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Biomedical subjects

L L Gustafsson

Publications and source records attributed to L L Gustafsson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers.

BACKGROUND: The effects of ketamine on respiration, alone, or in combination with opioids, have not been completely clarified. Both stimulant and depressant effects have been reported, as well as attenuation of opioid-induced hypoventilation at the expense of increased oxygen consumption. These conflicting results might partly be due to dose-dependent mechanisms. We have, therefore, determined the ventilatory effects of ketamine, in combination with alfentanil, using infusions to different pseudo steady-state concentrations. METHODS: On two separate days, eight healthy male volunteers were given alfentanil as a continuous computer-controlled infusion, aiming at a plasma concentration of 50 ng x mL(-1). After reaching apparent steady-state for alfentanil, racemic ketamine or placebo was administered in a protocol randomised for the two days. On the ketamine days a computer-controlled infusion, aiming for escalating ketamine plasma concentrations of 50, 100 and 200 ng x mL(-1), was added to the alfentanil infusion. On the placebo days saline was added. Using a face-mask with an occlusion valve, respiratory parameters were measured during air-breathing and after 6 repetitive 30-s CO2 challenges. RESULTS: The alfentanil infusion induced hypoventilation by decreasing respiratory rate, while tidal volume and respiratory drive were unaffected. This hypoventilation was antagonised by ketamine in a concentration-dependent manner mainly through an increase in respiratory rate. The CO2 response was not affected by alfentanil or ketamine. CONCLUSION: In the dose range of interest for postoperative, intensive-care and pain-clinic settings, ketamine antagonises the resting hypoventilation induced by alfentanil.

Adult↗
PubMed1999

Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity.

AIMS: To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine. METHODS: Eight healthy volunteers received single oral doses (2 mg) of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of the subjects participated in a multiple-dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the single and multiple dose tolterodine administration phases. Blood samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined. RESULTS: A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant administration of ketoconazole, yielding at least a two-fold increase in the area under the serum concentration-time curve after single as well as after multiple doses following single dose administration of tolterodine. The mean (+/-s.d.) terminal half-life increased by 50% from 9.7+/-2.7 h to 15+/-5.4 h in the presence of ketoconazole. CONCLUSIONS: CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in AUC.

Adult↗
PubMed1999

Decreased capacity for debrisoquine metabolism among black Tanzanians: analyses of the CYP2D6 genotype and phenotype.

The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate debrisoquine with 59% of the Tanzanian extensive metabolisers having debrisoquine metabolic ratios (MRs) > 1 versus 20% in Caucasians. This decrease in metabolic capacity was not fully explained by the partially or fully detrimental CYP2D6 gene mutations analysed for in this study. As many as 7% poor metabolizers of debrisoquine were identified but none was homozygous for defective CYP2D6 alleles. The majority among the group of poor metabolizers had relatively low metabolic ratios. The mutational profile indicated a closer association of the Tanzanian CYP2D locus to that of Zimbabweans rather than to that of Ethiopians. The defective alleles CYP2D6*3, *4, *5 and *6 were found at low frequencies (0%, 1%, 6%, 0%, respectively), whereas the CYP2D6*17 allele causing an enzyme with altered specificity was common (allele frequency = 17%). It is concluded that the CYP2D6 genotype in the Tanzanian Bantu population is different from that of other African populations examined to date and that further studies are required to explain the generally lower capacity to metabolize CYP2D6 substrates.

Base Sequence↗
PubMed1998

High-performance liquid chromatographic method for the determination of the major quinine metabolite, 3-hydroxyquinine, in plasma and urine.

The determination of 3-hydroxyquinine in urine and plasma samples is described. Extraction was performed using a mixture of toluene-butanol (75:25, v/v), followed by back-extraction into the mobile phase, which consisted of 0.1 M phosphate buffer, acetonitrile, tetrahydrofuran and triethylamine. A reversed-phase liquid chromatography system with fluorescence detection and a CT-sil C18 column were used. The within-assay coefficient of variation of the method was 2% at the higher concentration values in plasma, 2.95 microM, 4% at 227 nM and 9% at the lower limit of quantitation, 4.5 nM. In urine, the coefficient of variation was 11% at the lower concentration, 227 nM and was 3% at 56.8 microM. The between-assay coefficient of variation was 4% at the low concentration (5.1 nM) in plasma, 2% at 276.8 nM and 3% at 1.97 microM. In urine, the between assay coefficient of variation was 4% at 204.6 nM, 3% at 5.12 microM and 2% at 56.8 microM.

Chromatography, High Pressure Liquid↗
PubMed1998

Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.

OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.

Administration, Oral↗
PubMed1998

Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors.

BACKGROUND: Potential drug-drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine. METHODS: In a randomized, 3-way crossover study, 12 healthy subjects received a single dose of 40 mg ropivacaine intravenously alone or combined either with 25 mg fluvoxamine as a CYP1A2 inhibitor or with 100 mg ketoconazole as a CYP3A4 inhibitor twice daily for 2 days. Venous plasma and urine samples were collected over 10 hours and 24 hours, respectively. The samples were analyzed for ropivacaine base, 3-hydroxyropivacaine, and (S)-2',6'-pipecoloxylidide. RESULTS: Coadministration with fluvoxamine decreased the mean total plasma clearance of ropivacaine from 354 to 112 mL/min (68%), whereas ketoconazole decreased plasma clearance to 302 mL/min (15%). The relative changes in unbound plasma clearance were similar to the changes in total plasma clearance. The ropivacaine half-life (t1/2) of 1.9 hours was almost doubled during fluvoxamine administration and the plasma concentration at the end of infusion increased slightly, whereas the corresponding parameters after ketoconazole administration remained unchanged. Coadministration with ketoconazole almost abolished the (S)-2',6'-pipecoloxylidide concentrations in plasma, whereas fluvoxamine administration increased the (S)-2',6'-pipecoloxylidide levels. The fraction of dose excreted as 3-hydroxyropivacaine in urine decreased during fluvoxamine administration from 39% to 13%. CONCLUSIONS: CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.

Adult↗
PubMed1998

Discrepancy in plasma melarsoprol concentrations between HPLC and bioassay methods in patients with T. gambiense sleeping sickness indicates that melarsoprol is metabolized.

OBJECTIVE: With the use of a specific high-performance liquid chromatography (HPLC) method and a bioassay which determines trypanocidal activity, concentrations of melarsoprol were assessed in plasma, urine and cerebrospinal fluid (CSF) from 8 patients with late-stage Trypanosoma gambiense sleeping sickness. The aim was to unravel to what extent the bioassay codetermines biologically active metabolites of melarsoprol. METHODS: Subjects were given one dose of melarsoprol i.v. per day for 4 days (1.2, 2.4, 3.0-3.6, 3.0-3.6 mg per kg b.w., respectively). Plasma samples were obtained before the first melarsoprol injection, immediately after and at 1 h, 24 h and 5 days after the 4th injection. Urine was collected before melarsoprol therapy and at 24 h after the 4th injection. CSF samples were taken once before treatment and at 24 h after the 4th injection. RESULTS: HPLC analyses showed that plasma concentrations immediately after the 4th injection varied from 2200 to 15,900 nmol/l; dropping to 0-1800 nmol/l at 1 h; and to undetectable levels at 24 h. In urine small amounts of melarsoprol were recovered. Melarsoprol could not be detected in CSF by HPLC. Immediately after injection, bioassay analyses showed plasma concentrations of the same magnitude as HPLC assays but at 1 h they were 4-65-fold higher than the levels assessed by HPLC. Even 24 h and 5 days after the 4th injection there was significant but decreasing activity. Urine levels were 40-260-fold higher than the measured HPLC concentrations, whereas there was low but detectable activity in CSF. CONCLUSION: Results indicate that melarsoprol is rapidly eliminated from plasma. The significant trypanocidal activity determined by bioassay and simultaneous low or undetectable levels of melarsoprol assayed by HPLC indicate that the compound is transformed into metabolites with parasiticidal activity.

Adolescent↗
PubMed1998

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.

BACKGROUND: Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain conditions, including neuropathic and phantom-limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood. METHODS: Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS). RESULTS: Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all the patients at the highest dose (0.45 mg/kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. These 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/kg ketamine doses than for morphine 10 mg. CONCLUSION: We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.

Aged↗
PubMed1997

Liquid chromatography-tandem mass spectrometry applied to a study of the metabolism of pentamidine. Discussion of possibilities and problems.

Tandem mass spectrometry is usually employed to achieve rapid screening or structure elucidation. We have used liquid chromatography-tandem mass spectrometry in order to detect metabolites of the antiprotozoal drug pentamidine in urine. Samples of urine from rat and man were analysed both by direct injection and after solid-phase extraction. The present paper discusses advantages and disadvantages of using direct injection of urine samples, optimization of chromatographic conditions with regard to the performance of the mass spectrometer, automation and stability of the entire system.

Animals↗
PubMed1997

Determination of melarsoprol in biological fluids by high-performance liquid chromatography and characterisation of two stereoisomers by nuclear magnetic resonance spectroscopy.

The analysis of melarsoprol in whole blood, plasma, urine and cerebrospinal fluid is described. Extraction was made with a mixture of chloroform and acetonitrile followed by back-extraction into phosphoric acid. A reversed-phase liquid chromatography system with ultraviolet detection was used. The relative standard deviation was 1% at concentrations around 10 mumol/l and 3-6% at the lower limit of determination (9 nmol/l in plasma, 93 nmol/l in whole blood, 45 nmol/l in urine and 10 nmol/l in cerebrospinal fluid). Melarsoprol is not a stable compound and samples to be stored for longer periods of time should be kept at -70 degrees C. Plasma samples can be stored at -20 degrees C for up to 2 months. Chromatography showed that melarsoprol contains two components. Using nuclear magnetic resonance spectroscopy the two components were shown to be diastereomers which slowly equilibrate by inversion of the configuration at the As atom.

Animals↗
PubMed1997

"Academic drug-detailing": from project to practice in a Swedish urban area.

OBJECTIVES: To develop and test the long-term feasibility of an interdisciplinary independent drug information service providing both written and oral drug information to physicians in an urban area of Sweden (> 400,000 inhabitants). METHODS: A drug information service was developed encouraging a cooperative approach between a department of clinical pharmacology, general practitioners (GPs), pharmacists, and Drug and Therapeutic Committees. Scientifically-based drug information was condensed and interpreted by a team and presented in both written and oral form. In one part of the area, both oral and written information was provided, while in another part of the area, only written information was distributed. Questionnaires and one prescription survey were performed to elucidate the knowledge and attitudes of the GPs regarding drug treatment of one condition (urinary tract infection, UTI, and norfloxacin were used as examples), as well as their opinion of our services. RESULTS: Over a period of 10 years, 75 issues of a drug bulletin (2000 copies) were distributed. Oral producer-independent drug information, provided jointly by a GP and a pharmacist, was given on 16 occasions in each of 30 health centres (150 GPs). Around 80% of the GPs participated in the meetings. Of these GPs, 75% found the service important for their daily work. A majority of the GPs had prescribed the test drug, norfloxacin, not a first-line drug according to local recommendations, 1 year after approval. A significantly lower proportion of prescribers were observed in the area where the GPs had been provided with both written and oral information regarding recommended treatment (including first-line drugs) for uncomplicated cystitis. The approximate cost for this service in 1995 was SEK 0.685 million (USD 0.1 million); the prescribing costs of the 150 GPs were estimated at SEK 255 million per year. This means that the cost of the service per GP is only around 0.3% of normal prescribing costs. CONCLUSION: Over a period of 10 years the information/education method described here has proven sustainable and feasible in terms of providing the information, regarding participation of the target group GPs in the oral sessions, and regarding integration of the service into the existing health care system.

Anti-Infective Agents↗
PubMed1997

Chloroquine blood concentrations and malaria prophylaxis in Tanzanian women during the second and third trimesters of pregnancy.

OBJECTIVE: Routine malaria prophylaxis with chloroquine (CQ) is recommended to pregnant semi-immune women in several countries in Africa. The dosage is empirically based. We investigated whether blood CQ concentrations and apparent oral blood clearance (CL/F) change during the course of pregnancy. We also studied whether malaria parasites could be detected together with low CQ blood levels. METHODS: Forty nine semi-immune Tanzanian women were recruited in the 16th week of pregnancy. They were given 310 mg oral CQ base once per week as prophylaxis during the whole pregnancy. Capillary blood samples were taken for analysis of CQ before treatment and at weeks 26 and 36. Blood samples were dried on filter paper and analysed by HPLC. Blood was also drawn to detect occurrence of malaria parasites. RESULTS: A total of 25 women fulfilled the sampling schedule. CL/F increased significantly from 160 ml.min-1 at week 26 to 180 ml.min-1 at week 36. In 7 of 25 women, CL/F increased > 20%. Trough blood CQ concentrations, determined on four occasions at week 26 and at week 36 varied between 200 and 900 nmol.l-1. No statistically significant differences between occasions were seen. Malaria parasites were seen in two individuals early in pregnancy. CONCLUSION: Blood CQ CL/F showed a small increase during the course of pregnancy. The estimated mean blood CL/F values of 160 and 180 ml.min-1 (week 26 and 36, respectively) were higher than the mean CL/F of 125 ml.min-1 in non-pregnant individuals, published previously. Efficacy of higher dosages of CQ in malaria prophylaxis in pregnant women could, therefore, be evaluated in controlled trials in high-risk malaria areas.

Adult↗
PubMed1997

Extradural morphine gives better pain relief than patient-controlled i.v. morphine after hysterectomy.

We examined if patient-controlled analgesia (PCA) with i.v. morphine provided comparable postoperative analgesia after hysterectomy as extradural morphine, without increasing the incidence of side effects. The study (n = 40) was randomized and double-blind. An extradural catheter was inserted before surgery and anaesthesia was standardized. The extradural group received extradural morphine 0.06 mg kg-1 by the end of surgery and a second dose 6 h later. The i.v. group received an i.v. infusion of morphine 0.2 mg kg-1 after surgery. PCA with morphine 0.04 mg kg-1 i.v. was used in both groups. Pain relief (VAS), side effects and cognitive functions were evaluated for 18 h. Plasma samples were obtained for analysis of morphine concentrations. Mean consumption of PCA morphine was 2.4 mg h-1 for the i.v. group and 1 mg h-1 for the extradural group. Despite unlimited access to morphine, the i.v. group had higher VAS scores as the extradural group (P < 0.001). Plasma concentrations of morphine varied 8-10-fold in both groups. In the i.v. group itching, tiredness, blurred vision and vertigo correlated with cumulative consumption of i.v. morphine whereas in the extradural group this correlation existed only for tiredness. Both groups showed reduced ability to perform tests of cognitive function, indicating a central effect of both i.v. and extradural morphine, despite markedly lower plasma morphine concentrations in the extradural group.

Adult↗
PubMed1997

Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers.

BACKGROUND: For local anesthetics, the process of removal from the site of administration influences the duration of anesthesia and the risk for systemic toxicity to develop. The systemic absorption of epidural ropivacaine and the time profile of sensory and motor block were studied in healthy volunteers. METHODS: Nine persons simultaneously received 150 mg ropivacaine hydrochloride (7.5 mg/ml) epidurally and 40 mg deuterium-labeled (2H3)ropivacaine hydrochloride (0.25 mg/ml) intravenously. Peripheral arterial and venous plasma samples were collected, and assessments of sensory and motor block were made. RESULTS: The arterial plasma concentrations increased faster than the venous concentrations, with 50% higher maximum concentrations after both intravenous and epidural administration. The absorption was biphasic. A correlation was seen between the duration of sensory block and the slower absorption half-life; that is, the longer the half-life, the longer the duration. The extent of spread varied among the volunteers, with the median upper block level not exceeding T12. The motor block (Bromage score 1) was of slower onset (median, 0.4 h) and of shorter duration (median, 4.1 h) than the sensory block (onset, 0.2 h; duration, 6.5 h at L2 medians). CONCLUSIONS: As much as 50% differences were seen in the arteriovenous plasma concentrations of ropivacaine during the first hour, which has implications for the interpretation of systemic toxic plasma concentrations. The absorption into the general circulation was biphasic, with a correlation between the sensory block and the slower absorption half-life. A faster onset and a longer duration of sensory compared with motor block was seen.

Absorption↗
PubMed1997

Intraindividual and interindividual variability in the disposition of the local anesthetic ropivacaine in healthy subjects.

To predict the risk of adverse reactions to local anaesthetics used in clinical practice, it is crucial to know whether any nonlinearity exists in their pharmacokinetics. The disposition of ropivacaine, a new local anesthetic agent, was evaluated in healthy subjects on the basis of plasma levels in the concentration range obtained after regional anaesthesia. Three intravenous doses of ropivacaine hydrochloride (20, 40, and 80 mg) were given in a double-blind, randomized, complete crossover design. Analysis of variance was used to assess the importance of intra- versus interindividual variability in the basic pharmacokinetics. The mean plasma clearance (400 ml/min), volume of distribution at steady state (40 l), and terminal half-life (1.7 h) were similar, irrespective of dose. The intersubject variability for these parameters was higher than the intrasubject variability. A slight increase in free fraction (15%) with increasing dose might indicate that the lower limit for saturation of protein binding may be reached at the higher plasma levels. One subject (80 mg) reported numbness of the lower lip 2 min after the end of the infusion, which may be a sign of systemic CNS toxicity. The total and free plasma concentration was extrapolated to 1.7 and 0.08 mg/l, respectively.

Adult↗
PubMed1997

Preoperative infiltration of bupivacaine--effects on pain relief and trauma response (cortisol and interleukin-6).

HYPOTHESIS: Subcutaneous infiltration of bupivacaine before skin incision can reduce postoperative pain and modulate the stress response. METHODS: In a randomized study on pain relief after hysterectomy 29 patients were referred into one of three groups, receiving 30 ml of bupivacaine 0.25% with adrenaline, 30 ml of saline or no infiltration along the line of the proposed incision 10 min before start of surgery. A Visual Analogue Scale was used for repeated pain ratings. Postoperative pain relief was provided with patient-controlled analgesia with intravenous morphine 0.04 mg/kg. Lockout time was 10 min. The immunological and endocrine stress response to trauma was reflected by blood interleukin-6 (IL-6) and cortisol concentrations measured during 72 h following skin incision. RESULTS: There were large individual variations in the accumulated postoperative consumption of morphine at 20 h after start of surgery. It was significantly reduced in patients receiving infiltration of bupivacaine. They used 39 mg (9-62) median (range) of intravenous morphine whereas the patients in the saline group used 65 mg (47-120) and patients in the control group used 54 mg (36-130) (P < 0.05). Significant elevation of plasma IL-6 and serum cortisol levels appeared in all groups with peak values at 3 h. There were no differences between the groups. There was a correlation between cortisol and IL-6. Six of the 29 patients had a postoperative infection which was reflected in increased IL-6 levels. CONCLUSION: Preoperative subcutaneous infiltration of bupivacaine significantly reduced the postoperative consumption of intravenous morphine.

Adult↗