因合并用药导致患者洋地黄中毒1例

一患者在使用常规剂量去乙酰毛花苷治疗过程中,因合并使用托拉塞米、胺碘酮、抗菌药物等多种药物,加之患者高龄、肾功能不全等因素,导致发生患者洋地黄中毒。因此,在临床实践中,对于使用洋地黄类药物的患者,应注意监护患者合并用药情况及其生理、病理状况,及时监测血药浓度并调整用药方案,避免中毒事件的发生。     

Phosphotriesterase activity identified in purified serum albumins

The phosphotriesterase in chicken serum that hydrolyses O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) was purified in three chromatographic steps. The activity copurified to apparent homogeneity with albumin monitoring by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS/PAGE) and by SDS-capillary electrophoresis in the purified fractions. Commercial chicken serum albumin was further purified and the phosphotriesterase activity remained associated with albumin. Capillary electrophoresis established a molecular weight of 59 ± 4 kDa for both purified proteins (chicken serum and commercial chicken serum albumin). The purified samples were assayed for hydrolytic activity against several carboxylesters, organophosphates and phosphoramidates. From carboxylesters, only p-nitrophenylbutyrate ( p-NPB) hydrolysing activity was found to copurify with the phosphotriesterase. The purified human, chicken, rabbit and bovine serum albumins and recombinant human serum albumin obtained from commercial sources hydrolysed HDCP and p-NPB. Serum albumin also hydrolysed O-butyl O-2,5-dichlorophenyl phosphoramidate, O-ethyl O-2,5-dichlorophenyl phosphoramidate and O-2,5-dichlorophenyl ethylphosphonoamidate but not other organophosphates and phosphoramidates. Received: 10 September 1997 / Accepted: 17 November 1997     

Protection of Organophosphate-Inactivated Esterases with Phosphotriesterase

The protective effect of phosphotriesterase (PTE) on cholinesterase(ChE) and carboxylesterase (CaE) activities was studied in mice.The PTE pretreatment (120 U/g body wt, 9.6 µg/g body wt)given iv 10 min before diisopropyl fluorophosphate, sarin, orso-man variably prevented ChE inhibition in erythrocytes andplasma and CaE in plasma. PTE also protected the brain and lungChEs against inactivation by organophosphates (OPs). The recoveryof the enzymes was dependent on the OP used. Postexposure therapywith PTE, given 1.5 hr after paraoxon, also prevented ChE inhibitionin erythrocytes, brain, and lung 24 hr after exposure. The distributionstudies with [¹²⁵I]PTE showed that PTE does not markedly gainaccess into the central nervous system.     

Motor nerve dysfunction in delayed DFP neuropathy

A localized neuropathy was produced in cats by an intra-arterial injection of diisopropyl fluorophosphate (DFP). The soleus nerve-muscle system, and especially the motor nerve endings, were functionally evaluated during the following 1–56 days. Nerve conduction velocities remained unchanged. At 24–72 hr after DFP, the indirectly evoked but not directly evoked contractile strength of muscle fell to about 20% of normal; recovery had commenced by the 7th day. Motor nerve ending function was assessed by measurement of the neurogenic post-tetanic potentiation (PTP) of soleus muscle. PTP was initially unaffected, even though indirectly evoked contractile strength was severely attenuated. However, at day 7, a PTP reduction was evident and reached a loss of 62% on day 21. The underlying post-tetanic repetition (PTR) was lost at this time. Recovery of PTP and PTR occured over the next 5 weeks. These findings indicate that there is an initial functional damage of nerve endings in delayed organophosphate neuropathy. The pattern of nerve ending impairment suggests a trophic deprivation.     

Vergiftung mit Diisopropylfluorphosphat (DFP)

Zusammenfassung Es wird über Symptomatik und Verhalten der EsteraseaktivitÄt bei 3 akzidentellen DFP-Vergiftungen berichtet. Die Verabreichung des Fermentreaktivators PAM hatte nur innerhalb der ersten Stunden einen gewissen Erfolg. Trotz einer nur geringen Reaktivierbarkeit der durch DFP blockierten Cholinesterase kann die PAM-Behandlung eine lebensrettende Ma\nahme darstellen, wie aus ergÄnzenden Tierversuchen hervorgeht.     

Comparison of known sodium-channel blockers in DFP toxicity

Research on potential therapeutic agents for organophosphate toxicity has traditionally been directed toward blocking the action of acetylcholine on its muscarinic receptors or on reactivating the inhibited catalytic enzyme. Here, we used a whole-animal lethality paradigm to study another potential antidotal mechanism: pharmacological disruption of the sodium channel conductance associated with agonist action on cholinergic receptors. Mice were injected with several drugs which have in common the ability to block sodium-channels. Drugs tested were ketamine, phenobarbital, lidocaine, morphine, prednisolone, and lithium. All mice were injected with DFP (7.6 mg/kg) plus atropine; the treatment groups were simultaneously injected with the test drug, while controls received an equal volume of physiological saline. All the test drugs, at one or more doses, revealed protection, not only in terms of prolonging symptom onset but also in terms of mortality. The reduction in mortality was quantitatively similar for each drug. Although the various drugs could have protected by many different, coincidental mechanisms, a more parsimonious explanation is that the effect could have been due to one property which all had in common; namely, sodium-channel blockade.     

Antagonism of the Lethal Effects of Paraoxon by Carrier Erythrocytes Containing Phosphotriesterase

Annealed murine erythrocytes were employed as a carrier modelto antagonize the toxic effects of organophosphorus agents.These resealed cells containing a recombinant phosphotriesteraseprovided striking protection against the lethal effect of paraoxon,an active metabolite of an agricultural pesticide, parathion.Phosphotriesterase hydrolyzes paraoxon to the less-toxic 4-nitrophenoland diethylphosphate. This enzyme was encapsulated into carriererythrocytes by hypotonic dialysis with subsequent resealingand annealing. These carrier cells were administered to miceeither alone or in combination with pralidoxime (2-PAM) and/oratropine. The recipient animals were subsequently challengedwith paraoxon and a marked protection was noted. Protectionof free enzyme and encapsulated enzyme was compared and theencapsu lated enzyme was found to persist longer and possessmuch greater efficacy. Less serum cholinesterase inhibitionalso was observed with this enhanced protection. These resultsindicate that the erythrocyte carrier alone is quite effectivein the antagonism of organophosphorus intoxication. Moreover,when these carrier cells were administered in combination with2-PAM and/or atropine, a marked synergism was observed.     

化学物中毒的氧化应激机理

本文综合报告了五氧化二钒、顺铂、四氯化碳和氯丁二稀(CBD)引起肾或肝损害的氧化应激机理的研究结果。体内外试验显示,V_2O_5引起肾皮质及其微粒体丙二醛(MDA)增高和(或)膜流动性下降。顺铂引起肾皮质GSH耗竭、葡糖异生作用抑制及MDA增高。CCl_4和CBD引起肝细胞色素P450量下降、抗氧化物质耗竭、MDA增高、膜损害及钙但稳失调。上述结果提示这四种化学物所致靶器官损害在不同程度上与氧化应激有关。本文还报告了某些化学品对这些毒物引起的氧化应激和损伤的防护作用。     

Motor nerve terminal response to edrophonium in delayed DFP neuropathy

A localized peripheral neuropathy was induced in cats with di-isopropyl fluorophosphate (DFP). Soleus nerve-muscle preparations, and the motor nerve terminals in particular, were evaluated for responsiveness to edrophonium (200 μg/kg i.v.). Potentiation of contractile strength was absent 24 hr after DFP, and showed a trend toward recovery 7–14 days post-DFP; it then fell to about 25% of normal 3 weeks following DFP administration. During the ensuing 5 weeks this aspect of edrophonium responsiveness was largely regained. The underlying post-drug repetition which gives rise to the potentiated responses was not demonstrable in either the nerve or muscle 3 weeks after DFP, but was again observed 8 weeks after poisoning. These findings suggest a delayed peripheral neuropathy indicative of a trophic deprivation and further illustrate a motor nerve terminal deficit as the initial function alteration in DFP neuropathy.     

Selective breeding for sensitivity to the anticholinesterase DFP

A selective breeding study was undertaken to test the hypothesis that genetic factors are involved in sensitivity of physiological and behavioral variables in rats to the irreversible anticholinesterase diisopropyl fluorophosphate (DFP). Three variables (drinking behavior, body weight, and core body temperature) were used as indices of the effects of DFP (1 mg/kg, i.m.) and selection was based on a composite score that gave equal weight to each variable. From the original parents, the six most resistant males were mated with the six most resistant females and the six most sensitive males were mated with the six most sensitive females. Subsequent generations were produced by mating the six most resistant pairs from the resistant line and the six most sensitive pairs from the sensitive line. When separation between the two lines appeared well advanced (F5), randomly bred males and females were introduced into the testing procedure. Regression analyses confirmed that the selective breeding procedure was successful in establishing a line with increased sensitivity to DFP, but that it failed to produce a line more resistant than the original population. Analyses of variance of the results for the F6, F7, and F8 generations revealed that the sensitive line was more sensitive than either the randomly bred line or the resistant line, while the latter two groups were not significantly different from each other. Biochemical studies indicated that the genetic differences in sensitivity to DFP were not related to differences in cholinesterase or acetylcholinesterase activity.     

Involvement of muscarinic and nicotinic receptors in behavioral tolerance to DFP

Effects of various cholinergic agents on the free operant responding and single alternation behavior of rats were examined following two regimens of chronic treatment with diisopropylfluorophosphate (DFP), an irreversible anticholinesterase, which lowered brain cholinesterase to 45% and 30% of normal, respectively. Reduction to 45% produced no observable changes in behavior; reduction to 30% gave rise to a decrease in the number of reinforced responses and an increase in the number of nonreinforced responses. Tolerance for the former measure developed within 10 days, whereas tolerance for the latter was not observed. Subsequent challenges were carried out using anticholinesterase agents, and muscarinic and nicotinic agonists and antagonists. The results suggest that the sensitivity og both muscarinic and nicotinic receptors to acetylcholine may be reduced during chronic treatment with DFP, but that muscarinic receptors may be more labile than nicotinic receptors. It is hypothesized that this reduction in sensitivity is one mechanism underlying the development of behavioral tolerance to DFP.     

Chelation in Metal Intoxication XXXVIII: Effect of Structurally Different Chelating Agents in Treatment of Nickel Intoxication in Rat

Some structurally different chelating agents viz. -mercapto-ß-(2-furyl)acrylic acid (MFA), -mercapto-ß-(2-thienyl) acrylicacid (MTA), meso 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercap-topropane-1-sulfonate(DMPS), diethyl dithiocarbamate (DE-DTC), and N-benzyl-D-glucaminedithiocarbamate (NBG-DTC) were evaluated for their efficacyto mobilize nickel and reverse some nickel-induced biochemicalalterations in experimental nickel intoxication. MFA, DMSA,and NBG-DTC appear more effective than their corresponding homologs,MTA, DMPS and DE-DTC, respectively, in enhancing urinary andfecal excretion of nickel and lowering tissue burden of nickelin nickel preexposed rats. These, particularly NBG-DTC, appearpromising in the treatment of nickel (II) poisoning. However,there seems no definite relationship between the structure ofthe chelating agents examined and their ability to counteractthe effects of nickel.     

Phencyclidine Intoxication Case Series Study

Background

Phencyclidine (PCP) is a synthetic compound derived from piperidine and used as an anesthetic and hallucinogenic. Little has been recently published regarding the clinical presentation of PCP intoxication. PCP use as a recreational drug is resurging.

Objective

Our objective was to describe clinical findings in patients presenting to the emergency department (ED) under the influence of PCP.

Methods

This was a case series study conducted at a tertiary care center with an annual census of 100,000 patients/year. Emergency physicians, residents, physician assistants, and research assistants identified patients with possible PCP intoxication. Self-reported PCP use, report by bystanders or Emergency Medical Services (EMS) staff, was used in this process. A structured data collection form was completed, documenting both clinical and behavioral events observed by the treating team during the ED visit.

Results

We collected data on 219 patients; 184 were analyzed; two patients were excluded secondary to incomplete data. The mean age of patients was 32.5 years (±7 years) with 65.2 % being males. PCP use was self-reported by 60.3 % of patients. Of the 184 patients, 153 (83.1 %) received a urine drug screen (UDS); 152 (98.7 %) were positive for PCP. On arrival, 78.3 % of patients were awake and alert, and 51.6 % were oriented to self, time/date, and place. Mean physiological parameters were the following: heart rate 101.1 bpm (±24.3), RR 18.9 bpm (±3.4), BP 146.3 (±19.4)/86.3 (±14.0) mmHg, 36.9° C (±0.5), and pulse oximetry 98.2 % (±1.9). Clinical findings were the following: retrograde amnesia in 46 (25 %), horizontal nystagmus in 118 (64.1 %), vertical nystagmus in 90 (48.9 %), hypertension in 87 (47.3 %), and agitation in 71 (38.6 %). Concomitant use of at least one other substance was reported by 99 (53.8 %) patients. The mean length of stay in the ED for all subjects was 261.1 (±172.8) minutes. Final disposition for 152 (82.6 %) patients was to home. Of the 184 patients, 14 (7.6 %) required admission; 12 were referred to Crisis Response Center.

Conclusion

Patients with PCP intoxication tended to be young males. The prevalent clinical signs and symptoms were the following: retrograde amnesia, nystagmus, hypertension, and psychomotor agitation. Co-use of other substances was the norm. Most patients presenting to the ED with PCP intoxication do well and can be discharged home after a period of observation.     

Parathion and diisopropylfluorophosphate (DFP) toxicity in partially hepatectomized rats

The toxic effects of parathion and DFP in male rats either increased or remained unchanged after partial hepatectomy. LD₅₀ values and blood cholinesterase activities were used as indices of toxicity. These results suggest that parathion toxicity is most likely not due to hepatic conversion of parathion to paraoxon.