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1.
J Appl Toxicol ; 21(6): 475-7, 2001.
Article in English | MEDLINE | ID: mdl-11746194

ABSTRACT

A mild and transitory increase in L-lactic acid (LAC) levels can be achieved by LAC infusion under normoxic/normocapnic/normohydrogenaemic conditions. This increase is probably sufficient to confer some protection to cholinesterases from inhibition by organophosphates.


Subject(s)
Lactic Acid/pharmacokinetics , Oxygen/blood , Swine, Miniature/physiology , Animals , Area Under Curve , Carbon Dioxide/blood , Cholinesterase Inhibitors/adverse effects , Hydrogen/blood , Infusions, Intravenous , Kinetics , Lactic Acid/administration & dosage , Swine
2.
J Appl Toxicol ; 21(4): 263-8, 2001.
Article in English | MEDLINE | ID: mdl-11481657

ABSTRACT

Organophosphorus compounds are inhibitors of serine hydrolases. Some of these compounds produce, in addition to their high acute toxicity, a more persistent effect: organophosphate-induced delayed neuropathy (OPIDN). The putative molecular entity whose inhibition is thought to be responsible for OPIDN is the neuropathy target esterase (NTE). Although in vitro NTE is resistant to paraoxon (PX), occasional case reports have associated PX with OPIDN. To assess clinically whether or not high-dose i.v. PX causes OPIDN in mini pigs, 14 mini pigs were anaesthesized, intubated and mechanically ventilated. In a first set of experiments eight pigs received 1 mg PX kg(-1) body weight (BW) dissolved in alcohol. Two control animals received alcohol in a corresponding amount. After infusion of PX, survival of the animals during the acute phase of intoxication was achieved by intensive-care support, using appropriate drugs and fluids according to a pre-established protocol. The mini pigs were extubated 1036 +/- 363 min later (mean +/- SD). The pigs were observed prior to PX application and for 6 weeks thereafter for any abnormalities and/or signs of OPIDN, such as leg weakness, ataxia and paralysis. Observations were graded on a scale for three categories (position, motor deficiency, reaction), with a maximal cumulative score of 9. In a second set of experiments (four additional pigs) larger PX doses were used (3, 9, 27 and 81 mg kg(-1) BW). After recovering from general anaesthesia/surgery, within 2 weeks all animals reached the initial score on the scale. It can be concluded that high-dose i.v. PX exposure does not induce OPIDN in mini pigs during the 6-week observation period.


Subject(s)
Insecticides/toxicity , Paraoxon/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/therapy , Animals , Ataxia/chemically induced , Ataxia/therapy , Biomarkers , Carboxylesterase , Carboxylic Ester Hydrolases/antagonists & inhibitors , Carboxylic Ester Hydrolases/metabolism , Female , Follow-Up Studies , Hypoxia/prevention & control , Infusions, Intravenous , Male , Paralysis/chemically induced , Paralysis/therapy , Paraoxon/administration & dosage , Peripheral Nervous System Diseases/enzymology , Reaction Time/drug effects , Swine , Swine, Miniature , Time Factors
3.
J Toxicol Clin Toxicol ; 39(1): 27-31, 2001.
Article in English | MEDLINE | ID: mdl-11327223

ABSTRACT

INTRODUCTION: Intoxications with organophosphorous compounds, especially paraoxon, are frequent. Organophosphorous compounds inhibit serine hydrolases such as acetylcholine, butyrilcholine, and carboxyl esterases although acetylcholine and butyrylcholine are too sensitive to paraoxon to be useful markers of severity. They cannot show a dose-dependent inhibition during an acute organophosphorous compounds exposure because maximal enzyme inhibition is reached at very low organophosphorous compounds concentrations. PURPOSE: To determine in vitro the dose-effect relationship between the activity of the paraoxon-sensitive phenylvalerate hydrolase, a member of the carboxvl esterases family, and the paraoxon dose, and to assess its utility as a putatively less sensitive enzyme marker to monitor the severity of an acute paraoxon intoxication. MATERIALS AND METHODS: Phenylvalerate hydrolase and butyrylcholine activities were determined in serum of nine healthy human volunteers before and after addition of different concentrations of paraoxon. The determination of phenyl-valerate hydrolase activity was carried out using a modification of the method described by Johnson. A commercially available kit was used to measure butyrylcholine activity. RESULTS: Paraoxon inhibits phenyl-valerate hydrolase activity at concentrations above 10 M. Maximal inhibition (approximately 50% of baseline) is achieved at concentrations above 2.5 x 10(-7) M. The IC50 value of paraoxon for phenyl-valerate hydrolase is 34+/-2 nM. The uninhibited phenyl-valerate hydrolase activity is due to paraoxon-resistent isoforms. Paraoxon begins inhibiting butyrylcholine activity at concentrations above 10(-9) M. At concentrations above 5 x 10(-5) M, no butyrylcholine activity is measulrable. The IC50 value of paraoxon for butyrylcholine is 150+/-23 nM. CONCLUSION: The paraoxon-sensitive subunit of phenyl-valerate hydrolase shows dose-dependent inhibition when exposed to paraoxon in vitro, but it is even more sensitive than butyrylcholine to paraoxon inhibition. Determinations of phenyl-valerate hydrolase activity to assess the severity of an acute organophosphorous compounds poisoning cannot be recommended, but phenyl-valerate hydrolase may have utility in worker surveillance.


Subject(s)
Carboxylic Ester Hydrolases/antagonists & inhibitors , Choline/analogs & derivatives , Choline/antagonists & inhibitors , Insecticides/poisoning , Paraoxon/poisoning , Biomarkers , Carboxylic Ester Hydrolases/blood , Choline/blood , Dose-Response Relationship, Drug , Female , Humans , Male
4.
J Appl Toxicol ; 21(1): 7-13, 2001.
Article in English | MEDLINE | ID: mdl-11180275

ABSTRACT

Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Although oximes are the only enzyme reactivators presently available, clinical experience with their use was rather disappointing. Recent work has shown that under certain conditions l-lactate is also able to reduce in vitro the POX inhibition of butyrylcholine- and acetylcholineesterase (BChE and AChE). To assess the practical relevance, if any, of these findings, the protective effects of pralidoxime (PRX) and those of lactate had to be compared in the same in vitro model. Effects of PRX on the inhibition of AChE by POX were assessed in vitro in plasma of 12 (six male and six female) healthy human volunteers. The determinations were repeated using different oxime and different POX concentrations. The AChE activity determinations were performed using the following sampler: sample BL-baseline (or untreated plasma); sample a-after addition of POX to plasma (pl + POX); sample b-after POX and plasma were incubated and then oxime was added (pl + POX/PRX); sample c-after addition of oxime to plasma (pl + PRX); sample d-after oxime and plasma were incubated and then POX was added (pl + PRX/POX); sample e-after oxime and POX were incubated and then added to plasma (PRX + POX/pl). Results were corrected for spurious enzyme 'pseudo-activity' due to interaction between PRX and substrate (acetylthiocholine) in the absence of enzyme. In the micro- and millimolar ranges, PRX is able to protect in vitro AChE from inhibition by POX when added to human plasma prior to POX or when incubated with POX prior to addition to plasma. Adding PRX to plasma after POX has no protective effect. The PRX results were compared statistically with historical lactate data (obtained under identical conditions) using the Wilcoxon matched pairs test, with significance assumed for p = 0.01. No difference between PRX and lactate's protective effect on the AChE inhibition by POX was found in the in vitro model used. We therefore conclude that in vivo testing of lactate as a POX protective agent is warranted.


Subject(s)
Acetylcholinesterase/drug effects , Cholinesterase Inhibitors/pharmacology , Lactic Acid/pharmacology , Paraoxon/pharmacology , Pralidoxime Compounds/pharmacology , Acetylcholinesterase/metabolism , Drug Interactions , Female , Humans , In Vitro Techniques , Male
5.
J Appl Toxicol ; 20(4): 249-57, 2000.
Article in English | MEDLINE | ID: mdl-10942900

ABSTRACT

Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Oximes are the only enzyme reactivators clinically available. Recent work has shown that lactate is able to reduce in vitro the POX effects on butyrylcholinesterase (BChE). Most of the acute clinical symptoms, however, are caused by inhibition of acetylcholinesterase (AChE). Effects of lactate on the inhibition of AChE by POX were assessed in vitro in plasma of 12 (six male, six female) healthy human volunteers. The determinations were repeated using different lactate and different POX concentrations. The AChE activity determinations were performed in the following settings: (BL) baseline (untreated plasma); (a) after addition of POX to plasma (pl + POX); (b) after POX and plasma were incubated and then lactate was added (pl + POX/lact); (c) after addition of lactate to plasma (pl + lact); (d) after lactate and plasma were incubated and then POX was added (pl + lact/POX); (e) after lactate and POX were incubated and then added to plasma (lact + POX/pl). In the micro- and millimolar ranges, lactate is able to protect in vitro AChE from inhibition by POX when added to human plasma prior to POX or when incubated with POX prior to addition to plasma. Lactate added to plasma after POX has no protective effect. In a second set of experiments, the effect of lactate on AChE activity was determined. At high millimolar concentrations, lactate itself inhibits AChE non-competitively (mixed inhibition) to an extent comparable to POX (inhibition constant K(I) = 254 mM).


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Lactic Acid/pharmacology , Paraoxon/pharmacology , Cholinesterase Inhibitors/administration & dosage , Drug Interactions , Female , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Kinetics , Lactic Acid/administration & dosage , Male , Paraoxon/administration & dosage , Substrate Specificity
6.
J Clin Gastroenterol ; 30(3): 321-4, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10777198

ABSTRACT

The efficacy of cisapride, omeprazole, and baclofen (COB) for treatment of idiopathic chronic hiccup (ICH). was proven in several studies. The combination is considered, at present, to be "therapy of choice" for this condition. Substituting gabapentin for baclofen in baclofen resistant ICH cases can occasionally be successful. We present here cases where gabapentin was used successfully in combination with cisapride and omeprazole (COG/one patient) or as an "add-on" with cisapride, omeprazole, and baclofen (COBG/three patients). We conclude that, with baclofen and gabapentin, we are in possession of two substances that are, as a part of a combination therapy, quite effective for ICH. Because of the far more extensive experience with baclofen, we use it as a first-line therapy, together with omeprazole and cisapride. In cases where the results are not entirely satisfactory, the addition of gabapentin should be considered.


Subject(s)
Acetates/administration & dosage , Amines , Baclofen/administration & dosage , Cisapride/administration & dosage , Cyclohexanecarboxylic Acids , Gastrointestinal Agents/administration & dosage , Hiccup/drug therapy , Omeprazole/administration & dosage , gamma-Aminobutyric Acid , Aged , Chronic Disease , Drug Administration Schedule , Drug Therapy, Combination , Follow-Up Studies , Gabapentin , Hiccup/diagnosis , Humans , Male , Middle Aged , Muscle Relaxants, Central/administration & dosage , Treatment Outcome
7.
Am J Emerg Med ; 18(1): 22-7, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10674526

ABSTRACT

We will examine the correlation between various bee venom phospholipase A2 (PLA2) concentrations and several parameters of coagulation in human plasma in order to offer a rationale for requesting a particular laboratory coagulation test after bee sting(s). We will also evaluate in vitro the influence of clinically available drugs with a noncompetitive inhibitory effect on PLA2 on the anticoagulant effect of bee venom PLA2. Prothrombin index (PTi), partial thromboplastin time (PTT), antithrombin III (AT III), soluble fibrin monomers (SFM), the activity of coagulation factors I, II, V, and VIII, and thrombelastography (TEG) parameters (split point [Sp], reaction time [R], kinetic time [K], coagulation time [R + K], maximal amplitude [MA], and the growth angle [alpha]) were determined before and after addition of 1.4, 2.7, and 4.1 units (1, 2, and 3 microg protein respectively) of bee venom PLA2. Linear regression was used to determine the significance of the relationship between these coagulation parameters and bee venom PLA2 concentrations used. To study the influence of ketamine, lidocaine, magnesium, furosemide, and cromolyn on the anticoagulant effect of bee venom PLA2, PTi and factor II- and V-activities were measured before and after addition of 2.7 units of PLA2 and PLA2 plus one of the tested substances. Determinations of F II, PTi, F V, and F VIII showed a negative correlation to bee venom PLA2 concentration (r = -0.88, -0.86, -0.81, and -0.79 respectively). A positive correlation was found for PTT (r = 0.69). FII- activity and PTi correlated better with bee venom PLA2 concentration than other parameters. F I, AT III, and SFM showed no changes. Whereas Sp, R, and K were prolonged by bee venom PLA2 and a was reduced, there was no correlation to the PLA2 concentration. Addition of none of the 5 substances could correct the effects of bee venom PLA2 on the coagulation. In a patient with toxic reaction or a severe anaphylactic reaction after bee sting(s) we suggest determinations of FII and/or PTi. This will allow a quick and economical assessment of coagulation abnormalities after bee sting(s). Noncompetitive PLA2-inhibitors (ketamine, lidocaine, magnesium, furosemide, and cromolyn) are unable to correct in vitro the anticoagulant effect of bee venom PLA2. They cannot be recommended at this stage for this purpose. Further investigations with competitive PLA2-inhibitors are warranted.


Subject(s)
Bee Venoms/enzymology , Bees , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Blood Coagulation Tests/methods , Insect Bites and Stings/complications , Phospholipases A/adverse effects , Animals , Antithrombin III/metabolism , Bee Venoms/chemistry , Cromolyn Sodium/pharmacology , Drug Evaluation, Preclinical , Factor V/metabolism , Factor VIII/metabolism , Female , Fibrinogen/metabolism , Furosemide/pharmacology , Humans , Ketamine/pharmacology , Lidocaine/pharmacology , Linear Models , Magnesium/pharmacology , Male , Phospholipases A/analysis , Phospholipases A/antagonists & inhibitors , Phospholipases A/drug effects , Phospholipases A2 , Prothrombin/metabolism
8.
J Appl Toxicol ; 19(5): 329-36, 1999.
Article in English | MEDLINE | ID: mdl-10513677

ABSTRACT

Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Oximes are the only enzyme reactivators clinically available. Serendipitous observation led us to the hypothesis that lactate might attenuate some of the POX effects. In vitro effects of lactate on the inhibition of butyrylcholinesterase (BChE) by POX were assessed in plasma of 12 healthy human volunteers. The determinations were repeated using different lactate and different POX concentrations. The BChE activity determinations were performed in the following settings: (i) baseline untreated plasma (BL); (ii) after addition of POX to plasma (pl+POX); (iii) after POX and plasma were incubated and then lactate was added (pl+POX/lact); (iv) after addition of lactate to plasma (pl+lact); (v) after lactate and plasma were incubated and then POX was added (pl+lact/POX); (vi) after lactate and POX were incubated and then added to plasma (lact+POX/pl). In the micro- and millimolar ranges, lactate is able to abolish in vitro the inhibition of BChE by POX in human plasma when added to plasma prior to POX or when incubated with POX prior to addition to plasma. Lactate added to plasma after POX has no protective effect. In a second set of experiments, the effect of lactate on BChE activity was determined. At high millimolar concentrations, lactate itself inhibits BChE to an extent comparable to POX. Lactate is a mixed inhibitor of BChE, being able to interfere with the enzyme-substrate complex (inhibition constant for the enzyme-inhibitor-substrate complex K'I(EIS) = 81 mM) and the enzyme (inhibition constant for the enzyme-inhibitor complex K(I) (EI) = 26 mM).


Subject(s)
Butyrylcholinesterase/drug effects , Cholinesterase Inhibitors/pharmacology , Lactic Acid/pharmacology , Paraoxon/pharmacology , Butyrylcholinesterase/metabolism , Dose-Response Relationship, Drug , Humans , Kinetics , Substrate Specificity
9.
Chem Biol Interact ; 119-120: 489-95, 1999 May 14.
Article in English | MEDLINE | ID: mdl-10421487

ABSTRACT

The in vivo effects of the organophosphorus compound (OPC) paraoxon (POX) on blood coagulation of mini pigs were assessed by measuring the partial thromboplastin time (PTT), prothrombin time (PT), fibrinogen, factor V, factor VII, factor VIII, antithrombin III, protein C, and platelet count. The mini pigs were randomly assigned to a POX-treatment group (n = 9) receiving 54 mg POX kg(-1) BW(-1) or the control group (n = 9). Measurements were carried out over a period of 150 min after poisoning. The exposure to POX did not have any influence on measurements of PT, factor VIII, factor VII, factor V, antithrombin III, protein C, or fibrinogen compared to the control group evaluated by rank order test (ROT) during the time of observation (150 min). Changes seen in the intrinsic coagulation followed a biphasic pattern corresponding to an early sympathomimetic phase with PTT-shortening and a decrease of the platelet count, and a late vagal phase, with PTT-prolongation. The hypercoagulability seen in the sympathomimetic phase is probably due to a massive release of catecholamines from the adrenals. Previous studies showed in vitro no coagulation activating effect of POX. The hypocoagulability in the vagal phase shown by the PTT-protongation is probably due to POX influencing platelet function or its inhibition of clotting factors, which are serine proteases, or a combination of the two.


Subject(s)
Blood Coagulation/drug effects , Cholinesterase Inhibitors/toxicity , Paraoxon/toxicity , Animals , Antithrombin III/analysis , Cholinesterase Inhibitors/blood , Factor V/analysis , Factor VIII/analysis , Fibrinogen/analysis , Injections, Intravenous , Paraoxon/blood , Partial Thromboplastin Time , Platelet Count/drug effects , Protein C/analysis , Prothrombin Time , Swine , Swine, Miniature
10.
Chem Biol Interact ; 119-120: 497-502, 1999 May 14.
Article in English | MEDLINE | ID: mdl-10421488

ABSTRACT

The purpose of the present study was to establish in the mini pig model the effects of paraoxon (POX) on PLA2 activity. Six anesthetized and mechanically ventilated mini pigs were infused over 50 min with 0.3, 1, 3, 9, 27 and 81 mg POX kg(-1) BW(-1) dissolved in ethanol, respectively. The control animal received no POX but the ethanol amount corresponding to the highest POX dose. PLA2 activity measurements were carried out immediately after POX application. Data were analysed with the Mann Whitney-Wilcoxon rank order test. Statistical significance was assumed for P < or = 0.05. Exposure to POX inhibited PLA2 activity to 50.5 +/- 8.9% of baseline activity. The changes seen were not dose-dependent. The dose dependency previously demonstrated in vitro was not reproducible in vivo. This is most probably due to the massive endogenous catecholamine release leading to PLA2 activation. An additional masking effect is due to the (co)administration of drugs needed for anesthesia and cardiovascular support, especially Mg2+. These substances also influence the PLA2 activity.


Subject(s)
Cholinesterase Inhibitors/toxicity , Paraoxon/toxicity , Phospholipases A/antagonists & inhibitors , Adrenal Glands/metabolism , Animals , Blood Platelets/enzymology , Catecholamines/metabolism , Dose-Response Relationship, Drug , Enzyme Activation , Ethanol/pharmacology , Infusions, Intravenous , Pharmaceutical Vehicles/pharmacology , Phospholipases A/blood , Phospholipases A2 , Reproducibility of Results , Swine , Swine, Miniature
11.
Crit Care Med ; 27(2): 348-55, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10075060

ABSTRACT

OBJECTIVE: A hallmark of amniotic fluid embolism is the induction of coagulation defects. Little is known about the nature of these defects or the causative agent or agents. The purpose of this study was to assess the effects of meconium containing (native) meconium-amniotic-fluid infusion (MAFI) and meconium-free (centrifuged) amniotic-fluid infusion (AFI) on the coagulation system in the mini-pig model. DESIGN: Laboratory study. SETTING: University institute animal laboratory. SUBJECTS: Near-term pregnant Göttingen bred mini-pigs in three groups (control, MAFI, AFI) of six animals each. INTERVENTIONS: After induction of anesthesia, amniotic fluid was collected by cesarean section in all animals. Depending on the group, animals received either Ringer's solution (control), native amniotic fluid (MAFI), or centrifuged amniotic fluid (AFI) via an ear vein. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken from a central vein before infusion (baseline), immediately after infusion, every 10 mins until 90 mins after infusion, and finally, every 20 mins until 150 mins after infusion. The following parameters were measured: Platelets, partial thromboplastin time, prothrombin time, fibrinogen, factors V, VII, VIII, antithrombin III, and protein C. The values relative to baseline in the MAFI and AFI groups were compared with control by rank order test. A p<.05 was considered statistically significant. Compared with the control group, platelets were lower in the MAFI group (p<.005), PTT was prolonged in both the MAFI and AFI groups (p<.005), fibrinogen was lower in both the MAFI and AFI groups (p<.05), prothrombin index was lower (i.e., prothrombin time was prolonged) in the MAFI group (p<.05), and protein C was lower in the MAFI group (p<.005). CONCLUSIONS: Both MAFI and, to a much lesser extent, AFI cause an activation of coagulation in mini-pigs. The changes induced by meconium-free AFI are probably not sufficient to explain the high mortality of the condition.


Subject(s)
Blood Coagulation/physiology , Embolism, Amniotic Fluid/blood , Meconium , Amniotic Fluid , Animals , Blood Coagulation Tests/statistics & numerical data , Disease Models, Animal , Embolism, Amniotic Fluid/etiology , Female , Pregnancy , Statistics, Nonparametric , Swine , Swine, Miniature , Time Factors
12.
Acta Otolaryngol ; 118(6): 803-7, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9870623

ABSTRACT

We examined the influence of an experimental venous and arterial air embolism on the hearing level in laboratory mini pigs. Before and after the injection of air a threshold ABR was measured in anaesthetized mini pigs (n=15). A venous air embolism was performed in 6 animals: no changes in the hearing level or in the interpeak latencies Jewett wave V-I were observed in any of the animals before, during or after the application of air. In 9 animals the arterial embolism was done, 2 animals died and had to be excluded. In 6 animals out of 7 a hearing loss was observed starting after the injection of 40 ml air and finally ending in deafness for these 6 animals. The detected hearing loss is probably of cochlear origin, as no prolongations of the interpeak latencies of Jewett wave V-I at 90 dB HL were observed prior to the deafness. Our results show that air bubbles in the arterial circulation lead to cochlear damage ending in deafness. Our research indicates that decompression sickness, which is comparable to the arterial air embolism, is more often the cause of a sensorineural hearing loss after diving than previously believed.


Subject(s)
Embolism, Air/complications , Hearing Disorders/etiology , Hearing/physiology , Animals , Audiometry, Evoked Response , Blood Pressure/physiology , Brain Stem , Carotid Artery, Common , Cochlear Diseases/etiology , Deafness/etiology , Decompression Sickness/complications , Evoked Potentials, Auditory, Brain Stem/physiology , Hearing Loss, Sensorineural/etiology , Intracranial Embolism and Thrombosis/complications , Jugular Veins , Labyrinth Diseases/complications , Oxygen/blood , Reaction Time/physiology , Swine , Swine, Miniature
13.
Am J Emerg Med ; 16(7): 677-80, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9827747

ABSTRACT

The performance of a new colorimetric CO2-indicator (Colibri) was assessed in mini-pigs. It performed well during 8-hour procedures. Neither nitrous oxide, nor halothane, nor carbon monoxide, nor intratracheal application of drugs (epinephrine, atropine, lidocaine, and naloxone) interfered with its function. It gave a distinct color change at high ventilation frequencies up to 120/min. The only problem observed was difficulty in matching the colors displayed with the comparison color chart provided. The Colibri's performance seems at least equal to that of the EasyCAP detector, although both devices share some disadvantages (no alarms, semiquantitative, difficult reading in the dark). After initial control of endotracheal tube position by an esophageal detector device, both the Colibri and the EasyCAP seem suited for monitoring of ventilation and circulation if quantitative capnometry is unavailable.


Subject(s)
Carbon Dioxide/analysis , Colorimetry/instrumentation , Animals , Capnography , Female , Intubation, Intratracheal , Pregnancy , Swine , Swine, Miniature
14.
Z Gastroenterol ; 36(7): 559-66, 1998 Jul.
Article in German | MEDLINE | ID: mdl-9738303

ABSTRACT

Idiopathic chronic singultus (ICS) describes recurring episodes of persistent hiccuping lasting longer than an arbitrary time limit (e.g. one month) for which no organic cause or consistently effective treatment can be found. It has been suggested that ICS may result from chronic stimulation of a supraspinal "hiccup center" by impulses originating from receptors in the gastrointestinaltract. This hypotesis implies the possibility of treating ICS by reducing gastric acid (via omeprazole), facilitating gastric emptying (via cisapride), or suppressing of the "hiccup centre" (via GABA-ergic offects of baclofen or gabapentin). 29 patients (28 male, one female; age 71 +/- 10 years) suffering from ICS for four to 564 months were treated with a combination of cisapride (30 mg/d), omeprazole (20 mg/d) and baclofen (45 mg/d) (COB). The patients rated the severity of hiccuping on a subjective assessment scale (SAS) that ranged from 0 (= no hiccuping) to 10 (= unbearable hiccuping). Hiccuping ceased in 38% (11/29) of the treated patients and decreased in severity in an additional 24% (7/29). Mean SAS-scores following 20 to 24 weeks of therapy (3.7 +/- 3.4) were significantly lower compared to before therapy (8.8 +/- 1.3) (Mann-Whitney rank order test [p < 0.02]). In the patients that failed to respond to COB, gabapentin (1.200 mg/d) was substituted for baclofen. Hiccuping ceased in one and improved in two of these ten subjects. We conclude that COB is an effective empirical therapy in the majority of patients with ICS. It may be useful to substitute gabapentin for baclofen in those not responding to COB.


Subject(s)
Amines , Cyclohexanecarboxylic Acids , Gastrointestinal Agents/administration & dosage , Hiccup/drug therapy , gamma-Aminobutyric Acid , Acetates/administration & dosage , Acetates/adverse effects , Aged , Aged, 80 and over , Baclofen/administration & dosage , Baclofen/adverse effects , Chronic Disease , Cisapride/administration & dosage , Cisapride/adverse effects , Drug Therapy, Combination , Female , Gabapentin , Gastrointestinal Agents/adverse effects , Hiccup/etiology , Humans , Male , Middle Aged , Omeprazole/administration & dosage , Omeprazole/adverse effects , Treatment Outcome
15.
J Appl Toxicol ; 18(4): 293-8, 1998.
Article in English | MEDLINE | ID: mdl-9719430

ABSTRACT

A therapeutic regimen was established to keep blood pressure, heart rate and haematocrit within the normal range during high-dose paraoxon (PX) exposure (ca. 150 x LD50) in mini pigs in order to achieve survival. Previous experiments showed that mini pigs exposed to high-dose PX died shortly after PX infusion due to hypertension, tachycardia and increased haematocrit if no antihypertensive and fluid therapy was initiated. Therefore, antihypertensive and fluid therapy with magnesium (MgSO4) and Ringer's solution was established to keep the blood pressure, heart rate and haematocrit within a pre-established normal range. Anaesthesized mini pigs received intravenously PX (54 mg kg(-1) body wt.) dissolved in alcohol. The control group received alcohol in corresponding amounts. When the blood pressure and heart rate increased, MgSO4 was given intravenously until measured values reached the normal range. When the haematocrit increased, fluids were given intravenously until the haematocrit reached the normal range. The measured values in the PX group were compared with the measured values of the control group using the 'rank order test'. As intended, no statistically significant differences between blood pressure, heart rate or haematocrit were found after therapy, but the PX group required statistically significantly more MgSO4 and fluids than the control group to keep the blood pressure, heart rate and haematocrit within the normal range. We assume that the increased need of antihypertensive therapy is due to a phaeochromocytoma-like pattern caused by an excessive release of catecholamines from the adrenal medulla, which is under sympathotonic control and activated by acetylcholine. Paraoxon is known to cause endogenous acetylcholine poisoning. The high fluid requirements in the PX group are most probably caused by extravasation of fluids due to the damage inflicted on biological membranes by organophosphorus compounds. An activation of secretory glands probably also contributes to the increase in haematocrit through consumption of fluids. In conclusion, the survival of mini pigs exposed to high-dose PX can be achieved by tight control of blood pressure, heart rate and haematocrit using MgSO4 and fluids.


Subject(s)
Blood Pressure/drug effects , Heart Rate/drug effects , Organophosphate Poisoning , Paraoxon/poisoning , Toxicity Tests , Animals , Antihypertensive Agents/therapeutic use , Cholinesterases/blood , Fluid Therapy , Hematocrit , Hypertension/prevention & control , Injections, Intravenous , Isotonic Solutions/therapeutic use , Magnesium Sulfate/therapeutic use , Organophosphorus Compounds/administration & dosage , Paraoxon/administration & dosage , Random Allocation , Ringer's Solution , Swine , Swine, Miniature , Tachycardia/prevention & control
16.
Am J Emerg Med ; 16(4): 399-400, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9672462

ABSTRACT

A new portable quantitative capnometer (Bruker CO2 Module) was tested in an animal lab (mini-pigs) during experiments on air embolism. The end-tidal CO2 values, as measured with this device, showed good agreement with the values of a stationary capnography unit. This device seems suited for quantitative capnometry in the prehospital setting.


Subject(s)
Capnography/instrumentation , Carbon Dioxide/metabolism , Embolism, Air/diagnosis , Tidal Volume , Animals , Disease Models, Animal , Embolism, Air/metabolism , Point-of-Care Systems , Reproducibility of Results , Swine , Swine, Miniature
17.
Toxicology ; 119(2): 167-73, 1997 Apr 30.
Article in English | MEDLINE | ID: mdl-9128188

ABSTRACT

The in vitro effects of the organophosphorus compound (OPC) paraoxon (POX) on human blood coagulation were assessed by fibrin monomer (FM) concentration measurements and thrombelastographic (TEG) determinations. Increasing doses of POX dissolved in alcohol (POX + ALO) or alcohol (ALO) only in corresponding quantities were added to blood drawn from six human volunteers. In both series (POX + ALO and ALO-only) FM concentrations increased in comparison to the baseline levels. No statistically significant differences exist, however, between FM measurements performed on blood with POX + ALO and those performed on blood with ALO-only. No coagulation-activating effect of POX in vitro was demonstrable; the changes seen in vitro are due to the ALO used as a vehicle. The thrombelastographic parameters showed several changes in the POX + ALO series as dosage increased. At high POX levels, reaction time r and clot formation time k became longer than in the baseline measurements, the clot formation rate alpha and the maximum amplitude MA were reduced. The TEG changes indicate a hypocoagulable state, probably due to the POX effect on platelet function and/or inhibition of clotting factors (serine proteases).


Subject(s)
Blood Coagulation/drug effects , Fibrin Fibrinogen Degradation Products/analysis , Insecticides/toxicity , Paraoxon/toxicity , Thrombelastography/methods , Humans , In Vitro Techniques
18.
Prehosp Disaster Med ; 12(2): 149-53, 1997.
Article in English | MEDLINE | ID: mdl-10187000

ABSTRACT

This study compares the performance of two commercially available devices (Ambu TubeChek and SCOTI) in establishing endotracheal (ET) tube position (oesophageal vs. tracheal) in a mannequin and in miniature pigs. The Ambu TubeChek is a syringe-type, Oesophageal Detector Device (ODD) that fits to the endotracheal tube connector. Air is aspirated easily from the rigid trachea, but not from the collapsing esophagus. The Sonomatic Confirmation of Tracheal Intubation device (SCOTI) is a lightweight battery-powered, sonomatic device. It emits sound waves into the tube and analyzes the reflection. The SCOTI purports to enable a user-independent and carbon-dioxide-independent assessment of tube position following intubation. Intubation followed by tube position assessment with Ambu TubeChek (ODD) was significantly faster and easier with the ODD than with the SCOTI. The SCOTI cannot differentiate tracheal from oesophageal ET-tube position in mini-pigs. In situations in which capnometry is not available or the CO2 production and transport are compromised (CPR), we recommend the use of an Oesophageal Detector Device (ODD) rather than the SOCTI.


Subject(s)
Intubation, Intratracheal/instrumentation , Animals , Disease Models, Animal , Equipment Design , Equipment Safety , Female , Intubation, Intratracheal/methods , Sensitivity and Specificity , Swine , Swine, Miniature
19.
Arch Toxicol ; 71(3): 187-92, 1997.
Article in English | MEDLINE | ID: mdl-9049056

ABSTRACT

This study examined the maternal and fetal blood kinetics of lead in pregnant, near term mini-pigs. A lead dose of 1 mg/kg was administered to the animals by i.v. injection as bolus. During the 5-h sampling period, the two-compartment maternal pharmacokinetics demonstrated a rapid phase T1/2 of 8 min and a slower phase T1/2 of 199 min. Lead reached the fetus with a time lag of 81 min. At 24 h after administration the ratio of fetal to maternal blood lead concentration seemed to become stable. When lead was injected directly into the fetal blood circulation, the decay of fetal blood lead fitted one-compartment model. The disappearance half-life was 92 min. Lead can obviously accumulate in fetal liver; the lead level in fetal brain showed no detectable changes. This study confirmed that lead can also pass through the epitheliochorial placenta.


Subject(s)
Lead/pharmacokinetics , Maternal-Fetal Exchange/physiology , Placenta/metabolism , Pregnancy, Animal/metabolism , Animals , Area Under Curve , Female , Half-Life , Lead/blood , Models, Biological , Pregnancy , Pregnancy, Animal/blood , Swine , Swine, Miniature
20.
Clin Ther ; 19(5): 1031-8, 1997.
Article in English | MEDLINE | ID: mdl-9385490

ABSTRACT

Idiopathic chronic hiccup (ICH) is defined as recurring hiccup attacks that last for longer than an arbitrary time limit (eg, 1 month) and for which no organic cause can be found. In patients with ICH, therapy is largely empiric. For practical purposes, idiopathic hiccup can be assumed to have its origin either in the viscera (gastrointestinal tract) or in the central nervous system. Cisapride and omeprazole--through reduction of gastric acid production and facilitation of gastric emptying, respectively--are thought to reduce an assumed afferent input from the periphery to a putative supraspinal hiccup center. Baclofen is thought to reduce excitability and depress reflex hiccup activity. Fifteen male patients (mean [+/- SD] age, 68.2 +/- 11.6 years) who had recurring hiccup attacks for a mean duration of 100.8 +/- 134.1 months (range, 12 to 564 months) were treated for ICH with a combination of cisapride, omeprazole, and baclofen (COB). Therapy led to a total disappearance of hiccup in 40% (6 of 15) of the treated patients. An additional 20% (3 of 15) of patients experienced substantial relief. A Mann-Whitney rank order test showed a highly significant reduction in the severity of the hiccup attacks as reflected in the subjective assessment scale scores taken before therapy (8.6 +/- 1.3) compared with those taken after 20 weeks of therapy (4.1 +/- 3.8). Thus we concluded that COB is an effective empiric therapy in at least some patients with ICH.


Subject(s)
Baclofen/therapeutic use , GABA Agonists/therapeutic use , Hiccup/drug therapy , Omeprazole/therapeutic use , Piperidines/therapeutic use , Serotonin Receptor Agonists/therapeutic use , Adult , Aged , Aged, 80 and over , Cisapride , Drug Therapy, Combination , Humans , Male , Middle Aged , Self-Assessment
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