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Biomedical subjects

Donald C Bolser

Publications and source records attributed to Donald C Bolser.

15 recordsLinked to original sources
PubMed2007

Codeine and cough: an ineffective gold standard.

PURPOSE OF REVIEW: Cough is one of the most common reasons why patients visit physicians. The opioid codeine has been a mainstay in the treatment of cough for decades and this drug is widely regarded as the 'gold standard' cough suppressant. RECENT FINDINGS: Recent placebo-controlled studies have shown that codeine is no more effective than placebo in suppressing cough caused by either upper respiratory disorders or chronic obstructive pulmonary disease. These recent reports are not consistent with several older placebo-controlled studies that demonstrated the efficacy of codeine. The reasons for this difference are not fully understood. SUMMARY: We propose that these differences, as well as results from animal models, can be explained by the existence of a complex hierarchical control system that regulates the expression of coughing. This system, known as a holarchy, is composed of regulatory elements known as 'holons' that interact with one another to regulate cough. Based on work in animal models, codeine is proposed to act on an intermediate order holon that may not be critical for coughing under some situations in humans. Testing of this hypothesis and further elucidation of the control system for cough will represent an important direction for future research in this area.

Animals↗
PubMed2006

Microinjection of DLH into the region of the caudal ventral respiratory column in the cat: evidence for an endogenous cough-suppressant mechanism.

The caudal ventral respiratory column (cVRC) contains premotor expiratory neurons that play an important role in cough-related expiratory activity of chest wall and abdominal muscles. Microinjection of d,l-homocysteic acid (DLH) was used to test the hypothesis that local activation of cVRC neurons can suppress the cough reflex. DLH (20-50 mM, 10-30 nl) was injected into the region of cVRC in nine anesthetized spontaneously breathing cats. Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airways. Electromyograms (EMG) were recorded bilaterally from inspiratory parasternal and expiratory transversus abdominis (ABD) and unilaterally from laryngeal posterior cricoarytenoid and thyroarytenoid muscles. Unilateral microinjection of DLH (1-1.5 nmol) elicited bilateral increases in tonic and phasic respiratory ABD EMG activity, and it altered the respiratory pattern and laryngeal motor activities. However, DLH also decreased cough frequency by 51 +/- 7% compared with control (P < 0.001) and the amplitude of the contralateral (-35 +/- 3%; P < 0.001) and ipsilateral (-34 +/- 5%; P < 0.001) ABD EMGs during postinjection coughs compared with control. The cough alterations were much less pronounced after microinjection of a lower dose of DLH (0.34-0.8 nmol). No cough depression was observed after microinjections of vehicle. These results suggest that an endogenous cough suppressant neuronal network in the region of the cVRC may exist, and this network may be involved in the control of cough reflex excitability.

Animals↗
PubMed2006

Neurogenesis of cough, other airway defensive behaviors and breathing: A holarchical system?

Cough and breathing are generated by a common muscular system. However, these two behaviors differ significantly in their mechanical features and regulation. The current conceptualization of the neurogenic mechanism for these behaviors holds that the multifunctional respiratory pattern generator undergoes reconfiguration to produce cough. Our previous results indicate the presence of a functional cough gate mechanism that controls the excitability of this airway defensive behavior, but is not involved in the regulation of breathing. We propose that the neurogenesis of cough, breathing, and other nonbreathing behaviors is controlled by a larger network, of which the respiratory pattern generator is part. This network we term a holarchical system. This system is governed by functional control elements known as holons, which confer unique regulatory features to each behavior. The cough gate is an example of such a holon. Neurons that participate in a cough holon may include behavior selective elements. That is, neurons that are either specifically recruited during cough and/or tonically-active neurons with little or no modulation during breathing but with significant alterations in discharge during coughing. We also propose that the holarchical system is responsible for the orderly expression of different airway defensive behaviors such that each motor task is executed in a temporally and mechanically discrete manner. We further propose that a holon controlling one airway defensive behavior can regulate the excitability of, and cooperate with, holons unique to other behaviors. As such, co-expression of multiple rhythmic behaviors such as cough and swallow can occur without compromising airway defense.

Animals↗
PubMed2006

Current and future centrally acting antitussives.

The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.

Animals↗
PubMed2006

Expiratory muscle strength training in persons with multiple sclerosis having mild to moderate disability: effect on maximal expiratory pressure, pulmonary function, and maximal voluntary cough.

OBJECTIVE: To determine the effect of expiratory muscle strength training (EMST) on maximal expiratory strength, pulmonary function, and maximal voluntary cough in persons with multiple sclerosis (MS) having mild to moderate disability. DESIGN: Before-after trial. SETTING: Assessments were completed in the privacy of the subject's home or exercise physiology laboratory. PARTICIPANTS: Seventeen persons with MS were age- and sex-matched to 14 healthy controls. INTERVENTION: Eight weeks of EMST and 4 weeks of detraining. MAIN OUTCOME MEASURES: Maximal respiratory pressures, pulmonary function, and maximal voluntary cough were assessed 3 times (pretraining, posttraining, detraining). Maximal expiratory pressure (MEP) was assessed weekly and training intensity adjusted based on the new measurement. RESULTS: Subjects with MS had lower MEP, decreased pulmonary function, and weaker maximal voluntary cough at each assessment. EMST increased MEP and peak expiratory flow. However, improvement in maximal voluntary cough only occurred in subjects with a moderate level of disability when the MS group was subdivided into mild and moderate disability levels based on the Expanded Disability Status Scale. CONCLUSIONS: EMST is a viable tool to enhance the strength of the respiratory muscles. However, further work is needed to determine the best parameters to assess change in cough following EMST.

Adult↗
PubMed2006

Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines.

BACKGROUND: Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis. METHODS: Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms "cough," "double-blind placebo-controlled," "antitussive," "mucolytic," "cough clearance," "common cold," "protussive," "guaifenesin," "glycerol," and "zinc." RESULTS: Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further. CONCLUSIONS: These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.

Antitussive Agents↗
PubMed2005

Augmented breath phase volume and timing relationships in the anesthetized rat.

Augmented breaths (ABs), or sighs, are airway protective reflexes and part of the normal repertoire of respiratory behaviors. ABs consist of two phases, where phase I volume and timing resembles preceding eupnic breaths, and phase II is an augmenting motor pattern and occurs at the end of phase I. Recent evidence suggest multiple respiratory motor patterns can occur following dynamic functional reconfiguration of one respiratory neural network. It follows that the response of the respiratory network to modulatory inputs also may undergo dynamic reconfiguration. We hypothesized that lung-volume related feedback during ABs would alter AB timing differentially during phase I and II. We measured phase I and II volumes and durations in urethane anesthetized rats with decreased lung volume secondary to three models of varying phrenic motor impairment (spinal injury alone, unilateral phrenicotomy, and combined injuries). AB phase I and II inspired volume were decreased after phrenic motor impairment (p<0.05). In contrast, only phase I duration following injury was altered compared to controls. Phase II duration remaining unchanged despite the greatest effect of injury on volume occurring during phase II. Thus, sigh volume-timing relationships differ between phases of an augmented breath suggesting that the response of the respiratory network to modulatory inputs has changed. These data support the hypothesis that multiple respiratory behaviors occur following dynamic reconfiguration of the respiratory neural network.

Anesthesia, General↗
PubMed2004

Experimental models and mechanisms of enhanced coughing.

Enhanced coughing can be produced in a variety of animal models, including the guinea pig, cat, dog and pig. Typically, airway inflammation has been produced by sensitization, exposure to cigarette smoke, sulphur dioxide or angiotensin-converting enzyme inhibitors. In some of these models, inflammatory mediators such as bradykinin and tachykinins have been shown to contribute to the enhanced coughing. While most of these studies have focussed on peripheral mechanisms, increases in central excitability of the cough reflex have been shown to occur as a result of airway inflammation. As such, we propose that enhanced coughing in pathological conditions is the result of plastic changes in both peripheral and central neural elements. Furthermore, we present a modified model of the neurogenesis of cough that takes into account peripheral and central plasticity induced by mediators of inflammation.

Animals↗
PubMed2003

Respiratory motor recovery after unilateral spinal cord injury: eliminating crossed phrenic activity decreases tidal volume and increases contralateral respiratory motor output.

By 2 months after unilateral cervical spinal cord injury (SCI), respiratory motor output resumes in the previously quiescent phrenic nerve. This activity is derived from bulbospinal pathways that cross the spinal midline caudal to the lesion (crossed phrenic pathways). To determine whether crossed phrenic pathways contribute to tidal volume in spinally injured rats, spontaneous breathing was measured in anesthetized C2 hemisected rats at 2 months after injury with an intact ipsilateral phrenic nerve, or with ipsilateral phrenicotomy performed at the time of the SCI (i.e., crossed phrenic pathways rendered ineffective) (dual injury). Ipsilateral phrenicotomy did not alter the rapid shallow eupneic breathing pattern in C2 injured rats. However, the ability to generate large inspiratory volumes after either vagotomy or during augmented breaths was impaired if crossed phrenic activity was abolished. We also investigated whether compensatory plasticity in contralateral motoneurons would be affected by eliminating crossed phrenic activity. Thus, contralateral phrenic motor output was recorded in anesthetized, vagotomized, and mechanically ventilated rats with dual injury during chemoreceptor stimulation. Hypercapnia, hypoxia, and asphyxia increased contralateral phrenic burst amplitude in the dual injury group more than in rats with SCI alone. Dual injury rats also had elevated baseline burst frequency. Together, these results demonstrate a functional role of crossed phrenic activity after SCI. Moreover, by preventing ipsilateral phrenic motor recovery in rats with unilateral SCI, segmental and supraspinal changes could be induced in contralateral respiratory motor output beyond that seen with SCI alone.

Animals↗
PubMed2002

Antitussive effect of nociceptin/orphanin FQ in experimental cough models.

Cough is an important defensive pulmonary reflex that removes irritants, fluids or foreign materials from the airways. However, often cough is non-productive and requires suppression. Opioid mu receptor agonists, such as codeine are commonly used as antitussive agents and are among the most widely administered drugs in the world. Codeine suppresses the responsiveness of one or more components of the central reflex pathway for cough and is an efficacious antitussive drug for cough due to diverse aetiologies. However, opioids produce side effects that include sedation, addiction potential and constipation. Therefore, novel cough suppressant therapies should maintain or improve upon the antitussive efficacy profile of opioids. Moreover, these novel therapies should have a safety profile significantly better than current antitussive therapies. Presently, we discuss preclinical findings showing that activation of the 'opioid-like' receptor (NOP(1)) inhibits cough in the guinea pig and cat.

Animals↗
PubMed2002

Functional organization of the central cough generation mechanism.

Recent studies evaluating the effects of pulmonary afferents, chemoreceptors, and antitussive drugs on the cough motor pattern indicate that this reflex is regulated in a different manner than breathing. Furthermore, regulatory differences exist between tracheobronchial and laryngeal cough. We propose a functional model of the brainstem elements participating in the production of cough that accounts for these regulatory differences. The model incorporates known brainstem interneuronal pathways as well as novel regulatory elements for tracheobronchial and laryngeal cough. Each of these novel regulatory elements controls the excitability of a common motor pattern generation network. Given that cough and breathing are associated with profoundly different spatiotemporal alterations in motor drive to respiratory motoneurons, brainstem elements common to the generation of both behaviours must be capable of a high degree of plasticity.

Antitussive Agents↗
PubMed1991

Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys.

The purpose of this study was to determine if electrical stimulation of vagal afferents inhibited activity of primate spinothalamic tract (STT) neurons located in cervical segments of the spinal cord. Previous studies show vagal inhibition of STT neurons in more caudal segments of the cord, which receive visceral spinal inputs and somatic inputs from proximal body regions. We hypothesized that activation of vagal afferents would inhibit cervical STT neurons that were excited by cardiopulmonary sympathetic afferents and not inhibit those cells inhibited or unaffected by this visceral input. Because visceral pain is referred to proximal somatic fields, we also hypothesized that STT neurons with excitatory somatic fields confined to distal areas would not be inhibited by vagal stimulation. In 42 cervical STT neurons, we found no difference in effects of vagal stimulation between cells excited or not excited by stimulation of cardiopulmonary sympathetic afferents. Responses to vagal stimulation also were the same for cervical STT cells with proximal or distal somatic fields. Furthermore, there was no difference in the inhibitory effects of vagal stimulation in cervical as compared to thoracic STT neurons. We concluded that vagal afferent stimulation causes a general inhibitory effect at all levels of the spinal cord on neurons which transmit nociceptive information.

Animals↗