Immunosuppressive and cytotoxic therapy: pharmacology, toxicities, and monitoring

Treatment strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic AAV. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine, mycophenolate mofetil) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening AAV. Recent studies suggest that rituximab may be useful for induction therapy or for CYC-refractory AAV. This article reviews the key agents used to treat AAV, with a focus on pharmacology, toxicities, and monitoring.     

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.     

Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD

Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5'-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.     

Cough: differential diagnosis and treatment

Cough is a complex physiologic event that protects the lungs from mechanical, chemical, and thermal injury. It is a normal reflex and therefore helps humans to adapt to an ever-changing environment. Cough can also be a pathologic reflex in that it may be an important and often the only sign of serious disease, may significantly contribute to the spread of airborne infection, and in some instances, may result in severe functional or structural damage to the organism. This article focuses on the pathophysiology of the afferent limb of the cough reflex, including a discussion of the causes, the diagnostic workup, and the treatment of cough.     

Optimal therapy for the geriatric patient: the challenge to clinical pharmacology

The elderly are an increasing proportion of the population. Their median life span should rise to 85 years, although in later life organs of drug distribution and elimination may deteriorate in function and 100 years will remain the general maximum. Progressive containment of chronic diseases will still leave them at lethal risk from acute infectious diseases because of depleted homeostatic reserves of vital systems (cardiovascular, hepatic, immunological and renal). A decline in chronic disease should lengthen the period of well-being and reduce medical needs and perhaps drug needs of older persons. To estimate further therapeutic requirements of the elderly, information is needed on the epidemiology of drug use and rates of efficacy and toxicity in the elderly. Implicit in the data gathering is a true need for systematic post-marketing surveillance (PMS) of drugs with particular respect to drug efficacy and unanticipated adverse or beneficial reactions in this age group. Observational, non-experimental techniques can be devised and should be tested as appropriate methods of establishing the rates of anticipated efficacy and unwanted effects of drugs. The application of such techniques may be one of the only feasible ways to establish utility functions for drugs used in the elderly.     

The Cough Hypersensitivity Syndrome: A Novel Paradigm for Understanding Cough

For many years patients with chronic cough have been investigated in an attempt to diagnose the cause of the cough. Here I suggest that the overwhelming majority of patients with chronic cough have a single diagnosis: cough hypersensitivity syndrome. This is demonstrated by the homogeneous nature of the clinical history and investigational results of patients attending cough clinics. The hypersensitivity facet of the syndrome is demonstrated by objective testing with capsaicin and other protussive agents. Within the cough hypersensitivity syndrome there are different phenotypes. Those patients with a predominantly Th2-type immune response will develop eosinophilic inflammation and either cough-variant asthma or eosinophilic bronchitis. Those with predominantly heartburn symptoms will have a phenotype that reflects GERD and cough. However, the similarities between the different phenotypes far outweigh differences in a unifying diagnosis of the cough hypersensitivity syndrome, providing a more rational understanding of chronic cough.     

Deep Inspiration-Provoked Cough: A Sign of Cough Reflex Arc Hypersensitivity

Deep inspiration-provoked cough (DIPC) is a form of allotussia. Allotussia is thought to be a manifestation of cough reflex arc hypersensitivity but objective evidence about this is lacking. 36 subjects with chronic cough and 25 healthy subjects underwent mannitol and citric acid cough provocation tests. DIPC was defined as two or more coughs after deep inhalation of an empty mannitol capsule. Citric acid was administered utilizing a dosimetric nebulizer during controlled tidal breathing. Nine subjects demonstrated DIPC, 8/36 subjects with chronic cough and 1/25 healthy subjects (p = 0.048). The concentration of citric acid to provoke five or more coughs (C5) was 23.4 (63.8) mM among subjects with DIPC and 750 (2941) mM among the subjects without it (p = 0.006). The number of deep inspiration-provoked coughs correlated with the citric acid C5 (Rs -0.38, p = 0.002). In conclusion, DIPC, a form of allotussia, is associated with cough reflex arc hypersensitivity.

Trial Registration Number.

ClinicalTrials.gov database KUH5801136.

     

The Cough Reflex in Animals: Relevance to Human Cough Research

All mammalian species studied cough or display some similar respiratory reflex upon aerosol challenge with tussigenic stimuli such as citric acid or capsaicin. Animals cough to the same stimuli that evoke coughing in humans, and therapeutic agents that display antitussive effects in human studies also prevent coughing in animals. The many invasive procedures and complementary in vitro studies possible in animals but not readily reproduced in human subjects, along with the proven predictive value of cough studies in animals, provide the rationale for animal modeling of human cough. The advantages and disadvantages of studying cough in animals are discussed.     

GERD-Related Cough: Pathophysiology and Diagnostic Approach

Chronic cough is a common problem resulting in significant impairment of quality of life. Along with cough variant asthma and nasal disease, gastroesophageal reflux is considered one of three main causes of cough. Despite this, acid suppression therapy is often far from effective. This review aims to explore whether reflux can lead to cough, the circumstances in which this is most likely to occur, and the potential mechanisms linking these processes. Particular mechanisms to be explored include laryngopharyngeal reflux, microaspiration, and neuronal cross-organ sensitization. Finally, diagnostic approaches are considered.     

Cough and Asthma

Cough is the most common complaint for which patients seek medical attention. Cough variant asthma (CVA) is a form of asthma, which presents solely with cough. CVA is one of the most common causes of chronic cough. More importantly, 30 to 40% of adult patients with CVA, unless adequately treated, may progress to classic asthma. CVA shares a number of pathophysiological features with classic asthma such as atopy, airway hyper-responsiveness, eosinophilic airway inflammation and various features of airway remodeling. Inhaled corticosteroids remain the most important form of treatment of CVA as they improve cough and reduce the risk of progression to classic asthma most likely through their prevention of airway remodeling and chronic airflow obstruction.     

Cough and Sleep

Cough and sleep are vital functions. The effects of cough on sleep and vice versa are important for a number of reasons. Sleep disruption is common in patients with cough and is often the reason why they seek medical attention. Sleep suppresses cough and the biological mechanisms for this action are poorly understood. Cough has recently been reported as a presenting symptom of obstructive sleep apnea. It is uncommon for healthy people to cough at night; however, approximately 50% of patients with chronic cough report sleep disruption due to cough. Cough frequency is much lower at night than during the day. There is reduced exposure to tussive stimuli at night and decreased cough reflex sensitivity. Cough is more difficult to induce in REM sleep compared to slow-wave sleep. Studies of anesthetized humans have shown that the cough reflex is suppressed; however, the expiratory reflex is less affected. The sleep–cough interaction has implications for the physician. The measurement of cough frequency with 24-h ambulatory cough monitors in patients with chronic cough suggests that the presence or absence of nocturnal cough is not helpful in establishing the etiology. Nocturnal cough may be a useful outcome parameter for clinical trials of antitussive drugs since it is under less voluntary control than daytime cough. Most antitussive drugs are sedatives. This suggests that part or all of their action may be through an effect on cortical neural pathways. Unexplained chronic cough has recently been reported as a presenting feature of obstructive sleep apnea. Patients are likely to be female and report gastroesophageal reflux and rhinitis. Continuous positive airway pressure therapy is effective in alleviating cough. Greater awareness of this condition is needed.     

Older-Generation Antihistamines and Cough Due to Upper Airway Cough Syndrome (UACS): Efficacy and Mechanism

Older-generation H1 antihistamines are recommended in empiric protocols for the treatment of cough due to upper airway cough syndrome (UACS). Data from double-blind placebo-controlled trials that support the use of older-generation antihistamines in UACS are limited to a single study of cough due to the common cold. However, several empiric trials strongly support efficacy of older-generation antihistamines in patients with chronic cough. Data from a variety of studies support the concept that newer-generation H1 antihistamines are not useful in the treatment of cough due to UACS. The mechanism of action of older-generation H1 antihistamines has been proposed to be anticholinergic activity, but the rank order potency of these drugs as muscarinic receptor antagonists is not consistent with this hypothesis. Actions of these drugs on histamine H1 and/or nonhistaminergic receptors in the central nervous system remain a possible explanation for their effects on cough due to UACS. The effects of older H1 antihistamines may also be molecule specific, rather than attributable to the entire class of compounds. Additional studies should be performed to document the activity of these drugs in double-blind placebo-controlled trials.     

Currently Available Cough Suppressants for Chronic Cough

Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.