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PubMed1970

Effects of drugs acting alone and in combination on the motor activity of intact mice.

1. When administered to intact white mice, the central depressants-diphenhydramine, promethazine, chlorpromazine, gammahydroxybutyrate, gammabutyrolactone, hyoscine, and pethidine-produced sedation in small doses, but excitement and convulsions in higher doses. When given to mice pretreated with subanaesthetic doses of phenobarbitone these drugs abolished the righting reflex both in convulsant doses (hyoscine excepted) and in non-convulsant doses. These effects are similar to the effects previously observed with local anaesthetics.2. Meprobamate, diazepam and chlorpromazine produced a loss of righting reflex both when given alone and following phenobarbitone. When given alone in higher doses, chlorpromazine induced convulsions.3. The central stimulants bemegride and picrotoxin antagonized the loss of righting reflex produced by phenobarbitone, but nikethamide, caffeine and strychnine did not alter the depressant effects of phenobarbitone.4. On the basis of these and previous studies with intact white mice a tentative classification of drugs having generalized depressant and stimulant effects on the central nervous system was proposed and discussed.

Adjuvants, Anesthesia↗

PubMed1975

Haloperidol catalepsy in grouped and isolated mice.

A method was worked out to assess in a quantitative and dose-dependent way the development of catalepsy of mice after low doses of haloperidol. This method was also capable of detecting the anticataleptic effect of phenytoin and the catalepsy-enhancing effect of nikethamide. After 4 weeks' isolation, the mice became aggressive and revealed increased susceptibility to the cataleptic effect of haloperidol. The analysis of the data indicates that in these experiments altered central mechanisms were more important than changes of the peripheral pharmacokinetics of haloperidol.

Animals↗

PubMed1983

Animal studies on the treatment of poisoning by amitraz (a formamidine pesticide) and xylene.

In Charles River CD rats the pesticide MITAC 20 EC (containing amitraz and 75% xylene) given orally at an LD80 dose caused toxicity featuring hypothermia, reduced spontaneous activity, episodes of increased activity and minor signs of general debilitation. Recovery in survivors was complete within about 8 days. Therapies including absorption retardants, diuretics, reduction of urine pH, thermal support and treatment with phentolamine or nikethamide were given to groups showing these signs of poisoning. None of the therapies gave consistent evidence of benefit during acute poisoning in terms of reduced intensity or duration of symptoms or reduced mortality. Comparison with animals given amitraz alone suggested that the hypothermia and the later phase of reduced spontaneous activity were attributable to the pharmacological effects of amitraz. While the product was apparently more acutely toxic by the oral route than xylene alone, the evidence was that xylene caused the early signs of poisoning. This work indicates that any case of poisoning by ingestion of MITAC 20 EC should initially be treated for the xylene exposure. There is no specific therapy or antidote for the subsequent possible pharmacological effects of amitraz. Many other pesticides also contain high proportions of aromatic solvents and the importance of the solvent in cases of ingestion is seen to be applicable to a variety of pesticides as well as MITAC 20 EC.

Ammonium Chloride↗

PubMed1977

Effect of erabutoxin on respiration of rabbits.

The effect of erabutoxin (ETX) was examined on respiration of rabbits. A single dose of 15 microgram/kg or 25 microgram/kg of ETX did not cause respiratory paralysis, but repeated administration of 15 microgram/kg of ETX at 3 hour intervals (three times) or 25 microgram/kg at 4 hour intervals (twice) caused fatal respiratory paralysis. Furthermore, a single administration of 50 microgram/kg of ETX caused fatal respiratory paralysis within 2 hours after the administration in all animals. This respiratory paralysis caused by ETX was reversible and of long duration (10-20 hour). This respiratory paralysis was not blocked by the administration of anticurare agents (neostigmine, edrophonium) or respiratory stimulants (nikethamide, picrotoxin, dimorpholamine). Since ETX had no influence on the circulatory system, death caused by ETX was prevented with application of artificial respiration.

Animals↗

PubMed1977

Quantifying drugs influence on cardio-respiratory synchronism.

The paper concerns the situation in which, for a considerable time, the onset of each respiratory cycle coincides with one and the same section of a cardiac cycle. A standardized procedure is described with which, in anesthetized rabbits, the potentiality of the biological mechanisms responsible for the phenomenon may be quantified. The procedure consists of progressively prolonging the cardiac cycles by selectively cooling the sinus node. Care is taken that during such procedure a situation is passed in which the respiratory cycles are a multiple of the cardiac cycles. The synchronizing kybernetic system, if any, must click in, then. As the prolonging of the cardiac cycles continues, the synchrony will get lost the sooner the weaker the potentialities of the kybernetic system and vice versa. Four drugs are tested as to their potential action on the kybernetic system. Nikethamide and methylphenidate tend to decrease its efficacy, allobarbital and benzoctamine tend to increase it, none of them, however, being conclusively effective.

Animals↗

PubMed1982

[Effects of respiratory drugs on the cough reflex].

In order to understand the relationship between the cough and respiratory centers in the brain stem, we investigated the effects of respiratory stimulants, pentylenetetrazol (PTZ) and nikethamide (NK), and a respiratory depressant, pentobarbital (PB)on the cough reflex. Coughs were induced in lightly anesthetized dogs by intraarterially into the vertebral artery. The rate (RR), amplitude (RA), and volume (RV) of the respiration and the number (NC) and amplitude (AC) of the cough reflex induced were used as indices. PTZ and NK, even at subthreshold doses for respiratory stimulation, enhanced the cough reflex (NC; not AC). On the other hand, PB at subthreshold doses for a respiratory depression decreased both NC and AC. The above findings suggest that respiratory stimulants generally enhance the cough reflex, and respiratory depressants reduce the cough reflex. Additionally, the thresholds for the cough responses to respiratory drugs are lower than those for the respiratory responses.

Animals↗

PubMed1981

[Studies on the reaction of plastics with drug solutions. Part 3: The effects of the pigment content and of the colouring techniques (author's transl)].

The effects of the pigment content and of the colouring technique on stress-cracking are demonstrated by the example of the low-density polyethylene Mirathen A 13 EA. A 99% aqueous nikethamide solution was used as the drug solution. The sorption increased as the pigment content increased, which testifies to a relationship between the amount of the medium sorbed and the pharmaceutical ageing.

Adsorption↗

PubMedDate not supplied

[The action of Essentiale and its combination with cordiamine and vitamin E on the processes of xenobiotic biotransformation and lipid peroxidation and on liver structure in rats with cholestasis].

Intensive regeneration of cholangia and cholangioles, fibrosis, microglobular cirrhosis, vacuolar and granular dystrophy, and necrosis of hepatocytes were found in the liver of rats 36 days after ligation of the common bile duct. Lipid peroxidation was activated, the activity of the mono-oxidase system was inhibited in maintained function of glucuro- and glutathione transferase. Essentiale (per os in starch mucilage, 1 ml/kg. for 35 days) increased the activity of cytosol glutathione-S-transferase and normalized the decreased blood plasma antioxidant activity. Combination of essentiale with cordiamin (nikethamide) and viatmin E (50 mg/kg for 35 days) considerably activated the mono-oxigenase, glucoro- and glutathione transferase systems of the liver: the free-radical processes became less intense. The structure of the liver improves insignificantly in both methods of treatment.

Animals↗

PubMed1989

Sensitivity of pentylenetetrazol discrimination increased by a stimulus fading technique.

The interoceptive stimulus produced by pentylenetetrazol (PTZ) is pharmacologically similar to anxiety and is used in a behavioral assay for anxiety-related stimuli (the PTZ model of anxiety). The stimulus fading technique was tested as a method to increase the sensitivity of this assay. Rats were trained with food-reward to press one lever after injection of PTZ and an alternate lever after saline. Rats initially learned the discrimination at a PTZ dose of 20 mg/kg. They were then trained with sequentially lower doses until they reliably discriminated a PTZ dose of 10 mg/kg. Substitution tests with other doses and drugs showed that, after the fading procedure, dose-response curves were shifted to lower doses for PTZ, Ro 5-3663, and nicotine Similarly, the dose of diazepam required to block the low dose of PTZ was lower than that required to block the higher dose of PTZ. These results indicated that the sensitivity of the discrimination was enhanced in rats trained to discriminate a lower dose of PTZ. Doses of nikethamide, cocaine, and yohimbine that did not substitute for the higher dose of PTZ also did not substitute for the lower dose. These data suggest that rats can be trained to discriminate a low dose of PTZ by the stimulus fading technique. Moreover, they suggest that this training method does not compromise the specificity of the discrimination.

Animals↗

PubMed1978

Halothane-induced sleeping time in the mouse: its modification by benzodiazepines.

The conditions under which prolongation of halothane-induced sleeping time in the mouse may be used as a test for centrally acting drugs are described. The test can be recommended for its practical advantages over methods using barbiturates to induce hypnosis; due cognizance must be taken of a diurnal variation in the response of mice to halothane. To assess the usefulness of the test the effects of amphetamine, chlorpromazine, histamine, morphine, nikethamide, pentobarbitone and SKF 525A have been investigated. The interaction between 5 benzodiazepines and halothane has been studied in particular. Results from sleeping time experiments, measurements of body temperature and of brain halothane concentrations suggest that the halothane-benzodiazepine interaction is due to additive CNS depressant effects. It was found that nitrazepam and diazepam were clearly more potent than chlorodiazepoxide, medazepam and oxazepam in respect of their interactions with halothane.

Animals↗

PubMed1985

Methylphenidate, but not other CNS stimulants, inhibits red blood cell calcium-activated potassium efflux.

The first-order rate constant of net potassium efflux, measured in human red blood cell (RBC) suspensions by means of a K+-sensitive electrode, was increased 26 fold (from 0.0025 min-1 to 0.0656 min-1) by 0.5 microM of the calcium ionophore A 23187. Both the basal or the calcium-stimulated potassium efflux remained unchanged following the addition of different CNS stimulants (nikethamide (1 mM), pentylenetetrazol (1mM), doxapram (1 mM), strychnine (0.1 mM), picrotoxin (0.1 mM), or nomifensine (0.1 mM). Methylphenidate (10-100 microM), however, inhibited in a concentration-dependent manner the calcium-stimulated, but not the basal potassium efflux. An IC50 of 190 microM was estimated for this effect.

Calcium↗

PubMed1989

Drug companies' evidence to justify advertising.

Ten international pharmaceutical companies were asked by letter to supply their best evidence in support of marketing claims for seventeen products. Fifteen replies were received. Seven replies cited a total of 67 references: 31 contained relevant original data and only 13 were controlled trials, all of which had serious methodological flaws. There were four reports of changes in advertising claims and one company ceased marketing nikethamide in the third world. Standards of evidence used to justify advertising claims are inadequate.

Advertising↗

PubMed2003

Confirmation of amphetamine, methamphetamine, MDA and MDMA in urine samples using disk solid-phase extraction and gas chromatography-mass spectrometry after immunoassay screening.

A method using mixed phase disk solid-phase extraction (SPE) and gas chromatography-mass spectrometry (GC-MS) was developed for confirmation of amphetamine (AMP), methamphetamine (MET), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) in urine samples after immunoassay screening. Disk SPE provided hydrophobic (C(18)) and strong cation-exchange (SCX) interactions. The analytes were retained on SCX functional groups in the disk and eluted with ammoniated ethyl acetate after washed with methanol. Confirmation and quantitation was exercised by selected ion monitoring using nikethamide as chromatographic standard. Recoveries of the amphetamines were between 73.0 and 104.6% with RSDs in range of 2.1-6.4% (n=3). The limits of detection were 2 ng/ml for AMP, MET and MDMA, and 4 ng/ml for MDA. Five real urine samples were tested with the method after immunoassay screening, and the results were comparable to those of traditional liquid-liquid extraction (LLE). The method was solvent-saved, simple, rapid and reliable, and the extract was cleaner than that of LLE.

3,4-Methylenedioxyamphetamine↗

PubMed1959

Mechanism of action of reserpine in producing gastric haemorrhage and erosion in the mouse.

Gastric haemorrhage was produced regularly in mice within 6 hours of the subcutaneous injection of a large dose (2 to 10 mg./kg.) of reserpine or of deserpidine. Rescinnamine, syrosingopine (SU-3118), and tetrabenazine (Ro 1-9569) were less active. Gastric haemorrhage was also produced within 6 hours when 5-hydroxytryptamine (10 mg./kg.) was injected every half-hour. Neither reserpine nor 5-hydroxytryptamine produced gastric haemorrhage in mice which had been vagotomized by tying the oesophagus at the cardio-oesophageal junction or which had been pre-treated with iproniazid. Amphetamine was less effective than iproniazid in preventing gastric haemorrhage after reserpine, and the following drugs were ineffective: cocaine, methyl phenidate (Ritalin), amarin, caffeine, nikethamide, lysergic acid diethylamide and its 2-bromo derivative (BOL148). Gastric haemorrhage was not observed in mice which had been given substantial doses of atropine or of hexamethonium before reserpine. The incidence of haemorrhage was substantially reduced by treatment with an antacid mixture. It is concluded that reserpine-like drugs cause gastric haemorrhage by a mechanism which has an important central component and which involves the liberation of 5-hydroxytryptamine.

Amphetamine↗

PubMed1969

Taloximine, a new respiratory stimulant with brochodilator properties.

1. A novel phthalazine analogue taloximine (1-hydroxyimino-4(2-dimethyl-aminoethoxy)-1,2-dihydrophthalazine monohydrochloride monohydrate) stimulated respiration in conscious rabbits at doses of 7 mg/kg and above.2. Taloximine antagonized the depressant action of morphine on respiration in rabbits at doses of 10 mg/kg. At high doses it resuscitated rabbits after they had been given lethal doses of sodium pentobarbitone.3. In in vitro preparations of the trachea or bronchus taloximine was about equiactive with aminophylline. In the Konzett-Rössler preparation the intravenous ED50 for taloximine was about 18% of that of aminophylline, whereas after oral administration the two drugs were equiactive.4. Taloximine, unlike aminophylline, did not protect guinea-pigs against anaphylactic microshock to egg albumen.5. Taloximine shortened the duration of the loss of righting reflex in mice due to hexobarbitone more effectively than bemegride, nikethamide or vanillic acid diethylamide.6. In the dose required to stimulate respiration taloximine had only slight cardiovascular effects. Up to four times this dose produced no evidence of general excitation of the central nervous system.

Anaphylaxis↗

PubMed1997

Analeptic use in clinical toxicology: a historical appraisal.

BACKGROUND: The introduction and increasing popularity of the barbiturates during the first two decades of the 20th century was associated with a new life threatening toxicological problem: the barbiturate overdose. METHODS: This paper reviews the four major phases of analeptic use. As interest in the principles of physiologic antagonism between stimulants and depressants grew, analeptic agents were increasingly used to treat the obtundation and respiratory depression of barbiturate overdose. At first, naturally occurring stimulants such as camphor, strychnine, picrotoxin, and caffeine were used in desperate attempts to awaken patients. During the 1930s, and continuing at some centers into the 1960s, an increasing number of synthetic analeptics agents such as nikethamide, pentylenetetrazol, bemegride, amphetamine, and methylphenidate were enthusiastically recommended as barbiturate antidotes, often at very high doses. Unfortunately, utilizing generous amounts of multiple convulsants was not without its share of complications. Using this analeptic strategy the mortality rate after moderate to severe barbiturate overdose remained as high as 45%. Beginning in the mid-1940s a group of Scandinavian physicians pioneered a revolutionary approach to sedativehypnotic overdose that rejected the use of analeptics and relied on respiratory ventilation and supportive care. CONCLUSIONS: Although barbiturate overdose mortality decreased to less than 1% using this strategy, it would take another 20 years before this technique was universally adapted. While analeptic therapies for the treatment of drug overdose have now been abandoned, one of these analeptics, methylphenidate, currently enjoys wide use in the treatment of attention deficit hyperactivity disorder.

Barbiturates↗

PubMed2002

Replacement of cyanogen bromide solution PH. EUR. with 1,3-dibromo-5,5-dimethylhydantoin (DBH). Analytical methods of pharmacopoeias with DBH in respect to environmental and economical concern, Part 13.

PH. EUR. 2002 identifies nicotinamid, nicotinic acid, and nikethamide according the reaction of König using cyanogen bromide solution prepared with bromine water and ammonium thiocyanate immediately before use. This colour reaction can be better performed with 1,3-dibromo-5,5-dimethylhydantoin (DBH) and sulphanilic acid as condensation component. The prescriptions of PH. EUR. have been improved in respect to environmental and economical concern.

Cyanogen Bromide↗

PubMed2002

[The application of a broard spectrum automatic rapid drug identification system in acute drug poisoning].

OBJECTIVE: To describe the usefulness of REMEDi HS in the diagnosis of acute drug poisoning patients. METHODS: Samples from 1 200 drug poisoning patients were analysed with REMEDi HS. REMEDi HS is a broad spectrum rapid drug identification system, designed for emergency toxicology screening and forensic applications. The total analysis time is about 30 min. The current library of the system has 916 drugs and their metabolites. RESULTS: Among the 1 200 poisoning patients identified by REMIDi HS, the most frequently encountered drugs were benzodiazepines, phenothiazine anti-psychotics, non-phenothiazine anti-psychotics, tricyclic anti-depressants and opioid analgesics. Estazolam (10.25%)diazepam (9.25%)cimetidine (4.33%)chlorpromazine (3.50%)clozapine(2.75%)caffeine (2.58%)nikethamide (2.42%)morpine (1.92%)lidocaine (1.75%) and alprazolam (1.50%) are the ten drugs of highest frequency identified. CONCLUSIONS: Our study demonstrated that REMEDi HS is particularly useful for rapid measurement of drug concentration in the samples from acute poisoning patients.

Acute Disease↗