Anders Berg

CLINICAL FEATURES IN 28 CONSECUTIVE CASES OF LABORATORY CONFIRMED MASSIVE POISONING WITH CARBAMAZEPINE ALONE

A retrospective study of consecutive cases of massive carbamazepine poisoning treated in an intensive care unit during the period 1981-1991 was performed, mainly to determine whether serum carbamazepine levels were predictive of toxicity. Out of a total of 51 admissions with a diagnosis of carbamazepine self-poisoning, 28 (25 patients) were included. The reasons for exclusion were coingestion of other drugs (11 cases), incorrect diagnosis or inadequate information (6 cases), a peak observed serum concentration of carbamazepine below 76 mumol/L [18 mg/L] (4 cases), and lack of any documented serum carbamazepine assay (2 cases). The peak serum concentrations ranged from 78 to 285 mumol/L [18.4 to 67.4 mg/L]. It was found that serum levels equal to or above 170 mumol/L [40 mg/L] were significantly associated with an increased risk of serious complications such as coma, seizures, respiratory failure and cardiac conduction defects. In 60% of the 10 patients with a serum level > or = 170 mumol/L at least two of these symptoms occurred, in 50% at least three, and in 40% all four. There were two fatalities. Among the 16 patients (18 admissions) with a serum carbamazepine concentration below 170 mumol/L, only one was comatose and none had any of the other severe symptoms. It is concluded that serum carbamazepine levels accurately predict the severity of toxicity in massive carbamazepine poisoning in adults.

Demonstration of a cytochrome P-450-dependent steroid 15β-hydroxylase in Bacillus megaterium

Abstract The steroid 15β-hydroxylase system of Bacillus megaterium was obtained in a cell-free preparation through sonication. The strictly NADPH-dependent 15β-hydroxylase activity, measured using progesterone as substrate, was inhibited by carbon monoxide, SKF 525-A, imidazole and metyrapone, indicating that the reaction is cytochrome P-450-dependent. A 40-fold purification of cytochrome P-450 in cell-free extracts was obtained by chromatography on DEAE-cellulose yielding a concentration of 0.32 nmoles of cytochrome P-450 per mg of protein. This partially purified cytochrome P-450 preparation catalyzed 15β- and 15α-hydroxylation of progesterone in the presence of NaIO4 or NaClO2 but not in the presence of NADPH or NADH.

considerations for the treatment of Ethylene glycol poisoning Based On Analysis Of Two Cases

The clinical picture as well as the principles of treatment in ethylene glycol poisoning differ with the time after ingestion. These time-related differences are illustrated by two case reports. During the first hours of ethylene glycol poisoning, the patient suffers from drunkenness, vomiting and somnolence due to the intoxicant effect of ethylene glycol on the central nervous system. In the following hours a poisoning with glycolate and oxalate develops, with increasing acidosis, renal and brain damage. A patient admitted within a few hours of an overdose, with no or only slight metabolic acidosis, may be successfully treated with ethanol. If the serum concentration of ethylene glycol is very high, hemodialysis may be deferred until the necessary staff and equipment are available. If the patient is admitted with severe metabolic acidosis, hemodialysis must be started immediately. The need for ethanol administration during hemodialysis merits reevaluation.

Stimulus-specific defect in platelet aggregation in polycythemia vera.

Abstract: We have previously reported that polymorphonuclear granulocyte (PMN) and monocyte oxidative metabolism is reduced in polycythemia vera (PV) patients compared to healthy control subjects, after stimulation with cell surface receptor‐dependent stimuli such as n‐formyl‐methionyl‐leucyl‐phenylalanine, leukotriene B4 and platelet‐activating factor (PAF). In contrast, the oxidative response to phorbol myristate acetate (PMA) is normal. We now show that, in PV patients exhibiting significantly reduced PMN chemiluminescence after PAF stimulation, PAF induced platelet aggregation was also reduced — 40 ± 3% compared to 50 ± 2% in controls (p<0.01). The defective aggregatory response to PAF in PV remained over a wide range of stimuli concentrations. Platelet aggregation induced by PMA and ADP, however, was similar in PV and controls. In contrast, platelet aggregation induced by PAF (or by ADP and PMA) was not significantly reduced in patients with chronic myeloid leukemia, essential thrombocythemia and multiple myeloma. Furthermore, the release of β‐thromboglobulin was slightly but not significantly higher after PAF stimulation in PV and this argues against an abnormal PAF receptor as the cause of the defective function. Thus, not only PV neutrophils, but also PV platelets show a discrete defect of the stimulus response coupling for PAF, indicating a disease‐specific abnormality that appears to be of clonal origin.

Suicidal chloral hydrate poisoning

BACKGROUND The cumulative reports of chlorate hydrate toxicity suggest an unacceptable risk for this commonly used sleep aid. CASE REPORT A 29-year-old male was admitted after ingestion of 70 g of chloral hydrate. He was hypotensive and hypothermic. Spontaneous respiration was insufficient. Fluid resuscitation did not restore adequate blood pressure levels. Low dose catecholamine infusion resulted in ventricular arrhythmias. The patient was treated with combined hemoperfusion and hemodialysis during an eight hour period. During this time, serum concentrations of trichlorethanol fell. Blood pressure and heart rate increased and consciousness was regained without signs of neurological deficits. CONCLUSIONS Although outcome was favorable, this case report illustrates the potentially high acute toxicity of chloral hydrate and supports its removal from the market.

Further studies of the defective stimulus-response coupling for the oxidative burst in neutrophils in polycythemia vera.

Samuelsson J, Berg A. Further studies of the defective stimulus‐response coupling for the oxidative burst in neutrophils in polycythemia vera. Eur J Haematol 1991: 47: 239–245.

1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine—A methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism

Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1-100 microM 1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH3) induced platelet aggregation but 1-O-hexadecyl-sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH3 (0.1 microM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [3H]WEB 2086 showed that Et-16-OCH3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 microM Et-16-OCH3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 microM. Thus, this study shows that Et-16-OCH3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.

Characterization of the ferredoxin component of the steroid 15β-hydroxylase system from bacillus megaterium

The iron-sulfur protein of the 15β-steroid hydroxylase system in Bacillus Megaterium has been purified to apparent homogeneity as judged by SDS-polyacrylamide gel electrophoresis. Its molecular weight, c:a 14000 Dalton, and amino acid composition closely resemble those of the corresponding proteins from bovine adrenal mitochondria (adrenodoxin) and Pseudomonas putida (putidadoxin).

STUDIES ON A CYTOCHROME P-450-DEPENDENT HYDROXYLASE SYSTEM ACTIVE ON STEROIDS IN Bacillus megaterium

ABSTRACT The steroid hydroxylase system in Bacillus megaterium that hydroxylates 3-oxo-Δ 4 -steroids primarily in position 15β has been resolved into an NADPH-specific FMN-containing reductase (megaredoxin reductase), an iron-sulphur protein (megaredoxin) and cytochrome P-450 meg . Megaredoxin reductase can be replaced by rabbit liver NADPH-cytochrome P-450 reductase. In reactions supported by oxygen-donating agents as NaIO 4 or iodosobenzene, hydroxylation occurs in both position 15α and 15β. Using hydrophobic chromatography cytochrome P-450 meg has been purified to 20% homogeneity. This protein has an isoelectric point of 4.9 and a molecular weight of approximately 37 000 D. Phosphatidylcholine stimulated NaIO 4 -supported, P-450 meg -catalyzed hydroxylation reactions by a factor of two.

Defective platelet aggregation in polycythaemia vera is not caused by impaired calcium signaling, phospholipase D activation or decreased amounts of focal adhesion proteins.

Abstract: We have previously demonstrated that platelets in polycythaemia vera (PV) exhibit decreased aggregation after stimulation with platelet activating factor (PAF) and reduced expression of GPIIIa on both resting and stimulated platelets. In the present study, we investigated if these results were related to changes in the mobilization of intracellular calcium, activation of phospholipase D (PLD) or amounts of GPIIIa and the intracellular tyrosine kinases Fak, Syk, Grb2, Shc and rhoA. Intracellular calcium levels were not different in resting platelets from 14 PV patients and 15 healthy controls (median 43 nmol/L, range 10–114, vs. 36 nmol/L, range 10–119). After stimulation with PAF (1 µmol/L) an equal increase was seen (125 nmol/L for PV platelets, range 67–257, vs. 113 nmol/L for controls, range 60–250). Also formation of phosphatidyl ethanol (PEt) was similar after exposure to 0.5 U/ml thrombin (0.28% PEt of total phospholipid, range 0.16–1.10, vs. 0.24 for controls, range 0.11–2.3) and 1 µmol/L PMA (0.25, range 0.16–0.32, vs. 0.14, range 0.09–0.6). In contrast to the reduced amount of GPIIIa on the surface of PV platelets, immunoblotting on whole cell lysates showed no reduction in PV patients compared to controls, indicating the possibility of an impaired incorporation of GPIIIa to the cell membrane. Levels of Fak, Syk, Shc, Grb2 and rhoA appeared equal in patients and controls. Similar intracellular proteins were tyrosine phosphorylated after stimulation with thrombin, PAF and PMA. In summary, defective platelet aggregation after stimulation with PAF is caused by neither defective mobilization of intracellular calcium nor, in contrast to the situation in PV granulocytes, an impaired activation of PLD. Moreover, no apparent differences in the intracellular amounts of Fak, Syk Shc, Grb2 and rhoA could be detected between PV and control platelets.