analgesics is necessary.
International journal of clinical pharmacology and therapeutics, 2015
Drug effects on the function of smell and taste are occasionally mentioned in prescription inform... more Drug effects on the function of smell and taste are occasionally mentioned in prescription information however, most originate from anecdotal reports without even distinguishing between gustatory or olfactory deteriorations. This includes the antifungal fluconazole. In a randomized, placebocontrolled, double-blind, two-way crossover study, 12 healthy men and 9 healthy women (age 26.8 ± 3.7 years) took oral doses of 400 mg fluconazole or placebo once daily for 8 days. Gustatory and olfactory functions were tested before and after the treatment using clinically validated tests ("Taste Strips" and "Sniffin' Sticks", respectively). Baseline taste scores of 12.3 ± 2.2 and 12.5 ± 1.7 for the fluconazole and placebo conditions, respectively, corresponded to normative values. Similarly, baseline (pretreatment) composite olfactory TDI scores (odor âthreshold discrimination identificationâ) of 35.0 ± 3.2 and 35.7 ± 4.3 for men and 34.8 ± 4.2 and 35.5 ± 2.8 for wome...
Clinical pharmacology and therapeutics, 2008
Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly ... more Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activat...
Clinical pharmacology and therapeutics, 2006
Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervou... more Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting. Candidate pharmacogenetic modulators were polymorphisms reported to be of functional consequence and therefore potentially important for metabolism, distribution, or pharmacodynamic action of levomethadone, consisting of genes coding for cytochrome P450 (CYP) 2B6 and 3A, as well as 1A2, 2C8, 2C9, 2C19, and 2D6, for P-glycoprotein (ABCB1), and for mu-opioid receptors (OPRM1). The central nervous effects of levomethadone were investigated by means of measuring pupil size in a random sample of 51 healthy volunteers for 9 hours after oral administration of 0.075 mg/kg levomethadone. Plasma concentrations of levomethadone and i...
Encyclopedia of Pain, 2013
Pharmacogenomics, 2008
Pharmacogenomics 9(2) future science group future science group * As given in respective publicat... more Pharmacogenomics 9(2) future science group future science group * As given in respective publications (reference ID if available). ‡ Owing to the absence of nerve pathology on histological examination, commonly referred to as 'congenital indifference to pain' (for a comprehensive review, see [18]). § To date, 37 different variations of the NTRK1 gene in families affected by CIPA are known (for a comprehensive review, see [43]). CIPA: Congenital insensitivity to pain with anhydrosis; FD: Familial dysautonomia; HSAN: Hereditary sensory and autonomic neuropathy; MIM#: Online Mendelian Inheritance in Man' database [201].
PAIN, 2013
Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenot... more Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences. Here we report increased methylation at a CpG rich island in the OPRM1 gene coding for l-opioid receptors and at a global methylation site (LINE-1) in leukocytes of methadone-substituted former opiate addicts compared with matched healthy controls. Higher DNA methylation associated with chronic opioid exposure was reproduced in an independent cohort of opioid-treated as compared to non-opioid-treated pain patients. This suggests that opioids may stimulate DNA methylation. The OPRM1 methylation had no immediate effect on l-opioid receptor transcription and was not associated with opioid dosing requirements. However, the global DNA methylation at LINE-1 was significantly correlated with increased chronic pain. This suggests inhibitory effects on the transcription of still unspecified nocifensive gene products. It further implies that opioids may be causally associated with increased genome-wide DNA methylation, although currently there is no direct evidence of this. This has phenotypic consequences for pain and may provide a new, epigenetics-associated mechanism of opioid-induced hyperalgesia. The results indicate a potential influence of opioid analgesics on the patients' epigenome. They emphasize the need for reliable and costeffective screening tools and may imply that high-throughput screening for lead compounds in artificial expression systems may not provide the best tools for identifying new pain medications.
British Journal of Pharmacology, 2013
Antimicrobial Agents and Chemotherapy, Apr 1, 2007
The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir ... more The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n ؍ 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n ؍ 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n ؍ 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (C min and C max ), area under the concentration-time curve under steady-state conditions (AUC ss ), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUC ss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUC ss was 22,794 versus 15,759 ng ⅐ h/ml (GM ratio [GMR] ؍ 1.45; P < 0.05), the GM of the C max was 3,257 versus 2,331 ng/ml (GMR ؍ 1.40; P < 0.05), and the GM of the C min was 438 versus 437 ng/ml (GMR ؍ 1.00); for ATV in groups 1 and 2, the GM of the AUC ss was 39,154 versus 33,626 ng ⅐ h/ml (GMR ؍ 1.16), the GM of the C max was 3,488 versus 2,924 ng/ml (GMR ؍ 1.20), and the GM of the C min was 515 versus 428 ng/ml (GMR ؍ 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.
The Journal of Biological Chemistry, Mar 6, 2009
The single nucleotide polymorphism 118A>G of the human -opioid receptor gene OPRM1, which leads t... more The single nucleotide polymorphism 118A>G of the human -opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the -opioid receptor-specific agonist DAMGO, we analyzed the -opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (S II ) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D -opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the S II region of homo-and heterozygous carriers of the variant 118G allele (n ؍ 18), DAMGO was only 62% as efficient (p ؍ 0.002) as in homozygous carriers of the wild-type 118A allele (n ؍ 15). In contrast, the number of [ 3 H]DAMGO binding sites was unaffected. Hence, the -opioid receptor G-protein coupling efficacy in S II of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p < 0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of -opioid receptor variant N40D. * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Equations S1-S4 and Tables S1 and S2. . 2 The abbreviations used are: SNP, single nucleotide polymorphism; ANOVA, analysis of variance; GTP␥S, guanosine 5Ј-3-O-(thio)triphosphate; rm, repeated measures.
Pharmacogenet Genomics, 2006
ABSTRACT To investigate whether OPRM1 118A>G polymorphism affects analgesic and respirator... more ABSTRACT To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil. In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency. The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression. OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 30, 2015
Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(... more Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled cross-over study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC firstly consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modelin...
Clinical pharmacology and therapeutics, 2014
Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent... more Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function, and side effects in 21 healthy volunteers, before and during steady-state concentrations of 1.5 and 3.0 ng/ml of remifentanil at the effect site (viz., the central nervous system), administration of 400 mg/day fluconazole for 8 days in a double-blind, placebo-controlled manner failed to attenuate opioid effects. Although CYP inhibitors such as fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because differences among opioid effects,...
PLOS ONE, 2015
The perception of pain is susceptible to modulation by psychological and contextual factors. It h... more The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far.
The journal of pain : official journal of the American Pain Society, Jan 5, 2015
Clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) batt... more Clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain), could be partly mimicked also in healthy volunteers following topical capsaicin application. However, similar to clinical neuropathic pain that will develop in only a subgroup of patients who have a neurologic lesion, this succeeded only in a small fraction (18 %) of the healthy subjects. In the present assessment, we pursued the hypothesis that the inducible subgroup differed from the other healthy subjects with respect to their psychological phenotype. Therefore, in an observational cohort study subjects were assessed using a comprehensive set of psychological variables comprising general psychological and pain-related cognitive-emotional mechanisms. The sum scores of the questionnaires were significantly linearly correlated with each other. Principal component analysis indicated that a major source of variance (46 %) could be attribut...
PLOS ONE, 2015
It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Dist... more It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.
Der Schmerz, 2015
Pain is one of the most common reasons for consulting a physician. Chronic pain patients often su... more Pain is one of the most common reasons for consulting a physician. Chronic pain patients often suffer from a variety of comorbidities, such as depression and anxiety and they are therefore often simultaneously treated with more than one drug. The probability of drug interactions increases with every additional drug. A systematic internet and literature search up to February 2015 was carried out. Systematic lists were included. In addition, the drug prescription information sheets were used and an internet search via Pubmed and google.com was carried out for drugs alone and in combination in order to find substance-specific interactions. A differentiation is made between pharmaceutical, pharmacodynamic and pharmacokinetic drug interactions. Pharmaceutical interactions are caused by chemical, physical or physicochemical incompatibility of drugs or adjuvants used. These can even occur outside the body and during concomitant administration via the same route. A pharmacodynamic interaction in pain management is for example the additive sedative effect of opioids and benzodiazepines when taken together. Pharmacokinetic interactions occur during the absorption, distribution, metabolism and in the elimination phases. Many drug interactions can be avoided by careful and continuous evaluation of pharmacotherapy and if necessary its adaptation; however, a sound knowledge of the underlying pharmacological mechanisms and the properties of currently used analgesics is necessary.
International journal of clinical pharmacology and therapeutics, 2015
Drug effects on the function of smell and taste are occasionally mentioned in prescription inform... more Drug effects on the function of smell and taste are occasionally mentioned in prescription information however, most originate from anecdotal reports without even distinguishing between gustatory or olfactory deteriorations. This includes the antifungal fluconazole. In a randomized, placebocontrolled, double-blind, two-way crossover study, 12 healthy men and 9 healthy women (age 26.8 ± 3.7 years) took oral doses of 400 mg fluconazole or placebo once daily for 8 days. Gustatory and olfactory functions were tested before and after the treatment using clinically validated tests ("Taste Strips" and "Sniffin' Sticks", respectively). Baseline taste scores of 12.3 ± 2.2 and 12.5 ± 1.7 for the fluconazole and placebo conditions, respectively, corresponded to normative values. Similarly, baseline (pretreatment) composite olfactory TDI scores (odor âthreshold discrimination identificationâ) of 35.0 ± 3.2 and 35.7 ± 4.3 for men and 34.8 ± 4.2 and 35.5 ± 2.8 for wome...
Clinical pharmacology and therapeutics, 2008
Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly ... more Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activat...
Clinical pharmacology and therapeutics, 2006
Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervou... more Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting. Candidate pharmacogenetic modulators were polymorphisms reported to be of functional consequence and therefore potentially important for metabolism, distribution, or pharmacodynamic action of levomethadone, consisting of genes coding for cytochrome P450 (CYP) 2B6 and 3A, as well as 1A2, 2C8, 2C9, 2C19, and 2D6, for P-glycoprotein (ABCB1), and for mu-opioid receptors (OPRM1). The central nervous effects of levomethadone were investigated by means of measuring pupil size in a random sample of 51 healthy volunteers for 9 hours after oral administration of 0.075 mg/kg levomethadone. Plasma concentrations of levomethadone and i...
Encyclopedia of Pain, 2013
Pharmacogenomics, 2008
Pharmacogenomics 9(2) future science group future science group * As given in respective publicat... more Pharmacogenomics 9(2) future science group future science group * As given in respective publications (reference ID if available). ‡ Owing to the absence of nerve pathology on histological examination, commonly referred to as 'congenital indifference to pain' (for a comprehensive review, see [18]). § To date, 37 different variations of the NTRK1 gene in families affected by CIPA are known (for a comprehensive review, see [43]). CIPA: Congenital insensitivity to pain with anhydrosis; FD: Familial dysautonomia; HSAN: Hereditary sensory and autonomic neuropathy; MIM#: Online Mendelian Inheritance in Man' database [201].
PAIN, 2013
Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenot... more Environmentally caused changes in chromosomes that do not alter the DNA sequence but cause phenotypic changes by altering gene transcription are summarized as epigenetics. A major epigenetic mechanism is methylation or demethylation at CpG-rich DNA islands. DNA methylation triggered by drugs has largely unexplored therapeutic consequences. Here we report increased methylation at a CpG rich island in the OPRM1 gene coding for l-opioid receptors and at a global methylation site (LINE-1) in leukocytes of methadone-substituted former opiate addicts compared with matched healthy controls. Higher DNA methylation associated with chronic opioid exposure was reproduced in an independent cohort of opioid-treated as compared to non-opioid-treated pain patients. This suggests that opioids may stimulate DNA methylation. The OPRM1 methylation had no immediate effect on l-opioid receptor transcription and was not associated with opioid dosing requirements. However, the global DNA methylation at LINE-1 was significantly correlated with increased chronic pain. This suggests inhibitory effects on the transcription of still unspecified nocifensive gene products. It further implies that opioids may be causally associated with increased genome-wide DNA methylation, although currently there is no direct evidence of this. This has phenotypic consequences for pain and may provide a new, epigenetics-associated mechanism of opioid-induced hyperalgesia. The results indicate a potential influence of opioid analgesics on the patients' epigenome. They emphasize the need for reliable and costeffective screening tools and may imply that high-throughput screening for lead compounds in artificial expression systems may not provide the best tools for identifying new pain medications.
British Journal of Pharmacology, 2013
Antimicrobial Agents and Chemotherapy, Apr 1, 2007
The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir ... more The objective of this study was to evaluate the pharmacokinetics of atazanavir (ATV), saquinavir (SQV), and ritonavir (RTV) in a boosted double-protease inhibitor (PI) therapy regimen without reverse transcriptase inhibitors (RTIs). The study design was as follows. Patients with limited RTI options received a PI combination of 300/100 mg ATV/RTV once daily and 1,000 mg SQV twice daily (group 1; n ؍ 49) without RTI comedication. The results were compared to the plasma concentrations of PIs of patients taking either 300 mg ATV/100 mg RTV once daily plus RTIs (group 2; n ؍ 72) or patients taking 1,000 mg SQV/100 mg RTV plus RTIs (group 3; n ؍ 90). The study methods were as follows. Patients were given a 12/24-h pharmacokinetic assessment at steady state. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. The minimum and maximum concentrations (C min and C max ), area under the concentration-time curve under steady-state conditions (AUC ss ), elimination half-life, time of maximum concentration and lag time were subject to statistical analysis. The results show that patients treated with ATV/SQV/RTV exhibited significantly high SQV concentrations and moderate enhancement of the AUC ss of ATV in comparison to those of patients of the control groups: for SQV in groups 1 and 3, the geometric mean (GM) of the AUC ss was 22,794 versus 15,759 ng ⅐ h/ml (GM ratio [GMR] ؍ 1.45; P < 0.05), the GM of the C max was 3,257 versus 2,331 ng/ml (GMR ؍ 1.40; P < 0.05), and the GM of the C min was 438 versus 437 ng/ml (GMR ؍ 1.00); for ATV in groups 1 and 2, the GM of the AUC ss was 39,154 versus 33,626 ng ⅐ h/ml (GMR ؍ 1.16), the GM of the C max was 3,488 versus 2,924 ng/ml (GMR ؍ 1.20), and the GM of the C min was 515 versus 428 ng/ml (GMR ؍ 1.21). RTV levels were comparable for all groups. A subgroup analysis detected only marginal differences in ATV plasma exposure if combined with tenofovir-disoproxilfumarate and without it. We conclude that our pharmacokinetic results support the use of a boosted double-PI regimen of ATV/SQV/RTV as a treatment option for patients who need antiretroviral therapy without RTIs.
The Journal of Biological Chemistry, Mar 6, 2009
The single nucleotide polymorphism 118A>G of the human -opioid receptor gene OPRM1, which leads t... more The single nucleotide polymorphism 118A>G of the human -opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the -opioid receptor-specific agonist DAMGO, we analyzed the -opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (S II ) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D -opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the S II region of homo-and heterozygous carriers of the variant 118G allele (n ؍ 18), DAMGO was only 62% as efficient (p ؍ 0.002) as in homozygous carriers of the wild-type 118A allele (n ؍ 15). In contrast, the number of [ 3 H]DAMGO binding sites was unaffected. Hence, the -opioid receptor G-protein coupling efficacy in S II of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p < 0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of -opioid receptor variant N40D. * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Equations S1-S4 and Tables S1 and S2. . 2 The abbreviations used are: SNP, single nucleotide polymorphism; ANOVA, analysis of variance; GTP␥S, guanosine 5Ј-3-O-(thio)triphosphate; rm, repeated measures.
Pharmacogenet Genomics, 2006
ABSTRACT To investigate whether OPRM1 118A>G polymorphism affects analgesic and respirator... more ABSTRACT To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil. In an open-label, single-occasion design, 10 non-carriers, four heterozygous and six homozygous carriers of the variant OPRM1 118G allele received a computerized infusion of alfentanil to achieve target effect-site concentrations of 0, 33.33, 66.67 and 100 ng/ml. At each concentration level, analgesia was assessed by means of electrically and chemically induced pain, and respiratory depression was quantified by hypercapnic challenge and breathing frequency. The relationship between the percent change of tolerance to electrical stimuli and measured alfentanil concentrations, described by power models, was flatter in carriers of the 118G variant allele than in non-carriers, indicating decreased opioid analgesia (P<0.05). For chemically induced pain, a flatter analgesia versus concentration relationship was found only for homozygous carriers of the 118G allele (P<0.05). The relationship between the percent changes in respiratory parameters was significantly flatter (P<0.01) only in homozygous carriers as compared to heterozygous carriers and non-carriers of the 118G allele. Higher alfentanil concentrations were needed in homozygous carriers as compared to wild-type subjects (2-4 times) to produce the same degree of analgesia, whereas 10-12 times higher alfentanil concentrations were needed to produce the same degree of respiratory depression. OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 30, 2015
Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(... more Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled cross-over study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC firstly consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modelin...
Clinical pharmacology and therapeutics, 2014
Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent... more Cytochrome P450 (CYP) inhibitors may reduce opioid analgesia by inhibiting CYP activity-dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function, and side effects in 21 healthy volunteers, before and during steady-state concentrations of 1.5 and 3.0 ng/ml of remifentanil at the effect site (viz., the central nervous system), administration of 400 mg/day fluconazole for 8 days in a double-blind, placebo-controlled manner failed to attenuate opioid effects. Although CYP inhibitors such as fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because differences among opioid effects,...
PLOS ONE, 2015
The perception of pain is susceptible to modulation by psychological and contextual factors. It h... more The perception of pain is susceptible to modulation by psychological and contextual factors. It has been shown that subjects judge noxious stimuli as more painful in a respective suggestive context, which disappears when the modifying context is resolved. However, a context in which subjects judge the painfulness of a nociceptive stimulus in exactly the opposite direction to that of the cues has never been shown so far.
The journal of pain : official journal of the American Pain Society, Jan 5, 2015
Clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) batt... more Clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain), could be partly mimicked also in healthy volunteers following topical capsaicin application. However, similar to clinical neuropathic pain that will develop in only a subgroup of patients who have a neurologic lesion, this succeeded only in a small fraction (18 %) of the healthy subjects. In the present assessment, we pursued the hypothesis that the inducible subgroup differed from the other healthy subjects with respect to their psychological phenotype. Therefore, in an observational cohort study subjects were assessed using a comprehensive set of psychological variables comprising general psychological and pain-related cognitive-emotional mechanisms. The sum scores of the questionnaires were significantly linearly correlated with each other. Principal component analysis indicated that a major source of variance (46 %) could be attribut...
PLOS ONE, 2015
It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Dist... more It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels.