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At least 19 recordsLinked to original sources
PubMed2000

Doxapram treatment for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram has been used to stimulate breathing and so prevent apnea and its consequences. OBJECTIVES: In preterm infants with recurrent apnea, does treatment with doxapram lead to a clinically important reduction in apnea and use of Intermittent positive airways pressure (IPPV), without clinically important side effects? SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal trials, the Cochrane Collaboration Clinical Trials Register, MEDLINE (using text words 'doxapram', 'apnea or apnoea' and Mesh term 'infant, premature') previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, mainly in the English language. Also an expert informant's search in the Japanese language was made by Prof. Y. Ogawa in 1996. SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation, in which doxapram was used for the treatment of apnea in preterm infants were included. DATA COLLECTION AND ANALYSIS: Each author evaluated the papers for quality and inclusion criteria. Independent data extraction was carried out. MAIN RESULTS: Only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo, was found. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [RR 0.45 (0.20, 1.05)]. Only one infant, who was from the placebo group, was given IPPV. Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm. REVIEWER'S CONCLUSIONS: Although intravenous doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No longterm outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.

Apnea↗
PubMed2000

Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: COPD is a progressive illness and in the later stages, exacerbations may lead to ventilatory failure. The combination of hypoxia and hypercapnia can lead to coma and death. Correction of these blood gas abnormalities is a medical emergency. Doxapram is a respiratory stimulant used to stimulate breathing in this setting. OBJECTIVES: The objective of this review was to assess the effects of doxapram on gas exchange and clinical outcomes in people with ventilatory failure due to acute exacerbations of chronic obstructive pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted experts in the field, study authors and drug companies. SELECTION CRITERIA: Randomised trials comparing doxapram with other treatments or placebo in people with ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. DATA COLLECTION AND ANALYSIS: One reviewer assessed trial quality and extracted data. MAIN RESULTS: Three trials involving 127 people were included. The trials were of variable quality. Doxapram was marginally superior to placebo in preventing blood gas deterioration (odds ratio 0.38, 95% confidence interval 0.14 to 1.02). In one small study, of 17 patients, doxapram and non-invasive ventilation appeared equally effective in terms of blood gases changes, although there were slightly more deaths with doxapram (odds ratio 11.34, 95% confidence interval 1.00 to 128.03). REVIEWER'S CONCLUSIONS: Doxapram may improve blood gas exchange in the short term, but newer techniques such as non-invasive ventilation may be more effective.

Acute Disease↗
PubMed2000

Doxapram versus methylxanthine for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram and methylxanthine drugs have been used to stimulate breathing and so prevent apnea and its consequences. OBJECTIVES: In preterm infants with recurrent apnea, how does treatment with doxapram compare with treatment with theophylline in leading to a clinically important reduction in apnea and use of mechanical ventilation, without clinically important side effects. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group, as outlined in the Cochrane Library, was used. SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation, in which doxapram was compared with methylxanthine (e.g. theophylline) for the treatment of apnea, were eligible. There must have been an effort to exclude specific causes of apnea. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, assess quality and to extract and synthesize data. The methodological quality of each trial was reviewed by the second author blinded to trial authors and institution(s). Additional information was requested from authors to clarify methodology. Each author extracted the data separately, then they were compared and differences resolved. Meta-analysis was carried out with use of relative risk and risk difference. MAIN RESULTS: In these trials involving a relatively small number of preterm infants with apnea of prematurity, there is no apparent difference between the effect of intravenous treatment with doxapram or methylxanthine on the incidence of apnea within 48 hours. There were no infants reported to have been given mechanical ventilation on either treatment. No adverse effects were reported. REVIEWER'S CONCLUSIONS: Implications for practice. The overall results of these small trials suggest that intravenous doxapram and intravenous methylxanthine are not different in their effectiveness in the short term in the treatment of apnea of prematurity. Caution is warranted as the number of patients in these trials is too small to exclude an important difference between these two treatments or to exclude the possibility of less common side effects. Longer term outcome of infants treated in these trials has not been reported. Implications for research. Further studies would require a large number of infants, stratified by gestation, to clarify which infants are likely to benefit and whether there might be differences in responses or side effects with these two drugs at different ages. It would be valuable to include important clinical outcomes such as use of mechanical ventilation as well as subsequent growth and development in future studies. Responses to treatment would have to take account of co-interventions, such as nasal continuous airway pressure which is frequently used post-intubation.

Aminophylline↗
PubMed1990

Pharmacodynamic effects and pharmacokinetic profiles of keto-doxapram and doxapram in newborn lambs.

Keto-doxapram (keto-dox), an oxidative metabolite of doxapram, is a possible ventilatory stimulating agent. Our study characterizes its ventilatory properties, pharmacodynamic effects, and pharmacokinetic profile, and those of its parent compound, doxapram. Two groups of five awake, unsedated, newborn lambs (2- to 6-d old) received, respectively, i.v. infusions of keto-dox or doxapram (2.5 mg/kg) over a period of 1 min. Ventilatory parameters were continuously recorded before and for 1 h after the drug infusion. The pharmacokinetic profiles of both drugs were determined from blood samples collected serially before and after drug injection. Both drugs stimulated ventilation. Keto-dox increased baseline minute ventilation by 46 +/- 6.1% and 27.8 +/- 8.1% (p less than 0.002) at 1 and 5 min, respectively, an effect that decreased after 5 min of infusion. Doxapram increased minute ventilation by 57 +/- 9% (p less than 0.002) at 1 min, and by 48 +/- 7% at 5 min, but its effect lasted for 20 min after injection. Compared with the effects of keto-dox, this doxapram increase was significantly higher (p less than 0.02). Also, doxapram, but not keto-dox, caused an increase in systolic blood pressure (from 110 +/- 3.5 to 118 +/- 3.4 mm Hg at 10 min, p less than 0.01), as well as a change in neuro-behavior. Both drugs exhibited a biexponential decay curve, characterized by a short alpha and a longer beta t1/2, but keto-dox has a faster elimination rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Antagonism of xylazine sedation in steers by doxapram and 4-aminopyridine.

Five groups of 6 fasted crossbred steers were injected IM with standard dosages of xylazine hydrochloride (0.3 to 0.5 mg/kg). At maximal sedation, the steers were injected IV with the antagonists' doxapram (1.0 mg/kg), doxapram + yohimbine (0.125 mg of yohimbine/kg), doxapram + 4-aminopyridine (4-AP; 0.3 mg of 4-AP/kg), or 4-AP + yohimbine. One group was given 1.0 ml of saline solution IV instead of antagonists. Doxapram, doxapram + yohimbine, doxapram + 4-AP, and 4-AP + yohimbine decreased mean standing time (time from antagonist injection until animal could stand unaided) to 17.0, 4.3, 3.3, and 4.5 minutes, respectively--significantly (P less than 0.05) down from a control value of 49.8 minutes. Mean total recovery time (time from xylazine injection until animal resumed eating) was decreased to 78 minutes by doxapram and 81.6 minutes by doxapram + 4-AP--significantly (P less than 0.05) down from the control value of 142.9 minutes. Respiratory character was improved (depth of respiration was increased) only by doxapram + 4-AP. Relapses to recumbency and marked sedation were not seen in steers given doxapram + 4-AP or the saline solution. One steer given doxapram, 2 given doxapram + yohimbine, and 1 given 4-AP + yohimbine relapsed to recumbency and sedation. Recovery was relatively smooth in steers given doxapram + 4-AP or 4-AP + yohimbine. Animals given doxapram or doxapram + yohimbine had difficult recoveries.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1992

Pharmacokinetics and metabolism of intravenous doxapram in horses.

The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated. Plasma doxapram concentrations decreased rapidly after drug administration and the disappearance of doxapram from plasma was best described by a polyexponential equation. Median values of total body clearance were 10.9, 10.6 and 10.9 ml/min/kg bwt for the three doses and were independent of dose. The steady-state volume of distribution was approximately 1,200 ml/kg bwt and the median biological half-life ranged from 121 to 178 mins. Plasma protein binding of doxapram ranged from 76.0 to 85.4 per cent. The blood:plasma doxapram concentration ratio was approximately 0.8 and the affinity of the red blood cells for doxapram ranged from 2.0 to 2.8 indicating sequestration of doxapram in erythrocytes. Renal clearance of doxapram was a minor route of elimination. Metabolic clearance of doxapram appeared to be a major route of elimination. Four metabolites of doxapram were isolated from urine and were identified. The metabolites were: a) 1-ethyl-4-[(2-hydroxyethyl) amino]ethyl-3,3-diphenyl-2-pyr-rolidinone, b) a glucuronic acid or sulphuric acid conjugate of 1-ethyl-3-(hydroxyphenyl)-4-(2-morpholinoethyl)-3-phenyl-pyrrolidinone, c) 3,3-diphenyl-4-(2-morpholinoethyl)-2-pyrrolidinone and d) 1-(2-hydroxyethyl)-3,3-diphenyl-4-(2-morpholinoethyl)-2-pyr-rolidinon e. The rapid disappearance of doxapram from plasma immediately after iv administration was attributed to redistribution of the drug from plasma to other tissues. The short duration of clinical effect from doxapram may be attributed to redistribution of the drug from plasma and other well-perfused tissues, such as the brain, to less well-perfused tissues such as the skeletal muscles and adipose tissue. Continuous or repeated administration of doxapram could prolong the duration of clinical effect because re-distribution is less important as steady-state conditions are approached.

Adipose Tissue↗
PubMed2000

Prophylactic doxapram for the prevention of morbidity and mortality in preterm infants undergoing endotracheal extubation.

BACKGROUND: When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory effort and tendency to develop hypoventilation and apnea, particularly in very preterm infants. Doxapram stimulates breathing and appears to act via stimulation of both the peripheral chemoreceptors and the central nervous system. This effect might increase the chance of successful tracheal extubation. OBJECTIVES: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with doxapram reduce the use of intubation and IPPV, or reduce other morbidity, without clinically important side effects? In this regard, how does doxapram compare with standard treatment or with an alternative treatment such as methylxanthine or CPAP? Subgroup analyses were prespecified according to birth weight and/or gestational age, use of co-interventions (methylxanthines or nasal CPAP), and route of administration (intravenous or oral). SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE and EMBASE. SELECTION CRITERIA: Eligible studies included published trials utilising random or quasi-random patient allocation in which preterm or low birth weight infants being weaned from IPPV were given doxapram compared with standard care or other treatments, to facilitate weaning from IPPV and endotracheal extubation. Trials were independently assessed by the authors before inclusion. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Each author extracted data separately; the results were compared and any differences resolved. The data were synthesized using the standard method of Neonatal Review Group with use of relative risk and risk difference. MAIN RESULTS: Two trials involving a total of 85 infants compared doxapram and placebo. In both the individual trials and the meta-analyses there were no significant differences between the doxapram and placebo groups in any of the outcomes (failed extubation, death before discharge, respiratory failure, duration of IPPV, side effects, oxygen at 28 days or oxygen at discharge). There was a trend towards an increase in side effects (hypertension or irritability leading to cessation of treatment) in the doxapram group [summary RR 3.21 (0.53, 19.43). In one of these two trials (Huon 1998) an 'alarming rise in blood pressure' occurred in five infants in the doxapram group and none of the controls, although in only one was treatment withdrawn. One additional trial involving only eight infants compared doxapram with aminophylline, but there were insufficient data for meaningful analysis. REVIEWER'S CONCLUSIONS: The evidence does not support the routine use of doxapram to assist endotracheal extubation in preterm infants who are eligible for methylxanthine and/or CPAP. The results should be interpreted with caution because the small number of infants studied does not allow reliable assessment of the benefits and harms of doxapram. Further trials are required to evaluate the benefits and harms of doxapram compared with no treatment or with other treatments, such as methylxanthines or CPAP, to evaluate whether it is more effective in infants not responding to these other treatments, and to assess whether the drug is effective when given orally.

Doxapram↗
PubMed1990

A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity.

A blinded, randomized, placebo-controlled trial was conducted to evaluate the effectiveness of theophylline and doxapram therapy in 31 infants with significant apnea of prematurity. Of 10 infants, two had a short-term response to placebo, 8 of 10 infants to theophylline, and 7 of 11 infants to doxapram (placebo vs treatment with theophylline or doxapram: p = 0.01). The two infants who initially responded to placebo remained responsive for the duration of the study. Of the eight infants in whom treatment with placebo failed, five were randomly assigned to receive theophylline, for a total of 15 infants treated with theophylline, and two of the eight were randomly assigned to receive doxapram, for a total of 13 infants treated with doxapram; the remaining infant required tracheal intubation. Of the 15 infants randomly assigned to receive theophylline, seven responded for the duration of the study; of the eight infants who did not respond to treatment with theophylline, five responded to doxapram, one responded to a combination of theophylline and doxapram, and two remained resistant to treatment. Of the 13 infants randomly assigned to receive doxapram four responded for the duration of the study; of the nine who did not respond to doxapram, seven responded to theophylline, one responded to a combination of theophylline and doxapram, and one remained resistant to treatment. This study demonstrates that although therapy with theophylline or doxapram is associated with a significant short-term reduction in the incidence of apnea compared with that in placebo-treated infants, the long-term response to treatment is frequently incomplete and is not sustained more than 1 week.

Apnea↗
PubMed1991

Doxapram metabolism in human fetal hepatic organ culture.

The biotransformation of doxapram, a respiratory stimulant was studied with use of explants from human fetal livers (n = 15 fetuses) obtained from therapeutic abortions (gestational age, 10 to 20 weeks). Explants were cultured in Leibowitz medium and the media from cultured samples were collected before and at 3, 6, 12, and 24 hours after incubation with 2.5, 5.0, and 10 micrograms/ml doxapram. The concentrations of doxapram and its metabolites (AHR 0914, an analog of doxapram, AHR 5955 or ketodoxapram, and AHR 5904) were measured by high pressure liquid chromatography. Explant histopathology and alkaline phosphatase activity showed no direct toxic effects of the drug on liver tissue. The fastest rate of doxapram metabolism occurred during the first 3 hours of incubation (198 +/- 73.3, 438 +/- 63.3, and 538 +/- 62 ng/mg/hr liver protein at doxapram concentrations of 2.5, 5.0, and 10.0 micrograms/ml, respectively). At 3 hours of incubation, the amount of doxapram metabolized (nanogram per milligram of liver protein) was significantly higher (p less than 0.01) at doxapram concentrations of 10.0 (1616 +/- 186) and 5.0 microgram/ml (1315 +/- 190) than at 2.5 micrograms/ml (594 +/- 220). The oxidative pathway producing keto-doxapram, or AHR 5955 and AHR 5904, is more active than the de-ethylation producing the analog of doxapram AHR 0914. Data indicate substantial metabolism of doxapram by the human fetal lives.

Biotransformation↗
PubMed2001

Low-dose doxapram therapy for idiopathic apnea of prematurity.

BACKGROUND: Doxapram is contraindicated for newborn infants in Japan because of its serious side effects. However, because of encouraging results of recent studies regarding the efficacy and safety of therapy for apnea of prematurity (AOP) with lower doses of doxapram than those previously proposed, approximately 60% of Japanese neonatologists continue to use doxapram at small doses. Caution is warranted because the sample sizes of the former studies are inadequate to evaluate doxapram for both its beneficial and harmful effects. Therefore, we conducted the present study in order to investigate the efficacy and harmful events of low-dose doxapram therapy for idiopathic AOP in very low-birth weight (VLBW) infants in a larger population. METHODS: One hundred and six VLBW infants with idiopathic AOP were treated with doxapram at a dose of 0.2-1.0 mg/kg per h in combination with methylxanthines and the frequency of apnea and secondary outcomes were compared with a group of control infants. RESULTS: An approximate 80% reduction in the frequency of apnea was found with only minimal side effects following low-dose doxapram. Although there were no significant differences in secondary outcomes between the doxapram-treated and control groups, mortality in doxapram-treated infants was significantly lower than that in control infants. CONCLUSIONS: Patients with AOP unresponsive to treatment with methylxanthines may benefit from the addition of low-dose doxapram.

Apnea↗
PubMed1985

Reversal of thiopental-induced anesthesia by 4-aminopyridine, yohimbine, and doxapram in dogs pretreated with xylazine or acepromazine.

Groups of atropinized dogs (6 dogs/group) were sedated, using xylazine HCl (2.2 mg/kg of body weight, IM) or acepromazine maleate (0.25 mg/kg, IM), and were anesthetized to loss of pedal reflexes, using thiopental, IV. The dogs were given 1 of the following test antagonists, IV: saline solution (2 ml; control group), 4-aminopyridine (4-AP; 0.5 mg/kg), yohimbine (0.4 mg/kg), doxapram (5.0 mg/kg), or dual combinations of the latter 3 substances in the same doses as used for each agent. In xylazine-treated dogs, the mean dosage of thiopental required to induce anesthesia was 4.8 mg/kg. Control mean arousal time (MAT) and walk time (MWT) were 37.1 minutes and 53.8 minutes, respectively. These values were decreased to less than 2 minutes and less than 3 minutes, respectively, by yohimbine, 4-AP + yohimbine, and doxapram + yohimbine. With doxapram and with 4-AP + doxapram, MAT was less than 2 minutes and MWT was less than 8 minutes. In acepromazine-treated dogs, the mean dosage of thiopental required for anesthesia was 15.0 mg/kg. Control MAT and MWT were 20.7 minutes and 36.5 minutes, respectively. These values were decreased to 8.1 minutes and 18.1 minutes, respectively, by doxapram, and to 3.5 minutes and 19.9 minutes, respectively, by doxapram + yohimbine. Doxapram, 4-AP + doxapram, and doxapram + yohimbine caused periodic extensor rigidity before and during arousal. This rigidity was accompanied by opisthotonos in 2 dogs of the doxapram + yohimbine group and may have been mild tonic seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed2005

[Determinants of doxapram utilization: a survey of practice in the French Neonatal and Intensive Care Units].

UNLABELLED: Methylxanthines and doxapram have been used to stimulate breathing and to prevent apnea in preterm infants. The use of doxapram is controversial because the therapeutic index seems to be narrow and short-term adverse effects have been described. OBJECTIVE: To determine the use of doxapram in the French neonatal and intensive care units. METHODS: A structured postal questionnaire was sent to all the 236 neonatology and neonatal intensive care units of level IIa, IIb and III in France. The questionnaires were analysed after four months. RESULTS: Answers were obtained from 159 chiefs of department (67.4%), 102 used doxapram (64.1%). Doxapram was mainly used as a second step, if methylxanthines failed to reduce the frequency of apneic spells (102/159 units, 64.1%). Doxapram was usually administered intravenously (91/102 units, 89.2%). Only 57 respondents (35.8%) did not use doxapram, because they were aware of the potential adverse effects or they did not know the drug. Monitoring of drug plasma concentrations was rarely performed (11/102 services, 10.8%). Nevertheless, there was a significant interest in this monitoring. CONCLUSION: Doxapram is frequently used in France to reduce apnea of prematurity if methylxanthine therapy fails. Further studies are needed to determine safety of doxapram at short and long-term. A multicenter, randomised, double-blinded clinical trial would be interesting to perform, similar to the ongoing caffeine for Apnoea of Prematurity trial (CAP) . The French setting seems appropriate for this kind of study.

Apnea↗
PubMed2005

Doxapram-induced panic attacks and cortisol elevation.

Numerous agents with differing biological properties and central nervous system (CNS) effects can induce panic attacks in predisposed individuals. A potential explanation of this finding is that panic disorder patients are more likely to panic than normal control subjects when given a panicogen due to an excessive fear response to somatic arousal. We test this hypothesis by using doxapram, a panicogen with minimal CNS effects, to induce panic in patients and control subjects. Doxapram was given to six subjects with panic disorder with or without agoraphobia and four healthy volunteers. Measures comprised the Acute Panic Inventory, the Borg Exertion scale, the 10-point Anxiety Scale, the 10-point Apprehension Scale, cortisol, prolactin, and MHPG, all obtained at baseline and multiple time points after the doxapram infusion. All panic disorder patients panicked with doxapram, whereas no control subjects had a panic attack. Panic patients had similar levels of breathlessness with doxapram compared with control subjects. Although panic patients had higher levels of anxiety and apprehension, these did not change significantly with doxapram compared with control levels. Doxapram led to similar increases in cortisol and prolactin in both groups, and MHPG was consistently elevated in panic patients, but unaffected by doxapram. These results show that doxapram is a useful panicogen in the study of panic disorder. Since the panic patients and control subjects had similar levels of physiological and psychological arousal, but the panic patients were more likely to have a panic attack, this lends support to the concept of a sensitized fear network in panic disorder patients.

Adult↗
PubMed2005

Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca(2+)-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K(+) channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K(+) channel activators; NS-1619 as a Ca(2+)-sensitive K(+) channel activator; and halothane as a TASK-like background K(+) channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

Anesthetics, Inhalation↗
PubMed2003

Rodent doxapram model of panic: behavioral effects and c-Fos immunoreactivity in the amygdala.

BACKGROUND: Panic attacks, the hallmark of panic disorder, are often characterized by hyperventilation. Existing animal models of anxiety have not addressed the effects of the hyperventilation on anxiety-related behaviors. Doxapram is a respiratory stimulant that reliably evokes panic attacks in patients with panic disorder. We examined doxapram in four rodent models of anxiety and sought to identify brain regions involved in its behavioral effects. METHODS: The effects of doxapram were determined for cue and contextual fear conditioning, the open field test, and the social interaction test. The effect of doxapram on c-Fos-like immunoreactivity was examined in three brain regions. RESULTS: Doxapram at 4 mg/kg increased anxiety-related behaviors in all four anxiety models. An inverted U-shaped dose-response curve was identified for fear conditioning to cue. Doxapram induced c-Fos-like immunoreactivity in the central nucleus of the amygdala but not the lateral nucleus or the nucleus tractus solitarius. CONCLUSIONS: Doxapram enhanced anxiety-related behaviors in four animal models of anxiety that involve conditioning or spontaneous avoidance. The effect of doxapram may result from activation of neurons in the amygdala. Doxapram, by inducing hyperventilation, may be a useful adjunct to existing animal anxiety models for improving validity for panic anxiety.

Amygdala↗
PubMed1993

Effects of doxapram on carotid chemoreceptor activity in newborn kittens.

Doxapram is a respiratory stimulant which acts on peripheral chemoreceptors and central respiratory neurons in a dose-dependent fashion in the adult cat. In the newborn, the mechanisms of action of doxapram are still unclear. To evaluate the effects of doxapram on the carotid chemosensory discharge and its relationship with dopaminergic mechanisms in the carotid body, two groups of kittens less than 13 days old, anesthetized, artificially ventilated and paralyzed, were prepared for the recording of a single or a few chemosensory afferents of the carotid sinus nerve. The chemosensory activity was recorded under five conditions of inspired gas mixtures (21 and 8% O2 in N2, 100% O2, 5 and 10% CO2 in O2). Group 1 (n = 9) received only doxapram and group 2 (n = 8) was pretreated with haloperidol (1 mg/kg), a dopamine D2-receptor blocker, before receiving doxapram. Doxapram significantly stimulated the discharge rate of the carotid chemoafferents under all conditions of inspired gas. The chemosensory discharge was increased by haloperidol, and was raised further after doxapram by an amount similar to group 1. For instance, in normoxia, the activity increased from 2.9 +/- 0.4 to 7.5 +/- 0.9 impulse/s (mean +/- SEM, p < 0.01) in group 1 and from 3.8 +/- 0.6 to 9.1 +/- 1.0 impulse/s (p < 0.01) in group 2. These results indicate that the mechanisms of response of carotid chemoreceptor to doxapram are developed in the newborn kitten and doxapram acts independent of the dopaminergic mechanisms in the carotid body.

Animals↗
PubMedDate not supplied

The effects of doxapram hydrochloride (dopram-V) on laryngeal function in healthy dogs.

Laryngeal dysfunction is assessed most accurately by direct visualization of the larynx under a light plane of anesthesia. If the plane of anesthesia used is too deep, laryngeal structures may appear paralyzed and remain in a paramedian position. Doxapram hydrochloride is a known respiratory stimulant. We hypothesized that doxapram would significantly increase intrinsic laryngeal motion in healthy anesthetized dogs. The goal of this study was to evaluate the effect of doxapram on the area of rima glottidis (RG) in healthy dogs. Thirty healthy dogs were studied. Dogs were premedicated with butorphanol tartrate (0.22 mg/kg IV), acepromazine maleate (0.05 mg/kg SC), and glycopyrrolate (0.005 mg/kg SC), followed by induction with propofol (4 mg/kg IV). Intrinsic laryngeal motion observed in each dog was recorded on videotape after induction. Doxapram then was administered (2.2 mg/kg IV) and respirations again were recorded. Representative breaths for each dog were photographed during 4 phases of respiration (inspiration at rest, inspiration with doxapram, expiration at rest, and expiration with doxapram). The area of the RG then was calculated by using a computer-assisted analysis program. Results of each category were compared by using a 1-way analysis of variance; P < or = .05 was considered significant. Doxapram visibly increased respiratory effort, and was associated with increased intrinsic laryngeal motion. Compared to the resting state, the area of the RG was significantly increased after doxapram administration during both inspiration and expiration. We propose the routine use of doxapram during laryngoscopy to increase intrinsic laryngeal motion and aid in the diagnosis of laryngeal dysfunction.

Animals↗