Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning

1 In vitro studies with human erythrocyte acetylcholinesterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazinon and other OPs is characterized by slow spontaneous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly susceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HL? 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 micrograms/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.     

Enzymes hydrolyzing organophosphates as potential catalytic scavengers against organophosphate poisoning

Mechanosensitive channels are ion channels whose activity is dependent on a mechanical stress on the membrane. They are believed to play a central role in mechanotransduction, the process by which mechanical energy is converted into electrical or chemical signals in biological cells. Recent progress, which has been made at the molecular level, is presented, and the two current models of activation of these channels are discussed.     

The clinical significance of compliance

The authors deal with a particular type of working alliance, called "compliance", which may be defined as mutual agreement between patient and physician with respect to prevention and therapy. This type of compliance may be influenced by the kind of disease (e.g. low compliance in psychiatric illness), by the mode of referral (verbal or written), by the kind of hospital care (an individual appointment with one particular physician in an outpatient department makes for better compliance) and by medication (intravenous or oral administration and color and size of pills). The number of medicines prescribed is of particular importance for compliance, i.e. the greater the number of drugs prescribed per day, the more the patient tends to be unreliable in taking them. Furthermore, the time spent in the waiting room, the amount of information given to the patient and the clarity of the instructions given by the physician play an important role. Situational factors and interaction in the physician-patient relationship seem to be more relevant than specific personality traits.     

Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector

The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 micrograms/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27 +/- 4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76 +/- 8.2% of baseline (p < 0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p < 0.01) to 20 +/- 3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15-20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs.     

The dependence of the blood level of the oxime HS-6 on the severity of organophosphate poisoning

Atropinised anaesthetised rats were injected i.v. with 4, 6 or 8 X LD50 of the organophosphorous anticholinesterase soman. Subsequent treatment with one dose of HS-6 (100 mg/kg, i.v.) delayed respiratory failure by 1 h or more; a further postponement was obtained when an additional HS-6 infusion was given. At the same infusion rate, HS-6 blood levels after 4 X LD50 soman remained stationary, but rose after the higher soman doses. The rise was greater the higher the soman dose had been. This rapid rise in oxime blood levels after high doses of organophosphate may seriously complicate therapy.     

The clinical significance of Acinetobacter species

Of 50 consecutive patients from whom Acinetobacter species were isolated, only one had an infection due to the organism which required antibiotic therapy. Fourteen of the isolates were associated with minor body surface infections and the remainder occurred as the result of either colonization without infection or culture contamination. The taxonomy, natural occurrence and antibiotic sensitivity of Acinetobacter species and their differentiation from more pathogenic organisms are reviewed.     

Unusual isomaylase in cancer-associated hyperamylasemia

Hyperamylasemia and hyperamylasuria were found in two patients with carcinoma of the pancreas and in two other patients with carcinoma of the lung. Detailed isoamylase analyses were conducted on the serum amylase of three and the urine amylase of all four of these patients, using a modified chromatographic procedure. The studies demonstrated the existence, in one of the lung cancer patients and in one of the patients with pancreatic cancer, of an unusual component of amylase given the designation "Y." This component had also been noted in some human milk samples. In one of the lung cancer patients, an isoamylase was found in the serum and urine after radiation treatment that was close to but not identical to the Y isoamylase in chromatographic position. Although a relationship of isoamylase component Y to generating tissue is suggested by these findings, such a relationship of isoamylase component Y to generating tissue is suggested by these findings, such a relationship remains to be proven.     

The influence of acute poisoning with an organophosphate compound on the regulation of breathing and the respiratory system efficiency

The female patient, aged 40, was admitted to the Department of Toxicology about fifteen hours after she had drunk 50 ml Basudin 25 EC (diazinon contents 25%) in a suicidal attempt. On admission the patients state was described as moderately severe (9 points). Starting with the first day after the poisoning, the functional state of the respiratory system was monitored. Ventilation efficiency was determined on the basis of the results from a flow-volume curve, spirometry and the measurements of the respiratory tract resistance (Rrs) in a computerised system Lungtest-MES company (Poland). Respiratory regulation was evaluated by means of synchronic measurements of the respiratory pattern and occlusion pressure. The results obtained from a respiratory pattern and P 0.1 were refereed to normal values. In the examination carried out directly after the poisoning slight obturation of the central bronchi and elevation in resistance of respiratory tract was noted. After a week, obturation was not noted and the resistance value was better. Also the respiratory pattern parameters and value of occlusion pressure were better. It seems that in this case the increase in resistance values in the respiratory tract should be related to the increased activity in the parasympathetic system. Basic, traditional spirometric even in the examination on the first day after the poisoning, were within normal limits, while the parameters of respiratory pattern, occlusion pressure and respiratory resistance were beyond the norm. The results obtained from the measurements of respiratory pattern parameters correlated well with the clinical condition of the patient and with the results of biochemical and enzymatic measurements.     

Phenformin and hyperamylasemia in lactic acidosis

All cases of lactic acidosis occurring during a 23-month period in a metropolitan teaching hospital were reviewed to ascertain the frequency of hyperamylasemia. Serum amylase activity had been measured in 12 of 26 patients and was elevated in eight (67%). Hyperamylasemia was not significantly more frequent in patients with phenformin-associated lactic acidosis than in patients with lactic acidosis who had not received phenformin. Serum amylase activity did not correlate with the severity of acidosis (arterial pH) or with renal function (serum creatinine).     

The meanings and measurement of clinical significance.

The previous articles in this special section (P. C. Kendall et al, see record 1999-03648-001; N. S. Jacobson et al, see record 1999-03648-002; S. L. Foster and E. J. Mash, see record 1999-03648-003; and M. M. Gladis et al, see record 1999-03648-004) make the case for the importance of evaluating the clinical significance of therapeutic change, present key measures and innovative ways in which they are applied, and more generally provide important guidelines for evaluating therapeutic change. Fundamental issues raised by the concept of clinical significance and the methods discussed in the previous articles serve as the basis of the present comments. Salient among these issues are ambiguities regarding the meaning of current measures of clinical significance, the importance of relating assessment of clinical significance to the goals of therapy, and evaluation of the construct(s) that clinical significance reflects. Research directions that are discussed include developing a typology of therapy goals, evaluating cutoff scores and thresholds for clinical significance, and attending to social as well as clinical impact of treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The clinical significance of type 1 fiber predominance

Having recently demonstrated that taurine supplementation prevents total parenteral nutrition (TPN)-induced cholestasis, we chose to use this model to examine plasma membrane composition in relation to bile formation. Male guinea pigs received daily a mixture of glucose and of the amino acid solution Travasol with or without added taurine (1.2 mM). After 3 days, bile was collected and liver plasma membrane fractions enriched in sinusoidal lateral membrane and bile canalicular membrane domains were isolated. In animals receiving TPN alone, bile flow and biliary secretory rate of bile acid and bicarbonate decreased significantly compared with controls. Although membrane ATPases (Na+K+ and Mg+) were unchanged, TPN induced an increase in the lipid to protein ratio and a decrease of polyunsaturated fatty acids, in conjunction with a higher content of diene conjugates in sinusoidal lateral membrane fractions. Taurine corrected these changes and, in addition, reduced significantly the cholesterol to phospholipid ratio in both membrane fractions. The data show that changes in liver cell membranes occur in TPN-induced cholestasis and suggest that free radical injury may play a role. As taurine prevented cholestasis as well as membrane changes, it is suggested that taurine should be added to amino acid solutions used for parenteral nutrition.     

The clinical significance of granulocyte colonies in bone marrow cultures

The culture system for in vitro evaluation of "colony forming units - culture (CFU-c)" is briefly outlined. This method offers a new approach to studies of proliferation and differentiation of hemopoietic progenitor cells, especially in disorders of granulopoiesis. From available published data it is evident that quantitation of CFU-c is also an indicator of diagnostic and prognostic value for assessment of various types of leukemia. The CFU-c assay has furthermore been introduced to test the viability and proliferating capacity of cryopreserved bone marrow, especially with a view to possible transfusion of stored autologous bone marrow as an adjuvant to cytostatic therapy.     

The clinical significance of flow cytometry crossmatching in heart transplantation

BACKGROUND: Flow cytometry crossmatching is more sensitive than cytotoxic methods in identifying preformed antibodies to donor alloantigens. However, the significance of a positive flow crossmatch remains unknown for a recipient of a heart transplant who has a negative anti-human globulin crossmatch. METHODS: Flow crossmatching was performed retrospectively for 92 recipients of a primary cardiac allograft who underwent transplantation with a negative AHG crossmatch. RESULTS: Forty-six patients were flow crossmatch-positive for alloantibody: 20 were positive on both T and B lymphocytes, 12 were positive only on B lymphocytes, and 13 were positive only on T lymphocytes. Eleven had autoantibody invalidating the flow crossmatch with donor cells. Thirty-six patients had negative flow crossmatch. A significantly higher incidence of graft dysfunction with vascular rejection by 6 months was found for patients who had a positive flow crossmatch on B lymphocytes. This group also had an increased incidence of mortality within this same period. Patients who were flow crossmatch-positive on T and B lymphocytes were more likely to experience greater than two episodes of treated cellular rejection within the first 6 months. Flow crossmatch-positive patients stayed longer in the hospital in comparison to the other two groups, although the increases were not statistically significant. There were no differences between groups with regard to time to first rejection, absence of rejection episodes, episodes of decreased cardiac index (<2.3 L/m2), depressed left and right ventricular ejection fraction, or development of transplant atherosclerosis. CONCLUSION: A positive flow crossmatch identified a subset of patients who are predisposed to development of vascular rejection or are more likely to have frequent cellular rejection.     

The clinical significance of disorders in the hemostatic system in infectious endocarditis

AIM: Study of blood clotting to evaluate hemostatic disorders in infectious endocarditis (IE). MATERIALS AND METHODS: The trial included 124 patients with IE (61 males and 63 females aged 15-70 years). Primary and secondary IE was in 38 and 62% of patients, respectively. RESULTS: Clinically evident hemostatic disorders were observed in 93(74.2%) cases. They manifested as intravascular platelet activation with development of hypercoagulatory status and chronic DIC-syndrome. CONCLUSION: A differentiated approach is advisable to correction of thrombotic disorders in IE basing on the severity of blood coagulation impairment.