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Cannabinoids and Cystic Fibrosis
Abstract
Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its major active ingredient ?-tetrahydrocannabinol (THC).Endogenous cannabinoids (“endocannabinoids”) are found in maternal milk. We have recently shown that endocannabinoids are critical for milk ingestion and survival of newborns because blocking CB1 receptors resulted in death from malnutrition.Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis (CF) patients. It is proposed here for the first time, to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients.Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterizes the CF condition is responsible for the dysregulation. Endocannabinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoid synthesis, through regulation of fatty acid biosynthesis. According to this hypothesis, CF patients display decreased levels of endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypo-algesic effects.
... Certainly, caveats are necessary, and one might expect the emergence of depression and hyperalgesic states in patients taking this agent, such as migraine and fibromyalgia. Additionally, hypervigilance will be necessary in administering such a drug to women of child-bearing age, as SR141716 has profound effects on neonatal feeding and growth (Fride 2002). ...
... Emerging concepts have demonstrated the key role that endocannabinoids play in regulation of pain (Pertwee 2001), hormonal regulation and fertility (Bari et al. 2002), hunger (Fride 2002) and gastrointestinal function (Pertwee 2001), and even regulation of memory (Hampson and Deadwyler 2000), and proper extinction of aversive events (Marsicano et al. 2002). ...
... Another possible pediatric indication for cannabis-based medicines is cystic fibrosis. In a recent study (Fride 2002), an extremely compelling and well-conceived rationale for cannabis treatment was outlined that could vastly improve the clinical condition and well-being of affected children. Similar benefits might accrue to other serious failure-to-thrive states. ...
. This study reviews human clinical experience to date with several synthetic cannabinoids, including nabilone, levonantradol, ajulemic acid (CT3), dexanabinol (HU-211), HU-308, and SR141716 (Rimonabant ®). Additionally, the concept of "clinical endogenous cannabinoid defi-ciency" is explored as a possible factor in migraine, idiopathic bowel dis-ease, fibromyalgia and other clinical pain states. The concept of analgesic synergy of cannabinoids and opioids is addressed. A cannabinoid-medi-ated improvement in night vision at the retinal level is discussed, as well as its potential application to treatment of retinitis pigmentosa and other conditions. Additionally noted is the role of cannabinoid treatment in neuroprotection and its application to closed head injury, cerebrovas-cular accidents, and CNS degenerative diseases including Alzheimer, Huntington, Parkinson diseases and ALS. Excellent clinical results employing cannabis based medicine extracts (CBME) in spasticity and spasms of MS suggests extension of such treatment to other spasmodic and dystonic conditions. Finally, controversial areas of cannabinoid treatment in obstetrics, gynecology and pediatrics are addressed along with a rationale for such interventions.
... A much better understanding of the critical role of tonic endocannabinoid function in normal ontogeny has recently been elucidated when Ester Fride and colleagues investigated the role of anandamide in initiation of neonatal feeding, and inevitable demise with its blockade (Fride 2002). Therapeutic use in "failure-to-thrive" states and cystic fibrosis (Fride 2002) are obvious putative applications. ...
... A much better understanding of the critical role of tonic endocannabinoid function in normal ontogeny has recently been elucidated when Ester Fride and colleagues investigated the role of anandamide in initiation of neonatal feeding, and inevitable demise with its blockade (Fride 2002). Therapeutic use in "failure-to-thrive" states and cystic fibrosis (Fride 2002) are obvious putative applications. ...
Cannabis has been employed in human medicine for more than 4000 years. In the last century, political prohibition led to its disappearance from the conventional pharmacopoeia, but this trend is reversing due to the broad acceptance and application of this forbidden medicine by patients with chronic and intractable disorders inadequately treated by available therapeutics. This study addresses the “road back” for cannabis medicines, and reacceptance as prescription products.Current pharmacology of the two primary therapeutic phytocannabinoids, THC and CBD, is reviewed with respect to herbal synergy and as pertains to treatment of pain, spasm and the wide range of therapeutic applications and adverse effects of cannabis.In particular, the efforts of GW Pharmaceuticals to develop cannabis based medicine extracts (CBME) are documented including cultivation of genetically-selected medical-grade cannabis cloned strains in glass houses with organic and integrated pest management techniques, and their processing employing supercritical carbon dioxide extraction and winterization. These CBMEs are then available for formulation of dosage forms including sublingual extracts and inhaled forms. An optional Advanced Delivery System (ADS) is also discussed.
... Previous randomized controlled trials (RCTs) report that cannabinoids can induce improvements in body weight, appetite, physical functioning and QoL in cachectic patients with other chronic diseases including HIV infection and multiple sclerosis. [26][27][28] However, this is not well studied in cancer patients. Most reports suggesting the benefits of cannabinoids for appetite in CAC are anecdotal or lack methodological homogeneity, 29 and few RCTs and one meta-analysis are available. ...
Cancer‐associated cachexia (CAC) is a wasting syndrome characterized by involuntary weight loss and anorexia. Clear definition and diagnostic criteria for CAC are lacking, which makes it difficult to estimate its prevalence, to interpret research and to compare studies. There is no standard treatment to manage CAC, but previous studies support the use of cannabinoids for cachexia in other chronic diseases including HIV and multiple sclerosis. However, only a few randomized controlled trials (RCTs) and one meta‐analysis of this intervention in cancer populations are available. Non‐randomized studies of interventions (NRSIs) are often excluded from reviews due to variable methodology and potential for biases. This review aimed to consider NRSIs alongside RCTs to provide a complete summary of the available evidence that clinical decision makers could use in future investigations. Literature searches were conducted using three databases for relevant RCTs or NRSIs according to Cochrane methodology. Abstract and full texts of retrieved manuscripts were selected and retrieved by two investigators based on the PRISMA‐A guidelines, and risk of bias and quality of evidence assessments were performed. Outcome data on weight, appetite, quality of life, performance status, adverse effects, and mortality were combined by narrative synthesis and meta‐analysis where possible. Ten studies were included, four of which were RCTs and six NRSIs matching the eligibility criteria. Very low‐quality evidence from meta‐analysis suggested no significant benefits of cannabinoids for appetite compared with control (standardized mean difference: −0.02; 95% confidence interval: −0.51, 0.46; P = 0.93). Patient‐reported observations from NRSIs suggested improvements in appetite. Another meta‐analysis of moderate quality evidence showed that cannabinoids were significantly less efficient than active or inactive control on quality of life (standardized mean difference: −0.25; 95% confidence interval: −0.43, −0.07; P = 0.007). The effectiveness of cannabinoids alone to improve outcomes of CAC remains unclear. Low‐quality evidence from both RCTs and NRSIs shows no significant benefits of cannabinoids for weight gain, appetite stimulation, and better quality of life, three important outcomes of cachexia. Higher quality research integrating cannabinoids into multi‐modal therapies may offer better opportunities for developing CAC‐specific treatments. This review also highlights that findings from non‐randomized studies of interventions (NRSIs) can provide evidence of the effects of an intervention and advocate for the feasibility of larger RCTs.
... Pseudomonas aeruginosa is often a problem for burn victims and Cystic Fibrosis patients. Cannabinoids are popular amongst cystic fibrosis patients but it is unknown if such patients could or would want to resort to inhalation based delivery [91][92][93] . Corbus Pharmaceuticals has been advancing modified cannabinoids through the FDA to treat Cystic Fibrosis and other fibrotic diseases. ...
Cannabis microbial testing presents unique challenges. Unlike food testing, cannabis testing has to consider various routes of administration beyond just oral administration. Cannabis flowers produce high concentrations of antimicrobial cannabinoids and terpenoids and thus represent a different matrix than traditional foods 1, 2. In 2018, it is estimated that 50% of cannabis is consumed via vaporizing or smoking oils and flowers while the other half is consumed in Marijuana Infused Products or MIPs. Transdermal patches, salves and suppositories all present unique microbial safety considerations. Since the most harmful cannabis microbes are endophytes (live in side the plant), culture based plating system fail to adequately survey the microbial risks. The pros and cons of DNA based methods and culture based methods are discussed.
... Two recent studies of cannabis use in pregnancy seems to provide relative reassurance of lack of data to support birth defects, significant intrauterine growth retardation, or cognitive sequelae (Gunn et al., 2016;Torres and Hart, 2016). Eventually, cannabis based medicines will become available for serious pediatric conditions, such as nausea and vomiting with in chemotherapy and supportive oncology (Abrahamov and Mechoulam, 1995), primary treatment of cancer (Foroughi et al., 2011), cystic fibrosis (Fride, 2002), and severe neurologic impairment (Gottschling, 2011), and these concerns will require ongoing consideration. ...
This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.
... An extensive list of other disorders previously cited that may fall under the CED rubric included 3 neonatal failure to thrive, 9 cystic fibrosis, 10 causalgia, 11 brachial plexopathy, 12 phantom limb pain, infantile colic, glaucoma, 13 dysmenorrhea, 14 hyperemesis gravidarum, 15 unexplained fetal wastage (repetitive miscarriages), post-traumatic stress disorder (PTSD), 16,17 bipolar disease, 18 and possibly many others. All display as yet unfathomed pathophysiological features and remain treatment resistant. ...
Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocanna-binoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migrai-neurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.
... Endocannabinoid mechanisms also regulate bronchial function [104], and therapeutic efficacy in asthma treatment with cannabis preparations has been long known [105]. Based on similar analyses of the multi-organ involvement of cystic fibrosis [106], Fride has proposed endocannabinoid deficiencies as underlying the pathophysiology of that disorder, and its treatment with phytocannabinoids. ...
OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
... Endocannabinoid mechanisms also regulate bronchial function [104], and therapeutic efficacy in asthma treatment with cannabis preparations has been long known [105]. Based on similar analyses of the multi-organ involvement of cystic fibrosis [106], Fride has proposed endocannabinoid deficiencies as underlying the pathophysiology of that disorder, and its treatment with phytocannabinoids. ...
... Endocannabinoid mechanisms also regulate bronchial function [104], and therapeutic efficacy in asthma treatment with cannabis preparations has been long known [105]. Based on similar analyses of the multi-organ involvement of cystic fibrosis [106], Fride has proposed endocannabinoid deficiencies as underlying the pathophysiology of that disorder, and its treatment with phytocannabinoids. ...
... Endocannabinoid mechanisms also regulate bronchial function [104], and therapeutic efficacy in asthma treatment with cannabis preparations has been long known [105]. Based on similar analyses of the multi-organ involvement of cystic fibrosis [106], Fride has proposed endocannabinoid deficiencies as underlying the pathophysiology of that disorder, and its treatment with phytocannabinoids. ...
OBJECTIVES:
This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis.
METHODS:
Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources.
RESULTS:
Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging.
CONCLUSION:
Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
... Two recent studies of cannabis use in pregnancy seems to provide relative reassurance of lack of data to support birth defects, significant intrauterine growth retardation, or cognitive sequelae (Gunn et al., 2016;Torres and Hart, 2016). Eventually, cannabis based medicines will become available for serious pediatric conditions, such as nausea and vomiting with in chemotherapy and supportive oncology (Abrahamov and Mechoulam, 1995), primary treatment of cancer (Foroughi et al., 2011), cystic fibrosis (Fride, 2002), and severe neurologic impairment (Gottschling, 2011), and these concerns will require ongoing consideration. ...
Introduction
To help open the clinician dialogue regarding cannabis use in persons with CF in the U.S., we aimed to describe current practices of use assessment and documentation processes related to cannabis.
Methods
A cross sectional, anonymous survey study was distributed via email to CF directors and coordinators and to the Cystic Fibrosis Foundation (CFF) listservs of nurse, pharmacist, dietitian, social worker and psychology care team members. The survey tool included multiple choice, scaled and open ended items, which assessed participants' awareness of current cannabis laws in their state, prescribing practices for medical marijuana, screening and documentation practices, knowledge of and what indications participants believe cannabis and cannabidiol (CBD) could be beneficial. Data was analyzed using descriptive statistics.
Results
There were 282 survey participants, with majority as providers (28%) and social workers (29%), representing all U.S. regions. Participants varied in terms of frequency of evaluating cannabis use, with 15.4% “always,” 48.4% “sometimes,” and 41% “rarely” or “never” asking about it. Regarding recreational versus medical cannabis use, 55.4% and 62.5% reported documentation of each type in the medical record, respectively. Participants reported appetite, pain, and nausea as the top three advocated indications for use. About 35% and 72% of participants felt “slightly” or “not at all” prepared to answer patient/family questions about cannabis and CBD, respectively.
Conclusions
The approach to cannabis use assessment, documentation, and education across CF care centers is variable. There is a need for care team and patient/caregiver education materials about cannabis/CBD and CF.
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In a wide sense, a palliative agent is a remedy that attenuates some symptoms associated with a disease, whereas a therapeutic agent is the one capable of curing a disease. Marihuana (Cannabis sativa) is a plant from Central Asia and its main active components (cannabinoids) are three: tetrahydrocannabinol, cannabinol and cannabidiol. They possess psychotropic and vegetative effects and, empirically, are reputed to exert some supposedly therapeutic actions involving the control of pain, vomiting, intraocular pressure and many other ailments. In agreement with official data from the "Consejo Nacional contra las Adicciones" (CONADIC, Mexico), during 1998-2000, the most extensively abused substances were marihuana, cocaine and industrial solvents. The consumption of marihuana in Mexico has increased with time. The average prevalence of the use of cannabis among the urban population from 12 to 65 years of age is 5.3%. The cities with the highest consumption of marihuana are Tijuana (14.7%), Ciudad Juárez (9.2%), Guadalajara (7.5%), Mexico City (7.3%), Monterrey (4.1%) and Matamoros (3.6%), a fact that indicates that the north-central region of Mexico is the most affected. Marihuana is the main drug consumed by almost all age groups without any distinction of gender. The consumption is predominantly higher in males (13.9%) than in females (6.9%), and among children from 12 to 17 years old who do not live with their families. The percentage of adolescents consuming marihuana is larger among youths who are not students (4.2%) than in the student population (1.3%). Thus, marihuana consumption is a real problem of public health in Mexico. The existence of at least two receptors to cannabinoids is well known, as well as a group of substances synthesized by the organism itself, denominated endocannabinoids, whose pharmacological properties resemble those of the plant. These observations have caused some parliamentary discussions that have led some countries to approve the use of the synthetic cannabinoid-related substances for therapeutic purposes. In the present review, recent literature was analyzed in order to offer an objective scientific perspective about the use of marihuana. Five relevant observations are pointed out: 1) Studies with positive findings, lack adequate controls. 2) The standards of comparison used, are not the most suitable, for example, the supposed analgesic property of cannabinoids is commonly compared with codeine, and the possible antiemetic capability of cannabinoids is not compared with well-known commercial and safe drugs with verified potency, such as the 5HT 3 receptor subtype agonist, odansetron. 3) Some authors claim that the plant may acts as a whole, and therefore some of the synthetic cannabinoids approved in other countries for therapeutic uses might not produce notable effects. 4) Only a few patients experience some improvement in their symptoms; however most of them experience the psychotropic actions of cannabinoids. And, 5) there are ethical aspects to reconsider in the case of patients who never before had consumed cannabinoids. The following aspects of the clinical use of cannabinoids are discussed in this review. For example, diverse reports suggest that marihuana increases food intake through CB1 receptor-stimulation producing hyperphage by itself, as well as anorexia related to immunodeficiency syndrome and cancer treatment. However, these patients also experience the psychotropic side-effects of marihuana and which lead them to leave the treatment. Regarding pain, cannabinoids produce spinal analgesia in experimental animals, which might be mediated by suppression of neuronal nocyceptive activity and the activation of opioid receptors. Nevertheless, most researchers who are exploring the efficacy of cannabinoids in pain treatment employ codeine as a reference, although codeine is in disuse due to its vegetative effects and poor potency, and do not compare it with other powerful analgesics such as opioids or prostaglandin inhibitors. In the immunologic system, cannabinoids act on CB2 receptors, decreasing the function of immune T and B cells, killer cells and macrophages. Therefore, infection processes might be increased in debilitated patients. By contrast, the immunosuppressant action of cannabinoids could be useful in hyperactivity of the immunologic system, as in the case of multiple sclerosis. On the other hand, recent findings suggest that a lipid imbalance (mainly with arachidonic acid) is a primary factor in the etiology of cystic fibrosis. Since the endocannabinoids are fatty acid derivatives, it has been hypothesized that the patients who suffer cystic fibrosis can receive benefits by the administration of cannabinoids (i.e. restoring the balance between fatty acids, reducing the symptoms and increasing life expectancies). Regardind reproduction research, prenatal cannabinoid exposure has been associated with a high perinatal morbidity but the possible long-term consequences are still poorly understood. Therefore, animal models of perinatal cannabinoid exposure have provided a useful tool for examining the developmental effects of the offspring. Results show alteration in the ontogeny of spontaneous locomotor activity and exploratory behavior. Adult animals exposed during pregnancy and lactation exhibited persistent alterations of the behavioral response to novelty, social interactions and sexual behavior. However, available data regarding the long-term behavioral and cognitive effects in humans are scarce to be compared with animal results. In other studies, some endocannabinoids generated in monocytes and platelets show that they are potent vasodilators and related to hypotension following hemorrhagic shock. Thus, animals treated with anandamide reduce their survival rate. In contrast, administration of the CB1 antagonist (SR141716A) increases the arterial pressure, the respiratory frequency and the survival rate in a dose-response manner. Thus, inhibition of the endogenous cannabinoids reverts the hemorrhagic shock with notorious efficacy, similar to endogenous opioids. In this sense, some other reports suggest that cannabinoids are useful to treat glaucoma, because cannabis reduces intraocular pressure in 60% of the users, although there are other drugs lacking psychotropic effects with proved and accepted efficacy in the treatment of glaucoma. Marihuana may also have certain anticonvulsivant properties; however delta-9THC alters sleep patterns in humans and could not be recommendable. In spite of some positive reports on the treatment of partial or tonic-clonic seizures, there is a lack of controlled studies.
Cannabinoids are known to enhance appetite by activating cannabinoid (CB1) receptors. This phenomenon is exploited to combat cachexia and loss of appetite in cancer and AIDS patients. The endocannabinoid 2-arachidonylglycerol (2-AG) is present in milk. Evidence is presented supporting a critical role for CB1 receptors in survival of mouse pups. Thus neonates do not gain weight and die within the first week of life when their receptors are blocked. This is due apparently, to an inability to ingest maternal milk. This suggests that the endocannabinoid-CB1 receptor system is unique in its absolute control over the initiation of the neonatal milk suckling response. It is further proposed that cannabis-based medicines should be developed to benefit infant failure to thrive.
Cystic fibrosis (CF) is a hereditary disease caused by mutations of the gene encoding a channel protein CFTR, conducting Cl- and HCO3 - ions. The disease is characterized by disturbances in most physiological systems, and more than 95% of men are infertile. The mechanism underlying the etiology of CF is associated with an imbalance of fatty acids. It has been suggested that the function of the endocannabinoid system is also disturbed in CF, because endocannabinoids are derivatives of fatty acids. We assumed, therefore, that endocannabinoid activity, which plays an important role in fertility, is disrupted in CF and could be one of the causes of infertility. The aim of the present study was to test the hypothesis that stimulation of endocannabinoid receptors in infancy would normalize their function and prevent infertility in adulthood.
Knockout male mice (cftr-/-) were treated with tetrahydrocannabinol (THC), endocannabinoid receptors agonist, in infancy from days 7 until 28, daily.
CF males treated with THC were fully fertile, producing offspring comparable by the number of litters and the number of pups with wild-type mice. CF males that were not treated with THC were completely infertile.
The present study shows that (i) endocannabinoid function is impaired in CF mice, as evidenced by the regenerating effect of its stimulation on the fertility of otherwise infertile males, (ii) endocannabinoid system dysfunction is apparently the determining factor causing infertility in CF, and (iii) mild stimulation of the endocannabinoid system in infancy and adolescence appears to normalize many reproductive processes and thereby prevent infertility in CF males.
Cystic fibrosis (CF) is an autosomal recessive disease. It affects multiple body organs. The lungs and pancreas are the most affected which results in progressive lung damage and pancreatic insufficiency. Due to the disease process, CF patients require significantly higher caloric intake than recommended for other individuals. The nutritional goal for CF patients is to achieve normal growth and development and, once genetic potential is reached, to maintain good nutritional status throughout life. Evidence has shown that lung function is closely associated with nutritional status in CF and that nutritional status is an independent predictor of survival. Most CF patients are on a high calorie diet to help achieve normal growth and development and maintain good lung function. Inadequate caloric intake in CF can lead to malnutrition. Malnutrition in CF requires careful, multidisciplinary history taking, physical exam, and overall patient/family assessment. Only by determining the actual cause of the malnutrition can appropriate and safe therapies be used to treat it. Appetite stimulants, although efficacious in treating malnutrition in CF, should only be prescribed if decreased food intake secondary to inadequate appetite is the principal cause of the malnutrition and all other contributing factors have been assessed, ruled-out or treated. In this review, we attempted to summarize the use of several appetite stimulants used in CF and other diseases to improve appetite and maximize caloric intake. Pediatr Pulmonol. 2008; 43:209–219. © 2008 Wiley-Liss, Inc.
En un sentido amplio, un paliativo es un remedio que mitiga los trastornos asociados a lo incurable, mientras que un agente terapéutico es aquel capaz de curar una enfermedad. La marihuana (Cannabis sativa) es una planta originaria de Asia Central y sus principales componentes activos (canabinoides) son tres: el tetrahidrocanabinol, el canabinol y el canabidiol, los cuales poseen propiedades psicotrópicas y vegetativas. Empíricamente, se les han atribuido ciertas acciones, en el manejo del dolor, del vómito y del aumento de la presión intraocular, entre otros síntomas. Particularmente en nuestro país y de acuerdo con datos oficiales del Consejo Nacional contra las Adicciones (CONADIC), durante el periodo comprendido de 1998 a 2000, las sustancias de consumo más extendido fueron la marihuana, la cocaína y los disolventes industriales. El consumo de marihuana en México se ha incrementado a través del tiempo, sin distinción de sexo, aunque predomina en el género masculino (13.9%) con respecto al femenino (6.9%) y entre adolescentes de 12 a 17 años que no viven con su familia; asimismo se documenta un mayor consumo en no estudiantes (4.2%) comparado con la población de estudiantes (1.3%). La prevalencia promedio del consumo de Cannabis Sativa en la población urbana de 12 a 65 años es de 5.3%. En particular, las ciudades con mayor consumo son Tijuana (14.7%), Ciudad Juárez (9.2%), Guadalajara (7.5%), Ciudad de México (7.3%), Monterrey (4.2%) y Matamoros (3.6%), reflejándose que la zona norte-centro del país es la más afectada. Así, el consumo de marihuana es un problema real de Salud Pública. Por otro lado, se ha aislado una serie de sustancias sintetizadas por el propio organismo cuyas propiedades farmacológicas se asemejan a las de los canabinoides y que, por ser agonistas de los receptores específicos también presentes en el organismo, reciben la denominación de endocanabinoides, cuya manipulación farmacológica podría ser de utilidad terapéutica. Estas observaciones han llevado a la legalización del uso de los canabinoides con fines terapéuticos, en algunos países. En la presente revisión se analizó bibliografía reciente a fin de ofrecer una perspectiva científica y objetiva acerca del uso médico de la marihuana. Se tienen cinco observaciones a considerar a propósito de aceptar o no a la marihuana como una alternativa terapéutica: 1) Los estudios documentan hallazgos positivos, carecen de controles adecuados; 2) los estándares de comparación, no son los más idóneos, por ejemplo, la potencia analgésica de los canabinoides suele ser comparada con la codeína, que es un analgésico en desuso por su baja potencia, en tanto que la eficacia antiemética de los canabinoides no es comparada con compuestos de eficacia comprobada, es decir, los agonistas al receptor serotonérgico 5-HT3, como el odansetrón; 3) algunas investigaciones arguyen que la planta puede actuar como un todo, por lo que los canabinoides sintéticos aprobados para su uso terapéutico en otros países, podrían carecer de efectos notables; 4) son pocos los pacientes que responden de manera eficaz al tratamiento en comparación con los que experimentan los efectos psicotrópicos; y 5) cuando la población blanco son pacientes que nunca antes habían consumido canabinoides, se deben considerar aspectos éticos. El hallazgo de los endocanabinoides abre caminos para la comprensión de los procesos homeostáticos relacionados con los afectos y ciertos aspectos de la motivación, y los avances recientes en medicina genómica han conducido a especular sobre la manipulación de receptores a endocanabinoides. Sin embargo, la manipulación de estos receptores, si bien puede suprimir el uso de la marihuana en adictos, quizá tenga repercusiones en el apetito, el talante, la percepción y el sentido del tiempo entre otros aspectos conductuales, toda vez que los endocanabinoides tienen acciones bien definidas sobre los puntos antes mencionados. Por lo tanto, se concluye que los canabinoides poseen algunos efectos paliativos, no terapéuticos, cuya administración a enfermos graves y debilitados podría representar riesgos innecesarios y su posible uso terapéutico debe ser precedido por el análisis exhaustivo de otras opciones terapéuticas.
Endogenous cannabinoids (endocannabinoids) and their cannabinoid CB1 and CB2 receptors, are present from the early stages of gestation and play a number of vital roles for the developing organism. Although most of these data are collected from animal studies, a role for cannabinoid receptors in the developing human brain has been suggested, based on the detection of "atypically" distributed CB1 receptors in several neural pathways of the fetal brain. In addition, a role for the endocannabinoid system for the human infant is likely, since the endocannabinoid 2-arachidonoyl glycerol has been detected in human milk. Animal research indicates that the Endocannabinoid-CB1 Receptor ('ECBR') system fulfills a number of roles in the developing organism: 1. embryonal implantation (requires a temporary and localized reduction in anandamide); 2. in neural development (by the transient presence of CB1 receptors in white matter areas of the nervous system); 3. as a neuroprotectant (anandamide protects the developing brain from trauma-induced neuronal loss); 4. in the initiation of suckling in the newborn (where activation of the CB1 receptors in the neonatal brain is critical for survival). 5. In addition, subtle but definite deficiencies have been described in memory, motor and addictive behaviors and in higher cognitive ('executive') function in the human offspring as result of prenatal exposure to marihuana. Therefore, the endocanabinoid-CB1 receptor system may play a role in the development of structures which control these functions, including the nigrostriatal pathway and the prefrontal cortex. From the multitude of roles of the endocannabinoids and their receptors in the developing organism, there are two distinct stages of development, during which proper functioning of the endocannabinoid system seems to be critical for survival: embryonal implantation and neonatal milk sucking. We propose that a dysfunctional Endocannabinoid-CB1 Receptor system in infants with growth failure resulting from an inability to ingest food, may resolve the enigma of "non-organic failure-to-thrive" (NOFTT). Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Excellent clinical results have previously been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma. We suggest cannabinoid treatment for children or young adults with cystic fibrosis in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.
Recent research suggests that the endogenous cannabinoids ("endocannabinoids") and their cannabinoid receptors have a major influence during pre- and postnatal development. First, high levels of the endocannaboid anandamide and cannabinoid receptors are present in the preimplantation embryo and in the uterus, while a temporary reduction of anandamide levels is essential for embryonal implantation. In women accordingly, an inverse association has been reported between fatty acid amide hydrolase (the anandamide degrading enzyme) in human lymphocytes and miscarriage. Second, CB(1) receptors display a transient presence in white matter areas of the pre- and postnatal nervous system, suggesting a role for CB(1) receptors in brain development. Third, endocannabinoids have been detected in maternal milk and activation of CB(1) receptors appears to be critical for milk sucking by newborn mice, apparently activating oral-motor musculature. Fourth, anandamide has neuroprotectant properties in the developing postnatal brain. Finally, prenatal exposure to the active constituent of marihuana (Delta(9)-tetrahydrocannabinol) or to anandamide affects prefrontal cortical functions, memory and motor and addictive behaviors, suggesting a role for the endocannabinoid CB(1) receptor system in the brain structures which control these functions. Further observations suggest that children may be less prone to psychoactive side effects of Delta(9)-tetrahydrocannabinol or endocannabinoids than adults. The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including "non-organic failure-to-thrive" and cystic fibrosis.
The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB1 receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB1 receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB1 receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause.
This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis.
Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources.
Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging.
Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
Many constituents of cannabis exhibit beneficial anti-in- flammatory properties, such as 9-tetrahydrocannabinol (THC) in mar- ijuana and gamma-linolenic acid (GLA) in hemp seed oil. The effects of these cannabis constituents on eicosanoid metabolism is reviewed. THC and GLA modulate the arachidonic acid cascade, inhibiting the production of series 2 prostaglandins and series 4 leukotrienes. Canna- binoid receptor- as well as non-receptor-mediated signal transduction pathways appear to be involved. It is proposed that THC acts as a selective cyclooxygenase-2 (COX-2) inhibitor. (Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: Website: 2001 by The Haworth Press, Inc. All rights reserved.)
Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1\ (Ki>10\ mu M), but does so efficiently to CB2\ (Ki=22.7± 3.9\ nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.
Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands
for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry
and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a
radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent
inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids.
These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
In cystic fibrosis (CF), defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells and submucosal glands results in chronic pulmonary infection with Pseudomonas aeruginosa. The pulmonary infection incites an intense host inflammatory response, causing progressive suppurative pulmonary disease. Mouse models of CF, however, fail to develop pulmonary disease spontaneously. We examined the effects of bronchopulmonary infection on mice homozygous for the S489X mutation of the CFTR gene using an animal model of chronic Pseudomonas endobronchial infection. Slurries of sterile agarose beads or beads containing a clinical isolate of mucoid P. aeruginosa were instilled in the right lung of normal or CF mice. The mortality of CF mice inoculated with Pseudomonas-laden beads was significantly higher than that of normal animals: 82% of infected CF mice, but only 23% of normal mice, died within 10 d of infection (P = 0.023). The concentration of inflammatory mediators, including TNF-alpha, murine macrophage inflammatory protein-2, and KC/N51, in bronchoalveolar lavage fluid in CF mice 3 d after infection and before any mortality, was markedly elevated compared with normal mice. This inflammatory response also correlated with weight loss observed in both CF and normal littermates after inoculation. Thus, this model may permit examination of the relationship of bacterial infections, inflammation, and the cellular and genetic defects in CF.
Using a pre-feed paradigm, the effects of orally-administered delta9-tetrahydrocannabinol (THC) on low baseline levels of nocturnal feeding were assessed. Following 2-h access to a palatable wet mash diet at dark onset, adult male Lister hooded rats (Charles River) were treated with either sesame seed oil vehicle or delta9- tetrahydrocannabinol (0.063, 0.12, 0.25, 0.5, 1.0, or 2.0 mg/kg). One hour later, rats were allowed ad libitum access to standard chow, and intakes were monitored over the subsequent 24 h. Doses of 0.5, 1.0, and 2.0 mg/kg produced substantial hyperphagia during the first hour of testing. Subsequently, rats compensated for their overconsumption so that 24-h intakes were similar in all conditions. The data confirm anecdotal reports of the orexigenic actions of exogenous cannabinoids and suggest a critical role for endogenous cannabinoid systems in the regulation of appetite.
The discovery of the endogenous cannabinoid N-arachidonoylethanolamine (anandamide) and other N-acylethanolamines (NAEs) in chocolate has led to speculation that the purported rewarding properties of cocoa are due to the presence of compounds ``that could act as cannabinoid mimics''. This observation raises some important questions. First, are NAEs and anandamide, or the `endocannabinoid' 2-arachidonoylglycerol (2-AG), present in widely consumed foods (such as milk) that are less `rewarding' than chocolate? And second, to what extent do these compounds reach the bloodstream and exert pharmacological effects when consumed orally? We believe that the content of endocannabinoids in foods, and in cocoa in particular, is not sufficient to produce cannabis-like effects in mammals.
Role of CFTR in Airway Disease. Physiol. Rev. 79, Suppl.: S215-S255, 1999. - Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), which accounts for the cAMP-regulated chloride conductance of airway epithelial cells. Lung disease is the chief cause of morbidity and mortality in CF patients. This review focuses on mechanisms whereby the deletion or impairment of CFTR chloride channel function produces lung disease. It examines the major themes of the channel hypothesis of CF, which involve impaired regulation of airway surface fluid volume or composition. Available evidence indicates that the effect of CFTR deletion alters physiological functions of both surface and submucosal gland epithelia. At the airway surface, deletion of CFTR causes hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content, which impairs mucociliary clearance. In submucosal glands, loss of CFTR-mediated salt and water secretion compromises the clearance of mucins and a variety of defense substances onto the airway surface. Impaired mucociliary clearance, together with CFTR-related changes in the airway surface microenvironment, leads to a progressive cycle of infection, inflammation, and declining lung function. Here, we provide the details of this pathophysiological cascade in the hope that its understanding will promote the development of new therapies for CF.
Physiological Basis of Cystic Fibrosis: A Historical Perspective. Physiol. Rev. 79, Suppl.: S3-S22, 1999. - Cystic fibrosis made a relatively late entry into medical physiology, although references to conditions probably reflecting the disease can be traced back well into the Middle Ages. This review begins with the origins of recognition of the symptoms of this genetic disease and proceeds to briefly review the early period of basic research into its cause. It then presents the two apparently distinct faces of cystic fibrosis: 1) as that of a mucus abnormality and 2) as that of defects in electrolyte transport. It considers principal findings of the organ and cell pathophysiology as well as some of the apparent conflicts and enigmas still current in understanding the disease process. It is written from the perspective of the author, whose career spans back to much of the initial endeavors to explain this fatal mutation.
Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as delta9-THC, and hypophagic effects of selective cannabinoid receptor antagonists.
This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors.
Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food intake tests. In a second series of intake tests (n=8), anandamide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC).
All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by SR141716 pretreatment.
This first demonstration of anandamide-induced, CB -mediated, overeating provides important evidence for the involvement of a central cannabinoid system in the normal control of eating.
A deficiency in essential fatty acid metabolism has been reported in plasma from patients with cystic fibrosis (CF). However, its etiology and role in the expression of disease is unknown. The objective of this study was to determine whether alterations in fatty acid metabolism are specific to CF-regulated organs and whether they play a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr(-/-) mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr(-/-) mice corrected this lipid imbalance and reversed the observed pathological manifestations. These results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels.
Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)-transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.
Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition
and chronic respiratory infections. Chronic lung infections withPseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and
mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility to P. aeruginosa colonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished,
and transgenic mice. CFTRm1Unc−/−
knockout mice displayed body weight variations and showed variable pulmonary clearance of P. aeruginosa. This variability was not detected in bitransgenicCFTRm1Unc−/−
(FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J
mice resulted in impaired pulmonary clearance of P. aeruginosa. Tumor necrosis factor alpha (TNF-α) and nitrite levels detected upon exposure to P. aeruginosaaerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role
of TNF-α and reactive nitrogen intermediates in P. aeruginosaclearance was tested in TNF-α and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-α- and iNOS-deficient mice. In contrast to the effects of TNF-α and iNOS, gamma
interferon knockout mice retained a full capacity to eliminate P. aeruginosafrom the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished
in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defective CFTR in the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial
colonization, and excessive inflammation in the CF respiratory tract.
Cannabinoid CB1 receptors emerge early in the rat brain during prenatal development, supporting their potential participation in events related to neural development. In the present investigation, we completed earlier studies, analyzing CB1 receptor binding and mRNA expression by using autoradiography and in situ hybridization, respectively, in the brain of rat fetuses at gestational day (GD) 21 and of newborns at postnatal days (PND) 1 and 5, in comparison with the adult brain. These analyses were paralleled by quantitation of levels of anandamide and its precursor, N-arachidonoyl-phosphatidylethanolamine (NAPE), and of 2-arachidonoyl-glycerol (2-AG), carried out by using gas chromatography / mass spectrometry of the tri-methyl-sylyl-ether derivatives. As expected, CB1 receptor binding was detected at GD21 in a variety of brain structures. In most of them, such as the hippocampus, cerebral cortex, cerebellum, basal ganglia, and limbic nuclei, there were no marked differences in the density of CB1 receptors in animals at GD21 as compared to early newborns (PND1 and 5), although it markedly increased in these regions in adulthood. However, with the exception of the cerebellum and, in part, the caudate-putamen, the pattern observed for binding in these regions was clearly different from that observed for mRNA expression of the CB1 receptor, which currently exhibited the highest levels at PND1 and the lowest in the adult brain. This was also seen in the basolateral amygdaloid nucleus, ventromedial hypothalamic nucleus, medial habenula, and other structures. In the caudate-putamen and, particularly, in the cerebellum, mRNA expression was higher in the adult brain as compared with other ages. As previously reported, specific binding for CB1 receptors was also detected at GD21 in white matter areas, such as the corpus callosum, anterior commissure, fornix, fimbria, stria medullaris, stria terminalis, and fasciculus retroflexum. With the exception of the anterior commissure and the fimbria, specific binding progressively decreased at PND1 and PND5 until disappearing in the adult brain. In the fimbria, the highest values of binding were seen at PND1, but binding also completely disappeared in the adult brain, whereas in the anterior commissure, specific binding at PND1 and PND5 was lesser than that observed at GD21 and, particularly, in adulthood. CB1 receptor mRNA expression was not detected in these white matter areas, thus dismissing the possible presence of these receptors in glial cells rather than in neuronal axons. However, mRNA expression was detected in the brainstem, an area also rich in white matter, and it mostly correlated with receptor binding, exhibiting a progressive decrease from GD21 up to adulthood. CB1 receptor mRNA expression was also detected at GD21 in atypical areas where binding was not detected. These areas are proliferative regions, such as the subventricular zones of the neocortex, striatum, and nucleus accumbens. This atypical location only persisted at PND1 and PND5 in the striatal subventricular zone, but disappeared in the adult brain. We also found measurable levels of different endogenous cannabinoids in the developing brain. High levels of 2-AG, comparable to those found in the adult brain, were measured at GD21, whereas significantly lower levels were measured for anandamide and NAPE at this fetal age compared with the levels found in the adult brain. Levels of anandamide and NAPE increased during the early postnatal period until reaching the maximum in the adult brain. By contrast, 2-AG levels peaked at PND1, with values approximately twofold higher than those found at the other ages. In summary, all these data demonstrate that the endogenous cannabinoid system, constituted by endogenous ligands and receptor signaling pathways, is present in the developing brain, which suggests a possible specific role of this system in key processes of neural development. Synapse 33:181–191, 1999. © 1999 Wiley-Liss, Inc.
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (−)-11-OH-Δ8-THC-dimethylheptyl was 80–1150 times more potent than Δ9-THC. Stereospecificity was demonstrated by its (+)- enantiomer which was more than 1400–7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (−)-11-OH-Δ9-THC-DMH was found to be equipotent with (−)-11-OH-Δ8-THC-DMH. The aldehyde (−)-11-oxo-Δ9-THC-DMH was 15–50 times more potent than Δ9-THC. Surprisingly, (−)-11-carboxy-Δ9-THC-DMH was also active, being slightly more potent than Δ9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to Δ9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.
We have previously shown that the endogenous putative cannabinoid ligand arachidonylethanolamide (anandamide, 20:4, n − 6) induces in vivo and in vitro effects typical of a cannabinoid agonist. We now report that two other endogenous anandamides, docosatetraenylethanolamide (anandamide, 22:4, n − 6) and homo-γ-linolenylethanolamide (anandamide, 20:3, n − 6), have similar activities. The new anandamides bind to SV40-transformed African green monkey kidney cells transfected with the rat brain cannabinoid receptor cDNA and display KI values of 253.4 ± 41.1 and 244.8 ± 38.7, respectively. The value found for arachidonylethanolamide was 155.1 ± 13.8 nM. In addition, the new anandamides inhibit prostaglandin E1-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells transfected with the cannabinoid receptor, as well as in N18TG2 mouse neuroblastoma cells that express the cannabinoid receptor naturally. The IC50 values for the inhibition of adenylate cyclase in transfected Chinese hamster ovary-K1 cells were 116.8 ± 8.7 and 109.3 ± 8.6 nM for docosatetraenylethanolamide and homo-γ-linolenylethanolamide, respectively. These values were similar to that obtained with arachidonylethanolamide (100.5 ± 7.7 nM), but were significantly higher than the IC50 value observed with the plant cannabinoid Δ9-tetrahydrocannabinol (9.2 ± 8.6 nM). The inhibitory effects of the anandamides on adenylate cyclase activity were blocked by pertussis toxin, indicating the involvement of pertussis toxin-sensitive GTP-binding protein(s). In a tetrad of behavioral assays for cannabinoid-like effects, the two new anandamides exerted similar behavioral effects to those observed with Δ9-tetrahydrocannabinol and arachidonylethanolamide: inhibition of motor activity in an open field, hypothermia, catalepsy on a ring, and analgesia on a hot plate.
We studied the ontogenetic response to cannabinoid receptor ligands by measuring motor activity and analgesia in response to anandamide or Δ9-THC from day 6 of age. No response to anandamide was observed up to the age of weaning (day 23), while a nonsignificant response to Δ9-THC was observed starting between days 15 and 20. This is compatible with observations that children respond to the antiemetic effects of THC without psychotropic side effects.
The background knowledge leading to the isolation and identification of anandamide and 2-arachidonoyl glycerol, the principal endocannabinoids is described. The structure–activity relationships of these lipid derivatives are summarized. Selected biochemical and pharmacological topics in this field are discussed, the main ones being levels of endocannabinoids in unstimulated tissue and cells, biosynthesis, release and inactivation of endocannabinoids, the effects of `entourage' compounds on the activities of anandamide and 2-arachidonoyl glycerol, their signaling mechanisms and effects in animals.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
Cystic fibrosis is the most common potentially lethal autosomal recessive disease of Caucasians, affecting 1 in 2500 newborns. Since the recent identification of the gene that is defective in patients with cystic fibrosis, a wealth of information about gene structure, the mutational basis of disease, and the function of the protein product has been derived. The product of the gene is a chloride channel that is regulated by adenosine 3',5'-monophosphate (cyclic AMP)-dependent protein kinase phosphorylation and that requires binding of adenosine triphosphate (ATP) for channel opening. Several new approaches to drug therapy for cystic fibrosis are now emerging, and the possibility of successful gene therapy by transfer of the normal gene to airway epithelial cells is being vigorously pursued.
Previously, we reported catch-up weight gain, growth, and improved lung function in a group of malnourished cystic fibrosis (CF) children receiving aggressive nutritional supplementation for 1 year compared with a forced expiratory volume in 1 s (FEV1)-, height-, and sex-matched comparison group receiving standard therapy. To evaluate long-term effects, the clinical progress of both groups has been studied over a 5 year period. The supplemented group (n = 10) received supplements for a median of 1.35 years to achieve nutritional rehabilitation. Compared with the nonsupplemented group (n = 14), the previously supplemented group had lower mortality (2 vs. 4, N.S.) and significantly greater weight and height z scores at 4 and 5 years. The progression of pulmonary function abnormalities as measured by FEV1 and forced vital capacity (FVC) slopes was greater at 3 years in the nonsupplemented group (FEV1, p less than 0.05) but no significant differences in rates of deterioration of pulmonary function were seen after 5 years in the two groups of survivors. We conclude that intensive nutritional support for 1 year has both short- and long-term effects on nutrition and growth, still evident some years after the cessation of this therapeutic modality. Supplementation for periods of longer than 1 year may produce greater gains and possibly prolong the improvement in pulmonary function observed in the earlier study.
The effects of a sustained increase in energy and protein intake on weight gain, growth, body protein metabolism, and the course of pulmonary disease were studied in 10 undernourished patients with cystic fibrosis unable to maintain nutrition and growth by the oral route and with declining nutritional and pulmonary status in the year prior to study. A 1-year course of nutrient supplementation using a semielemental high-nitrogen formula was delivered by nocturnal intragastric feeding or as an orally administered supplement; progress was compared with that of 14 height-, sex- and FEV1-matched patients with cystic fibrosis receiving conventional therapy. Supplementation resulted in a catch-up weight gain and sustained improvement in linear growth, with fewer pulmonary infections per year than during the initial observation period. Better weight gain and linear growth than in the comparison group were observed, as well as a significant reversal of the trend for deteriorating lung function. Compared with data from healthy children, 15N-glycine kinetics demonstrated increased protein breakdown and negligible net protein deposition in the treatment group prior to supplementation. After supplementation, synthesis in excess of breakdown, with net protein accretion, occurred by 1 month of supplementation. By 6 to 12 months a significant reduction in the previously high rate of mean synthesis and breakdown was observed, with maintenance of net anabolism. These dynamic changes in whole-body protein turnover reflect a long-term improvement in energy and protein intake, which can favorably affect nutrition, growth, and the course of pulmonary disease in problem cases of cystic fibrosis.
Nineteen patients with cystic fibrosis (CF) were studied to determine whether plasma fatty acids correlated with severity of their lung disease as assessed by pulmonary function testing. Results were compared with 19 normal subjects of similar age and sex. Linoleic acid content of all lipid fractions was significantly lower in CF patients than controls including cholesterol ester fraction (CF 31%, control 50%, p less than 0.001), triglyceride fraction (7.6 to 16.6%, p less than 0.001), and phospholipid fraction (13.9 to 21.7%, p less than 0.001). Mean 20:3 omega 9/20:4 omega 6 ratio for CF patients was higher in all lipid classes and was suggestive of essential fatty acid deficiency. Correlations were found to exist between most pulmonary function parameters and fatty acids of plasma phospholipids but not any other lipid class. Positive correlations were found between all ventilatory tests and total omega 3 polyunsaturated fatty acids and also 22:5 omega 3 and 22:6 omega 3. There was no correlation between total saturated fatty acids, total monounsaturates, total omega 6 fatty acids, or triene/tetraene ratios and pulmonary function. Positive correlations were found between pulmonary function parameters and certain omega 6 polyunsaturates including 20:4 and 22:4 but not 18:2.
Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent, delta-9-tetrahydrocannabinol (delta-9-THC), was administered (18 mg/m2 in edible oil, p.o.) to eight children, aged 3-13 years with various hematologic cancers, treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC so far is 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. The side effects observed were negligible.
Appetite stimulation by cannabinoids is highly variable. Four within-subject design studies explored the effects of age, gender, satiety status, route of drug administration, and dose on intake. One study involved a single oral administration of active drug (15 mg males, 10 mg females) or placebo to an age and gender stratified sample of 57 healthy, adult light marijuana users. Eleven subjects received single doses by oral, sublingual, and inhaled routes in a second study. In the third study, 10 subjects ingested a single oral dose in fasted and fed states. A 2.5 mg dose was administered b.i.d. for 3 days by oral and rectal suppository routes in the fourth study. Mean daily energy intake was significantly elevated following chronic dosing by rectal suppository, but not oral capsule, relative to all acute dosing regimens except inhalation. Total daily energy intake was comparable on fed and fasted days, suggesting satiety mechanisms were not impaired by the drug. Subject age, gender, reported "high," and plasma drug level were not significantly associated with drug effects on food intake.
Anandamide (arachidonylethanolamide) is a brain constituent which binds to the cannabinoid receptor. We now report the first in vivo examination of this ligand. Anandamide administered i.p. in mice, caused lowering of activity in an immobility and in an open field test, and produced hypothermia and analgesia. These effects parallel those caused by psychotropic cannabinoids.
The present study demonstrates the presence of cannabinoid receptors in the brain from early postnatal ages. Specific and saturable binding was observed in the forebrain and remaining brain from early postnatal ages (2 and 5 days after birth). Female neonate forebrain exhibited a higher receptor density at 2 days after birth than males, but this trend was inverted at 5 days. From postnatal day 10, the receptors could be measured in more defined brain areas, i.e. the striatum, limbic forebrain and ventral mesencephalon. The ontogeny of the receptors in these three areas was relatively similar, exhibiting a progressive increase which maximised on days 30 or 40 and then subsequently decreased to adult values. Subtle sexual dimorphism was found in the striatum and ventral mesencephalon but not the limbic forebrain.
In this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.
The objective of this study was to examine the incidence and therapy of chronic pain in a group of older patients with cystic fibrosis (CF).
We identified two groups of patients followed at the CF Center at Children's Hospital (Boston); the first group consisted of all patients above the age of 5 years who died between 1984 and 1993, and the second was a cohort of 23 additional CF patients who had been referred to the Pain Treatment Service.
Medical charts were reviewed for the etiology and therapy of all pain episodes requiring medical intervention.
The incidence of chronic pain in this population increased sharply in the last 6 months of life. Headaches (55% of patients) and chest pain (65%) were frequently reported, although back pain (19%), abdominal pain (19%), and limb pain (16%) were also reported. In patients with headache, the main etiologies were hypercarbia or hypoxia, migraine, and sinusitis. The majority of chest pain was musculoskeletal, with pleuritis, pneumothorax, and rib fracture also reported as the cause of chest pain.
A variety of nonpharmacological and pharmacological therapies were reported. Forty-one patients (53%) had pain severe enough to require opioid treatment, and 10 patients (13%) received opioids for more than 3 months. In eight patients with more severe pain, regional analgesia was found to be particularly effective.
Chronic pain is a common problem in CF, particularly as the patient population ages. When administered with caution, opioids have proven to be effective and safe in this population; regional anesthesia can be used to preserve pulmonary toilet while adequately treating severe pain.
We studied the effects of long-term (12 months) dronabinol in 94 late-stage acquired immunodeficiency syndrome (AIDS) patients (mean CD4 count of 45/mm3) who previously participated in a 6-week study (placebo versus dronabinol). All patients received dronabinol orally-2.5 mg twice daily (90%) or 2.5 mg once daily (10%). Appetite was measured using a visual analogue scale for hunger (VASH). Dronabinol was associated with consistent improvement in mean appetite. Patients previously treated with dronabinol continued to show improvement in VASH (percent change from baseline of 6-week trial: 48.6-76.1% at each month), whereas those previously treated with placebo exhibited substantial improvement in mean appetite, particularly during the initial 4 months of treatment (48.5-69.9%). Thereafter, dronabinol was associated with a VASH change at least twice baseline. Patients tended toward stable body weight for at least 7 months. Adverse events were primarily related to known central nervous system effects of dronabinol. These data support long-term, safe use of dronabinol for anorexia associated with weight loss in patients with AIDS.
Although airway obstruction and chronic endobronchial infection have long been recognized as major factors in the pathogenesis of lung disease in cystic fibrosis (CF), only recently has it been recognized that the inflammatory process itself may be responsible in a major way for destroying the lungs. The most characteristic feature of inflammation in the CF lung is the persistent infiltration of massive numbers of neutrophils into the airways. Although neutrophils help to control infection, when present in great excess, they cause more harm than good. Major advances in our understanding of the inflammatory process in the CF lung have come from the use of bronchoscopy and bronchoalveolar lavage (BAL) to analyze the inflammatory process in patients who are relatively symptom free and/or do not regularly produce sputum. Recent BAL studies suggest that neutrophil-rich inflammation begins very early, even in infants without clinically apparent lung disease. A number of chemoattractants from epithelial cells, macrophages, neutrophils themselves, and bacterial products contribute to the neutrophil influx. Surprisingly, some infants have inflammation even in the apparent absence of infection, leading to the speculation that inflammation may precede infection. Links between the basic defect in CF and inflammation have been postulated, with dysregulation of cytokine production and abnormal epithelial host defenses being implicated as causal factors of sustained inflammation. Regardless of the details of how this process is initiated and/or perpetuated, it has become clear that inflammation begins at a very early stage and progresses throughout life, gradually worsening and destroying the lungs. For these reasons, anti-inflammatory therapy should be initiated in early life. Additional studies are necessary to define the optimal antiinflammatory drugs and regimens, and to confirm their long-term safety and efficacy.
This paper reviews recent publications on the interrelationship of nutrition and pulmonary function in patients with cystic fibrosis. It is unclear whether low weight is a cause or an effect of declining pulmonary status in patients with cystic fibrosis. Epidemiologic studies suggest that low weight may be an independent predictor of mortality. Elevations in energy expenditure are not seen in presymptomatic infants. The elevations in energy expenditure seen in those with lung disease are not totally explained by increased oxygen cost of breathing and can be decreased by improving lung function. Although circulating levels of natural antioxidants and inflammation-modulating nutrients are low in patients with cystic fibrosis and can be increased with supplements, there are no recent data on their clinical effects. Nutritional intervention for patients with chronic illness needs to take into account psychosocial and adherence factors as well as nutritional prescriptions. Pancreatic enzyme supplementation should be limited to no greater than 2500 lipase units per kilogram per meal to decrease the risk of developing dose-related fibrosing colonopathy.
Essential fatty acid deficiency is well known in cystic fibrosis patients, but its pathogenesis remains unclear. It might be related to protein-energy malnutrition which is a common feature of cystic fibrosis or to some specific defects in fatty acid metabolism. To avoid the deleterious effects of protein-energy malnutrition, this study assesses the plasma phospholipid fatty acid pattern in well nourished young cystic fibrosis subjects. Sixteen cystic fibrosis subjects aged 6.6–20.0 years were studied and compared to 16 healthy controls matched for gender, age and nutritional status. Plasma phospholipids were separated by thin layer chromatography and phospholipid fatty acid pattern was determined by gas liquid chromatography. Anthropometry and dual-energy X-ray absorptiometry showed that lean body mass, fat-free mass and fat mass were similar in the two groups. Nutritional inquiry showed higher ingestion of macronutrients by cystic fibrosis subjects than by controls. Plasma phospholipid palmitoleic acid and eicosatrienoic acid were higher, and by contrast linoleic acid and docosahexaenoic acid were lower in cystic fibrosis subjects than in controls. The ratio linoleic acid/arachidonic acid was lower and the ratio eicosatrienoic acid/arachidonic acid was higher in cystic fibrosis subjects than in controls.
Conclusion Essential fatty acid deficiency is present in young cystic fibrosis subjects in the absence of protein-energy malnutrition. It means that this deficiency is probably related to specific defects in fatty acid metabolism.
The effect of cannabinoid receptor activation and blockade on the propulsive activity in the mouse small intestine was assessed in the present study by measuring the transit of an orally administered, non-absorbable marker. The cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de-1, 4benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) inhibited, while the selective cannabinoid CB1 receptor antagonist SR 141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyraz ole-carboxamide) stimulated the marker transit. Furthermore, a per se non-effective dose of SR 141716A reversed WIN 55,212-2-induced reduction of the transit. The results of the present study suggest a role for cannabinoid CB1 receptors in the control of propulsive activity in the mouse small intestine.
Great progress has been made both in understanding the pathophysiology of cystic fibrosis and in providing comprehensive medical care for both children and adults with this illness. Cystic fibrosis is the most common genetic disease affecting white people in the United States. Whereas 30 years ago a minority of patients reached their teens, now the median survival is about 30 years and is steadily increasing. Considerable work remains to be done in order to better understand how the defect in the cystic fibrosis transmembrane conductance regulator interacts with other ion channels in the lung to create an environment of chronic infection and inflammation. There is promise in the fact that various treatment modalities are in different stages of investigation and that the improvement of the outcomes for patients with cystic fibrosis, and ultimately a cure for this disease, may be forthcoming.
To determine the spectrum of musculoskeletal complications of cystic fibrosis (CF) in a paediatric population in Australia.
Clinical assessment followed by serology and bone scan on patients attending a specialized CF clinic.
Of 125 patients studied, 21 had musculoskeletal complications, 17 attributable to CF. Eleven had joint involvement (six hypertrophic pulmonary osteoarthropathy (HPOA)), one CF arthropathy, two ciprofloxacin induced arthralgia, one joint contracture following long-line placement, one chest infection associated arthralgia), four kyphosis (two also with HPOA) and two thoracic deformity. HPOA was associated with older age, lower average pulmonary function and lower average Shwachman score. Three patients with HPOA died within 12 months of reporting symptoms. Kyphosis was also associated with older age and lower pulmonary function.
Increasing age with deteriorating clinical and pulmonary function were associated with a higher incidence of musculoskeletal involvement. The development of symptomatic HPOA is a marker of poor prognosis.
The use of cannabis for the management of a wide range of painful disorders has been well documented in case reports throughout history. However, clinical evaluations of cannabis and its psychoactive constituent THC have not led to a consensus regarding their analgesic effectiveness. On the other hand, THC and its synthetic derivatives have been shown to be effective in most animal models of pain. These antinociceptive effects are mediated through cannabinoid receptors in the brain that in turn appear to interact with noradrenergic and kappa opioid systems in the spinal cord to modulate the perception of painful stimuli. The endogenous ligand, anandamide, is also an effective antinociceptive agent. The extent to which the endogenous cannabinoid system is involved in the modulation of pain is currently unknown.
Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.
Cannabinoid CB(1) receptors emerge early in the rat brain during prenatal development, supporting their potential participation in events related to neural development. In the present investigation, we completed earlier studies, analyzing CB(1) receptor binding and mRNA expression by using autoradiography and in situ hybridization, respectively, in the brain of rat fetuses at gestational day (GD) 21 and of newborns at postnatal days (PND) 1 and 5, in comparison with the adult brain. These analyses were paralleled by quantitation of levels of anandamide and its precursor, N-arachidonoyl-phosphatidylethanolamine (NAPE), and of 2-arachidonoyl-glycerol (2-AG), carried out by using gas chromatography / mass spectrometry of the tri-methyl-sylyl-ether derivatives. As expected, CB(1) receptor binding was detected at GD21 in a variety of brain structures. In most of them, such as the hippocampus, cerebral cortex, cerebellum, basal ganglia, and limbic nuclei, there were no marked differences in the density of CB(1) receptors in animals at GD21 as compared to early newborns (PND1 and 5), although it markedly increased in these regions in adulthood. However, with the exception of the cerebellum and, in part, the caudate-putamen, the pattern observed for binding in these regions was clearly different from that observed for mRNA expression of the CB(1) receptor, which currently exhibited the highest levels at PND1 and the lowest in the adult brain. This was also seen in the basolateral amygdaloid nucleus, ventromedial hypothalamic nucleus, medial habenula, and other structures. In the caudate-putamen and, particularly, in the cerebellum, mRNA expression was higher in the adult brain as compared with other ages. As previously reported, specific binding for CB(1) receptors was also detected at GD21 in white matter areas, such as the corpus callosum, anterior commissure, fornix, fimbria, stria medullaris, stria terminalis, and fasciculus retroflexum. With the exception of the anterior commissure and the fimbria, specific binding progressively decreased at PND1 and PND5 until disappearing in the adult brain. In the fimbria, the highest values of binding were seen at PND1, but binding also completely disappeared in the adult brain, whereas in the anterior commissure, specific binding at PND1 and PND5 was lesser than that observed at GD21 and, particularly, in adulthood. CB(1) receptor mRNA expression was not detected in these white matter areas, thus dismissing the possible presence of these receptors in glial cells rather than in neuronal axons. However, mRNA expression was detected in the brainstem, an area also rich in white matter, and it mostly correlated with receptor binding, exhibiting a progressive decrease from GD21 up to adulthood. CB(1) receptor mRNA expression was also detected at GD21 in atypical areas where binding was not detected. These areas are proliferative regions, such as the subventricular zones of the neocortex, striatum, and nucleus accumbens. This atypical location only persisted at PND1 and PND5 in the striatal subventricular zone, but disappeared in the adult brain. We also found measurable levels of different endogenous cannabinoids in the developing brain. High levels of 2-AG, comparable to those found in the adult brain, were measured at GD21, whereas significantly lower levels were measured for anandamide and NAPE at this fetal age compared with the levels found in the adult brain. Levels of anandamide and NAPE increased during the early postnatal period until reaching the maximum in the adult brain. By contrast, 2-AG levels peaked at PND1, with values approximately twofold higher than those found at the other ages. In summary, all these data demonstrate that the endogenous cannabinoid system, constituted by endogenous ligands and receptor signaling pathways, is present in the developing brain, which suggests a possible specific role of this system in key processes of neural development. (c) 1999 Wiley-Liss, Inc.
Malnutrition was once thought to be an inevitable consequence of cystic fibrosis (CF). It is now considered preventable but still contributes considerable morbidity in children. Malnutrition is linked to poorer pulmonary function, reduced survival and quality of life. As the anticipated lifespan of children with CF continues to lengthen, the prevention of malnutrition attains greater importance. This review explores the complex organic and psychosocial factors implicated in the aetiology of malnutrition associated with CF.
The increased life expectancy of patients with cystic fibrosis (CF) may lead to medical complications such as osteoporosis. Based on data collected through a MEDLINE search (1985-May 1999) and review of references for additional relevant articles, nutrition status, weight, and disease severity are factors most highly correlated with osteopenia. Links also were noted with calcium and vitamin D intake, hypogonadism, chronic inflammation, and age, but findings in these areas are not consistent from one report to the next. Increased fracture rates and kyphosis are consequences of osteoporosis. Simple measures such as compliance with recommended nutrition guidelines and restrictions in corticosteroid therapy could be considered first-line management options. Further studies must be conducted to clarify factors involved in the etiology of osteoporosis in patients with CF and to identify the best treatment and prevention methods.
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