Biomedical subjects
Publications and source records attributed to P Hartvig.
A 64-year-old woman died after 12 years of progressive pulmonary disease which was initially diagnosed as sarcoidosis but later correctly identified as mineral oil pneumonia due to insufflation of paraffin instilled as nasal drops. In view of the potential damaging effect of liquid paraffin on the lungs, the current indications for its use must be strongly questioned.
Determination of plasma concentration of pyridostigmine in 20 myasthenic patients on maintenance therapy revealed rather small intraindividual variations within a dose interval. The predose concentration varied considerably between different patients and up to seven fold in patients on the same daily dose. No pharmacokinetic interaction between pyridostigmine and neostigmine was found in five patients studied. In six patients the decrement in the deltoid muscle was studied in parallel with determination of the plasma concentrations following administration of pyridostigmine or neostigmine. In these patients the existence of a "bell-shaped" dose response curve is suggested with the maximal effect at a concentration of 30-60 ng/ml for pyridostigmine and 5-15 ng/ml for neostigmine.
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Drug-use data in a large university hospital have been used as a means for evaluating the influence of the recommendations given by a drug committee on the use of analgesics. The results generally show a reasonable adherence to the recommendations in the hospital. A selected clinic, the Department of Oncology, where special efforts were directed, showed particularly close adherence to the guidelines given.
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The pharmacokinetics of pethidine has been studied in 12 patients subjected to major intraabdominal surgery. Pethidine and norpethine were analyzed in plasma samples collected during anesthesia and during patient-controlled administration of small intravenous doses of pethidine in the early postoperative period. A second study on the pharmacokinetics of pethidine was performed on the 3-5th postoperative day. The plasma clearance of pethidine was significantly lower in the preoperative study (8.9 +/- 1.8 ml x kg x min-1) compared with the postoperative study (12.0 +/- 3.1 ml x kg x min-1). Volume of distribution (Vd) was not significantly influenced, being 4.25 +/- 1.72 l x kg-1 peroperatively and 3.14 +/- 0.84 l x kg-1 postoperatively. Elimination half-life decreased from 5.91 +/- 3.57 h peroperatively to 3.25 +/- 1.40 h postoperatively. The kinetics of pethidine in the postoperative study agreed with pethidine kinetics reported for healthy volunteers. The fraction of unbound pethidine decreased from 0.26 +/- 0.1 peroperatively to 0.18 +/- 0.1 postoperatively. Norpethidine, a metabolite of pethidine, has been claimed to be responsible for several side effects like respiratory depression and convulsions during pethidine therapy. No side effect attributable to norpethidine was observed in the self-administration period. Norpethidine plasma concentrations did not exceed 500 ng/ml. The altered pethidine pharmacokinetics during anesthesia and the ensuing postoperative hours and the interindividual differences of the disposition of the drug strongly suggest that pethidine should be given by individualized regimens in surgical patients.
The single-dose kinetics and the oral and rectal bioavailability of ketobemidone have been studied in patients after surgery. Plasma concentrations were determined following intravenous administration of Ketogin 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic substance N, N-dimethyl-3, 3-diphenyl-l-methylallylamine chloride 50 mg and following oral or rectal administration of Ketogin. Ketobemidone was analyzed by gas chromatography-mass spectrometry using a deuterated internal standard. Ketobemidone disappeared rapidly from plasma after i.v. or oral administration, yielding a mean plasma half-life between 2.25 and 2.45 h. After rectal administration the plasma half-life was somewhat prolonged (3.27 h), probably due to late absorption., The bioavailability of oral ketobemidone was 34% +/- 16% s.d. (n = 6), and when given rectally 44% +/- 9% s.d. (n = 5). In contrast to earlier investigations performed without plasma analysis, ketobemidone was found to have a rapid elimination when given intravenously, orally or rectally.
Twelve patients scheduled for major abdominal surgery were selected for a study of the kinetics of ketobemidone during the day of surgery and in a follow-up study 3-5 days after surgery. In six patients ketobemidone was administered as ketobemidone plain and in the other six, it was given as Ketogin, a combination formula containing a spasmolytic substance in addition to ketobemidone. Plasma samples were collected for approximately 24 h following induction of anesthesia, during which time multiple doses of ketobemidone were administered. A single-dose study was performed 3-5 days after surgery using the same drug. No significant differences were found between the two formulations of ketobemidone. Plasma clearance did not change significantly between the two periods of study, being 18.0 +/- 4.4 ml . kg-1 . min-1 peroperatively and 21.7 +/- 7.6 ml . kg-1 . min-1 postoperatively. Peroperative Vd area was significantly larger than post-operative Vd area, 5.84 +/- 2.62 l . kg-1 and 3.63 +/- 0.38 l . kg-1, respectively. T1/2 terminal decreased from 3.84 +/- 1.6 h peroperatively to 2.06 +/- 0.44 h postoperatively.
A dose-adjustment program for oral methadone and the long-term effects of the analgesic therapy have been evaluated in 15 patients with incurable cancer. Rapid and continuous pain relief without serious side-effects was achieved by "ad libitum" dosage in the first 3-5 days. Thereafter, a dosage based on each patients's subjective need was instituted. The mean daily dose was 44 during the first day and it decreased to 22 mg daily at the end of the dose-adjustment week. Three patients did not complete the program because of insufficient effect or severe nausea. Among the 12 patients who chose to continue the methadone treatment after the initial dose-adjustment period, four continued the therapy to their death, three discontinued the therapy due to insufficient effect, and three due to adverse reactions. In one case it was possible to stop the treatment due to decreased pain. The treatment period in these 12 patients varied between 8 and 270 days. Oral methadone offers good pain relief for long periods of time in this group of patients and has obvious advantages as compared to long term parenteral therapy with narcotic analgesics.
Fifty-six surgical patients self-administered i.v. narcotic analgesics to combat postoperative pain. Analgesic demand per h was 2.7 +/- 1.1 mg of morphine, 26 +/- 10 mg of pethidine or 2.3 +/- 0.8 mg of ketobemidone, which reflects the equianalgesic ratios. Acute respiratory depression was seen in two hypovolaemic patients as evidenced by a raised PaCO2 on air breathing. Carbon dioxide retention disappeared upon correction of hypovolaemia. Late respiratory complications of short duration were encountered in 13%. Drowsiness and dry mouth were the most frequent complaints. Self-administered analgesia was considered highly satisfactory by the patients.
Electron capture gas chromatography was used to determine plasma concentrations after various doses of acetazolamide. In 40 patients steady state plasma concentrations were determined for daily doses of 187.5, 375, 750, and 1000 mg. Mean plasma concentrations increased with increasing dosages but there were marked interindividual variations. Part of the interindividual variation was explained by a positive correlation between age and plasma concentration. In 10 patients with previously untreated glaucoma intraocular pressure (IOP) responses and plasma concentrations were determined for increasing doses of acetazolamide. Increasing IOP reductions were obtained up to a dose of 750 mg while a daily dose of 1000 mg acetazolamide had no further effect on IOP. The relationship between IOP reduction and plasma concentration showed great interindividual variations, from a pressure reduction of 11 mmHg at 6 micrograms/ml acetazolamide to a pressure reduction of 0 mmHg at 11 micrograms/ml. As a rule, the maximal effect on IOP was obtained at a plasma concentration between 5 and 10 micrograms/ml. In most patients a daily dose of 1000 mg resulted in plasma concentrations above 10 micrograms/ml.
An analytical procedure was developed for the determination of 6-mercaptopurine in plasma. Owing to the polar character and low plasma concentration of the compound, extraction and derivatization was carried out directly from the plasma sample by extractive alkylation. Determination was made using gas chromatography-mass spectrometry with multiple-ion detection. Conditions with respect to the rate of formation and the stability of the derivative formed in the extractive alkylation step were evaluated. The selectively of the method to azathioprine and to metabolites was thoroughly investigated. No 6-mercaptopurine was formed from azathioprine added to water or plasma and run through the method. The method enables the detection of 2 ng of 6 mercaptopurine in a 1.0-ml plasma sample. Quantitative determinations were done down to 10 ng/ml 6 mercaptopurine in plasma.
Fourteen patients with severe cancer pain participated in a trial of methadone given in a fixed dose (10 mg) but at intervals selected by the patients themselves during the loading phase. The aim was to achieve rapid pain relief while avoiding the risk of toxicity from accumulation of methadone. As expected, the dosage intervals increased gradually over the first few days of treatment, the daily dose decreasing from 30-80 mg on the first day to 10-40 mg at the end of the week. Plasma concentrations of methadone varied sevenfold after four to five days (0.24 to 1.75 mumol/1; 7.4 to 54.2 microgram/100 ml). Eleven patients reported complete or almost complete pain relief and elected to continue with methadone after the study. In no case was treatment withdrawn because of intoxication. From these findings a patient-controlled dosage regimen of oral methadone may be an effective and safe alternative to parenteral narcotic medication, adjusting both for individual variation in pain intensity and for pharmacokinetics.
The pharmacokinetic constants and rectal bioavailability of the narcotic analgesic ketobemidone were determined in six male patients after surgery. Plasma concentrations were measured following intravenous administration of Ketogin 2 ml, containing ketobemidone chloride 10 mg, and a spasmolytic compound N,N-dimethyl-3,3-diphenyl-1-methylallylamine chloride 50 mg, and following rectal administration of one suppository of Ketogin, containing ketobemidone chloride 10 mg and the spasmolytic component 50 mg. Following intravenous administration, the disposition of ketobemidone followed a biexponential pattern with a fast distribution phase and a slower elimination phase: the plasma half-life (t1/2) was 2.42 +/- 0.41 h (m +/- SD). After rectal administration, the disposition of ketobemidone fitted a one-compartment model. The elimination half-life was 3.27 +/- 0.32 h. The mean rectal bioavailability for ketobemidone was 44% +/- 9%. The pharmacokinetic constants of the spasmolytic component, N,N-dimethyl-3,3-diphenyl-1-methylallylamine, were also determined in five of the patients, both after intravenous and after rectal administration. The plasma half-life was 3.07 +/- 0.53 h and 3.79 +/- 1.14 h, respectively. The rectal bioavailability was estimated to be 33% +/- 14%.
Defined daily doses per day and 10(3) inhabitants [Formula: see text] of the different types of antiparkinson agents have been compared in the period 1975-1979 for Norway, Sweden, Denmark and Finland. A marked increase in the utilization of L-DOPA containing drugs has taken place especially in Sweden following the introduction of the "combined drugs" (L-DOPA + decarboxylase inhibitor). Statistically, nearly all patients with parkinsonism in Sweden have since 1977 been treated with L-DOPA, while in the other nordic countries about 10% of the patients are not on this therapy. These data are discussed in relation to the current concept of pharmacotherapy of parkinsonism. Further, many patients treated with neuroleptic drugs do in addition take anticholinergic agents. Drug utilization figures indicate this method of treatment to be most common in Denmark and Sweden.
Pethidine (100 mg) was administered i.m. to women in labor at different times before delivery. The interval before respiration in the newborn became sustained was shorter if pethidine was given less than one hour before delivery. The respiratory rate of the newborn increased after naloxone injection in 40 per cent of the cases, mostly when intrauterine exposure to pethidine exceeded one hour. The plasma concentrations of pethidine and norpethidine were measured in mother and newborn. The concentrations in the umbilical vein and artery indicted a continuous net transfer of pethidine from mother to fetus for approximately two hours. This correlated with the clinical finding of maximal neonatal depression 2-3 hours after maternal injection. The concentrations of norpethidine increased with a longer time interval between injection and delivery, but were probably too low to have any effect on the newborn. Neonatal depression seems to be related to the amount of unmetabolized pethidine that has been transferred from mother to fetus but not to norpethidine as had been suspected earlier.
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