[Color and 3-dimensional information].
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Audiovisual Aids↗
Biomedical subjects
P Mustajoki
Publications and source records attributed to P Mustajoki.
Effects of heme arginate on cytochrome P450-mediated metabolism of drugs in patients with variegate porphyria and in healthy men.
We investigated the effects of heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without heme, a single infusion of heme arginate (3 mg/kg heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of heme on drug metabolism is P450 isozyme-specific.
Adult↗
Effects of a cognitive-behavioural weight loss programme on overweight obstructive sleep apnoea patients.
Thirty-two obese patients (Body Mass Index (BMI) = 38.5 +/- 3.7) with obstructive sleep apnoea (the average number of oxygen desaturations per hour of sleep exceeding 4% from the baseline (ODI4) = 38.64 +/- 23.9) underwent a one-year cognitive-behavioural weight reduction programme with a one year follow-up period. The criteria for successful treatment were (i) a decrease in ODI4 to less than 10 and (ii) a decrease in ODI4 that was greater than 50%. Fourteen (44%) patients were considered to be treated successfully at six months. When the patients were grouped according to weight loss 23 patients had lost more than 5 kg; 12 (52%) of them belonged to the group treated successfully. At 24 months, however, only three (9%) patients could be regarded as treated successfully and six patients had been transferred to other treatment modes (Nasal Continuous Positive Airway Pressure (nCPAP) and uvulopalatopharyngoplasty (UPPP)). The changes in weight correlated with the changes in ODI4 (r = 0.47 and 0.63 at the 6-month and the 24-month evaluation, respectively).
Journal Article↗
Long-term Results of Gastroplasty for Morbid Obesity: Binge-Eating as a Predictor of Poor Outcome.
We investigated the long-term results after vertical banded gastroplasty (VBG) for morbid obesity and evaluated some predictors of poor outcome. Twenty-seven morbidly obese patients (mean BMI 50 kg/m(2)) who underwent VBG a mean of 5.4 years earlier were studied. The mean weight loss was 31 kg or 40.5% of excess weight. Ten patients (37%) were within 50% of their ideal weight. The patients were classified as bingers (n = 10) and non-bingers (n = 17) according to the modified Binge Eating Scale. One-year postoperative weight losses were 55% and 57% respectively of excess weight, but at the time of the study weight losses were 24% and 50% of excess weight (p = 0.04) in the bingers and non-bingers, respectively. The mean weight regain was 23 kg in the bingers vs 8 kg in the non-bingers, p = 0.01. Two bingers had excellent weight loss results, but otherwise an unsuccessful outcome. Weight reduction did not correlate with age, sex or age of onset of obesity. These results show that binge-eating strongly predicts poor weight loss maintenance after gastroplasty in the long-term, though initial weight reduction is good. We suggest that binge-eating should be evaluated before gastroplasty and taken into consideration in the design of treatment.
Journal Article↗
Treatment of the porphyrias.
There are seven porphyrias which are caused by defective functions of the enzymes in the haem biosynthesis. Pathogenic mechanisms and symptoms differ greatly in individual porphyrias and, consequently, most of them require a specific therapy. Clinically, the three most important entities are acute porphyric attack, porphyria cutanea tarda and protoporphyria. For an acute porphyric attack the treatment of choice is administration of haem; the other measures are elimination of precipitating factors and symptomatic therapy for many associated symptoms. Porphyria cutanea tarda is controlled by removal of iron by phlebotomies or with low-dose chloroquine. Skin symptoms in protoporphyria can be alleviated with betacaroten but there is no effective procedure to normalize disturbed porphyrin metabolism; hepatic failure seen in some patients may need a liver transplantation. The only effective treatment in congenital erythropoietic porphyria is probably a bone marrow transplantation. No satisfactory treatment is available for very rare delta-aminolevulinic acid dehydrase deficiency porphyria.
Acute Disease↗
Early administration of heme arginate for acute porphyric attacks.
BACKGROUND: We investigated the efficacy of early administration of heme arginate in acute porphyric attacks. METHODS: The series consisted of 51 consecutive acute attacks in 22 patients with acute intermittent porphyria and in two patients with variegate porphyria referred to a hospital in France or in Finland. Four attacks were associated with pareses, and 47 attacks were not. Heme in a dose of 250 mg or 3 mg/kg was started within 24 hours after admission in 37 (72.5%) of the attacks and within 4 days in 49 (96%) of the attacks. During all except five attacks, four daily infusions were given. RESULTS: The mean (+/- SD) duration of abdominal or nonabdominal pain was 2.5 +/- 0.97 days, and opiates were stopped an average of 2.8 +/- 0.72 days after the first heme infusion was started. All patients responded. In 46 (90%) of the attacks, the total hospitalization time was 7 days or less. The mean urinary excretion of porphobilinogen decreased to 16.2% +/- 7.7% and that of 5-aminolevulinic acid to 11.6% +/- 5.6% of pretreatment values. The only side effect was moderate thrombophlebitis in one patient. CONCLUSION: Favorable responses in every attack suggest specific effects of heme. In patients with acute attacks, heme therapy should be started immediately on admission.
Adult↗
[The very-low-calorie diet--a new way to treat obesity].
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Diet, Reducing↗
CRIM-positive mutations of acute intermittent porphyria in Finland.
Acute intermittent porphyria (AIP) is a dominantly inherited metabolic disease caused by a partial deficiency of the third enzyme, porphobilinogen deaminase (PBGD), in the heme biosynthetic pathway. AIP has been divided into two subtypes according to the ratio of enzyme polypeptide concentration and enzyme activity measured in erythrocytes: cross-reacting immunologic material (CRIM) positive or negative. In this study six out of the seven known CRIM-positive AIP families in Finland were analyzed and two also previously identified mutations in the PBGD gene were found to be responsible for AIP in this genetically isolated population. The search for mutations was focused on exon 10 based on previously found mutations. SSCP analysis revealed a known polymorphism but the two mutations in that region were found only by direct sequencing of the PCR products. A G518-->A substitution changing Arg173 to Gln was found in three families and a C499-->T substitution changing Arg167 to Trp was detected in three families. DNA analyses of the family members revealed that conventional assays of erythrocyte PBGD activity identified correctly only 72% of the carriers for the AIP mutation.
Amino Acid Sequence↗
Rapid normalization of antipyrine oxidation by heme in variegate porphyria.
Effects of heme on hepatic xenobiotic drug metabolism were investigated in eight subjects with variegate porphyria. A single infusion of heme arginate (3 mg/kg heme) reversed rapidly the prolonged mean elimination half-life of antipyrine from 27.2 to 12.7 hours (p less than 0.001) and increased total clearance from 0.23 to 0.44 ml/min/kg (p less than 0.001). Excretion of 6 beta-hydroxycortisol and D-glucaric acid increased significantly during heme infusion. Excretion of urinary porphyrin precursors increased during the antipyrine test but was normalized by heme. It is concluded that in variegate porphyria a partial block in heme biosynthesis results in subnormal capacity of P450-associated monooxygenases, but this is easily normalized by exogenous heme.
Adult↗
Weight loss normalizes the inhibitory effect of N6-(phenylisopropyl)adenosine on lipolysis in fat cells of massively obese human subjects.
1. Fat cells were isolated from massively obese patients at or before gastric bypass, from other patients after normalization of body weight after gastric bypass or gastroplasty (post-bypass patients) and from control subjects of a stable normal body weight. 2. The inhibition of isoprenaline-stimulated lipolysis by N6-(phenylisopropyl)adenosine in the presence of adenosine deaminase was much attenuated in cells from the massively obese patients as compared with those from normal-weight control subjects, but was normal in cells from post-bypass patients. 3. Isolated fat cells of the massively obese patients were larger (913 +/- 197 pl, mean +/- SEM) than those of the normal-weight group (437 +/- 95 pl). The volume of cells from the post-bypass patients was only 125 +/- 49 pl, although the body mass index of this group was almost exactly the same as that of the normal-weight control subjects. 4. Although epidemiological studies have suggested that genetic factors are important in the development and maintenance of obesity, these results demonstrate that the changes observed in the inhibitory regulation of lipolysis in obesity are secondary.
Adenosine Deaminase↗
Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer: no porphyric symptoms.
The pathogenesis of the acute porphyric attack is not known. One hypothesis is that porphyrin precursors, especially 5-aminolaevulinic acid (ALA), are toxic for neuronal tissue. This was tested by infusing ALA in a male volunteer after a loading dose at a rate of 50-80 mg h-1 for 92.5 h. During the experiment plasma ALA concentration was 9-11 mumol 1-l and porphobilinogen concentration 3-6 mumol 1-l which are the levels seen during acute attacks. Urinary excretion of these porphyrin precursors was also markedly increased. ALA infusion caused no subjective symptoms and no change in pulse rate, blood pressure, or autonomic nerve function or conduction velocity of peripheral nerves. Photosensitivity was not demonstrable. It is concluded that sustained high plasma ALA concentration does not cause porphyria-like symptoms.
Aminolevulinic Acid↗
Frequency of low erythrocyte porphobilinogen deaminase activity in Finland.
The frequency of low erythrocyte porphobilinogen deaminase (PBGD) activity was investigated in 2234 blood donors and in 30 patients with acute intermittent porphyria. The mean enzyme activities (+/- SD) were 3.38 +/- 0.58 U and 1.82 +/- 0.41 U, respectively. Eighteen blood donors without any history of symptoms of porphyria or haematological disease had low PBGD activity (less than 2.20 U), and they were studied further. All of them also had subnormal concentrations of the erythrocyte enzyme protein, as determined by an immunological method. Lymphocyte PBGD activity was within the normal range, but this parameter does exhibit a wide overlap between normal and porphyric values. Urinary excretion of porphobilinogen was moderately increased in two of the blood donors. In four of the 18 families of the blood donors with low PBGD activity several first-degree relatives had low erythrocyte enzyme activity, consistent with a dominant mode of inheritance. The 5-aminolaevulinic acid loading-test was normal in the blood donors with familial occurrence of low erythrocyte PBGD. It is concluded that inherited defects in erythrocyte PBGD occurred among Finnish blood donors with a frequency of about 1 in 500. The defects may be identical with those in acute intermittent porphyria (AIP), but other mechanisms are also possible, e.g. a mutation in the erythroid-specific part of the PBGD gene.
Adult↗
[Management of obesity--a physician's blind spot].
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Attitude of Health Personnel↗
[Frequent stomach aches leading to surgery].
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Appendectomy↗
Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases.
We evaluated the prognosis of acute porphyria among 206 adult Finnish patients with acute intermittent porphyria (AIP) or variegate porphyria (VP). The series represents all known patients with these porphyrias in Finland. Of the 47 patients who had a total of 117 acute attacks during the period 1967-1989, 6 died during an attack and 21 attacks were associated with paresis; the frequency of severe attacks was significantly smaller than before 1967 (p = 0.00002). Most pareses and deaths occurred because of a delay in diagnosis and inappropriate treatment of porphyria. For those patients who were symptom-free at the time of diagnosis (1365 follow-up years), the risk of the first subsequent attack was significantly smaller than for those who had had an acute attack before the diagnosis of porphyria (1047 follow-up years, p = 0.005). In addition, milder symptoms of porphyria were more common among those who had had previous attacks than among those who had not (p less than 0.00001). In AIP the risk of attacks correlated with the excretion of porphobilinogen in the urine during remission among adults (p = 0.03); a low rate of excretion predicted freedom from acute attacks. A regular use of many precipitating drugs was never associated with symptoms of porphyria. Two percent of the surgical operations and 4% of the pregnancies were associated with acute attacks. Nearly one-third of the women had symptoms of porphyria associated with the menstrual cycle, but these seldom proceeded to an acute attack. Forty-six percent of the women had used sex-hormone preparations regularly; 2 of them (4.5%) experienced associated acute attacks. Patients with AIP or VP showed increased incidences of hepatocellular carcinoma, and probably also chronic renal failure and hypertension.
Acute Disease↗
Skin morphology in porphyria cutanea tarda does not improve despite clinical remission.
Five patients with porphyria cutanea tarda (PCT) were treated with a prolonged, low-dose chloroquine regimen (250 mg twice weekly). Their skin symptoms disappeared, and the abnormal urinary porphyrin excretion normalized during treatment periods ranging from 6 to 17 (mean 11.8) months. The morphology of the skin was studied by light and electron microscopy methods before treatment, at the onset of remission, and 6-12 months later. In samples taken during remission, the PAS-positive thickening of the superficial dermal vessels was comparable to that before treatment. In electron microscopy, the vessels showed thickening because of reduplication of the basal lamina and perivascular deposition of amorphous material; no consistent changes were found during remission. The results show that the histopathological changes of the skin in PCT are of chronic nature, and are probably irreversible.
Adult↗