Emetic Potential Research Articles

Pranlukast prevents cysteinyl leukotriene-induced emesis in the least shrew ( Cryptotis parva)

Many chemotherapeutic agents activate multiple signaling systems, including potentially emetogenic arachidonic acid metabolites. Of these messengers, the emetic role of the leukotriene family has been neglected. The aims of this study were to test the emetic potential of key leukotrienes (LTA 4, LTB 4, LTF 4, and the cysteinyl leukotrienes LTC 4, LTD 4 and LTE 4), and to investigate whether the leukotriene CysLT 1 receptor antagonist pranlukast or mixed leukotriene CysLT 1/2 receptor antagonist Bay u9773 can prevent the LTC 4-induced emesis. Least shrews were injected with varying doses of one of the six tested leukotrienes and vomiting parameters were measured for 30 min. LTC 4 and LTD 4 were most efficacious, and significantly increased both the frequency and percentage of animals vomiting at doses from 0.1 and 0.05 mg/kg, respectively. The other tested leukotrienes were either weakly emetic or ineffective at doses up to 4 mg/kg. The relative emetogenic activities of the cysteinyl leukotrienes (LTC 4 = LTD 4 > LTE 4) suggest that leukotriene CysLT 2 receptors have a key role in emesis. However, pranlukast dose-dependently, and at 10 mg/kg completely, blocked LTC 4-induced vomiting, implicating a leukotriene CysLT 1 receptor-mediated emetic effect. Bay u9773 dose-dependently reduced the percentage of animals vomiting, but did not significantly reduce vomiting frequency. Fos immunoreactivity, measured subsequent to LTC 4-induced vomiting to define its putative anatomical substrates, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC 4 ( P < 0.05) versus vehicle injections. This study is the first to show that some leukotrienes induce emesis, possibly involving both central and peripheral leukotriene CysLT 1 and/or leukotriene CysLT 2 receptors.

The caring profession: Paediatricians and altruism

For my sins, I am on a national committee called the Pharmaceutical Benefits Advisory Committee (PBAC). Actually, I love it. Since 1988, the PBAC has been advising the Australian Government on which medicines should be funded through the national Pharmaceutical Benefits Scheme, based on cost-effectiveness and other criteria. Since 2006, the PBAC has also considered funding of new vaccines. It is a unique approach, designed to improve equity and to reduce the cost of medicines and vaccines to the Australian people. There are two paediatricians on the committee at present. Applications to the PBAC for funding are prepared by a sponsor, usually a pharmaceutical company. Under the Free Trade Agreement, the sponsor can opt for a special hearing to present their case verbally to the PBAC before the committee considers the application in private. These special hearings add significantly to the duration of an already jam-packed 3-day meeting, and since the companies are not allowed to present new data not already included in the hugely detailed applications, some members of the committee are not exactly enamoured of hearings. The best hearings are generally those in which a clinician is brought along by the company to talk about the implications to the patient of a rare condition or to clarify important clinical queries. At a recent meeting, the PBAC considered an application for botulinum toxin to be used to treat spasticity in children with cerebral palsy. There was a hearing. To my surprise, a consultant in paediatric rehabilitation who works at the same hospital as I entered with the pharmaceutical company representatives and proceeded to explain the clinical details of the benefits of botulinum toxin for affected children and different ways of assessing the children's response to therapy. He talked beautifully and helped the committee reach what I feel was a good decision. Earlier, there had been some internal committee gossip about the considerable honoraria that some clinicians were reputedly paid for a 5- or 10-min hearing presentation. After his presentation, I emailed my colleague asking him what he had been paid to appear. He replied almost instantly that the pharmaceutical company had only paid for his airfare and asking jokingly if he should have requested an honorarium. I replied that his position as an unpaid advocate for his patients was far more honourable than accepting an honorarium. I shared this exchange with some of the committee, who all responded, to the effect, ‘You paediatricians are all so nice and you care about your patients more than you care about money.’ Charles Dickens was a genius and a strong advocate of the rights of disadvantaged children, but his least endearing quality was a somewhat saccharine sentimentality. Over-sentimental paediatricians also have emetic potential, but at least paediatricians care. I am proud that altruism in medicine and particularly in paediatrics is not dead.

Pharmacology of a Novel, Orally Active PDE4 Inhibitor

Background: Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting. Methods: We evaluated NIS-62949 in a wide range of in vitro and ex vivo cell-based assays to ascertain its anti-inflammatory potential. The compound was evaluated in murine models of lipopolysaccharide-induced endotoxemia and pulmonary neutrophilia. Parameters of airway inflammation, airway hyperreactivity and bronchoconstriction were evaluated in a guinea pig model of antigen-induced allergy. In order to assess the emetic potential, the compound was evaluated biochemically for binding to high-affinity rolipram-binding site. Subsequently, the compound was tested in a surrogate model for emesis, and the results obtained were correlated directly to tests conducted in a Beagle dog model. Results: NIS-62949 is a potent, highly selective PDE4 inhibitor. The compound demonstrated potent ability to inhibit tumor necrosis factor-α release from human peripheral blood mononuclear cells, lymphocyte proliferation and cytokine production. The in vitro profile of NIS-62949 prompted further evaluation of the compound in vivo and the compound was found to be comparable to roflumilast in several experimental models of pulmonary inflammation. Importantly, NIS-62949 displayed a safer profile compared to roflumilast. Conclusions: Our results report the development of a promising, novel PDE4 inhibitor, NIS-62949, with a wider therapeutic window as compared to second-generation PDE4 inhibitors such as roflumilast.

THE FUNCTIONALLY RELEVANT “HIGH” STATES OF THE DA RECEPTORS — RELEVANCE TO SCHIZOPHRENIA AND ANTIPSYCHOTICS

Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing. A 3-week treatment with FFPM, at doses of 0.25 mg/kg and 0.5 mg/kg, significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the Morris water maze and the Step-down passive avoidance task. Interestingly, we found that while rolipram (0.5 mg/kg) reduced the duration of the α2 adrenergic receptor-mediated anesthesia induced by xylazine/ketamine, FFPM (0.5 mg/kg) or the vehicle did not have an evident effect. FFPM increased the cAMP, PKA and CREB phosphorylation and BDNF levels, and reduced the NF-κB p65, iNOS, TNF-α and IL-1β levels in the hippocampi of APP/PS1 trangenic mice, as observed by ELISA and Western blot analysis. Taken together, our data demonstrated that the reversal effect of FFPM on cognitive deficits in APP/PS1 transgenic mice might be related to stimulation of the cAMP/PKA/CREB/BDNF pathway and anti-inflammatory effects. Moreover, FFPM appears to have potential as an effective PDE4 inhibitor in AD treatment with little emetic potential.

Adapting ASCO and NCCN guidelines in institutional antiemetic guidelines benefits patients receiving chemotherapy

20508 Background: The primary endpoint of the present study was to determine the impact of adapting ASCO and NCCN guidelines for antiemetics (AE) in our institutional antiemetic guidelines. Methods: The emetic risk of chemotherapy regimens was calculated using the Hesketh classification. AE guidelines were adapted and approved by a multidisciplinary team and the Drugs and Therapeutics Committee. We have compared 2 groups: patients receiving the new adapted institutional AE with those receiving non-established antiemetic treatment. Patients recorded episodes of nausea and vomiting in a diary the day of chemotherapy administration and the following 4 days. Patients also recorded rescue antiemetic medications. Patients completed the Functional Living Index- Emesis (FLIE) questionnaire at baseline and on day 6. The FLIE total scores >108 was defined as ‘no impact on daily functional‘. The main updates of the new adapted AE guidelines included the addition of aprepitant in cisplatin-based schedules, granisetron dose of 1 mg instead of 3 mg or ondansetron and dexametasone dose based on the emetic potential of each chemotherapy protocol. A delayed antiemetic protocol was recommended for each chemotherapy protocol. Results: From February 2007 to August 2007 225 consecutive patients were prospectively included in the study, 119 patients before the implementation of new AE guidelines and 106 patients after. Patients receiving the new AE guidelines achieved a trend for more complete response (defined as no nausea, no vomiting and no AE rescue): 52% vs 66.7% (p=0.065). In the cisplatin-based group, patients receiving the new AE guidelines obtained a statistically significant benefit with the new protocol (47.6% vs 73.3 % [p=0.017]), and less patients presented a reduction in the FLIE score below 108 (42 % vs 24% [p=0.142]). Conclusions: Implementation of revised AE guidelines provides a better control of CINV with higher complete response rate, especially in patients receiving cisplatin-based schedules. No significant financial relationships to disclose.

Antiemetics: an update and the MASCC guidelines applied in clinical practice

Nausea and vomiting are two of the most severe problems for patients treated with chemotherapy. Until the late 1970s, nausea and vomiting induced by chemotherapy was an almost neglected research area. With the introduction of cisplatin, the cytotoxin with the highest emetic potential, research was stimulated and has now resulted in the development of two new classes of antiemetics, the serotonin and neurokinin antagonists. A large number of trials have fine-tuned antiemetic therapy and made evidence-based recommendations possible for the majority of patients receiving chemotherapy. This Review discusses the pathophysiology of nausea and vomiting, the development of antiemetics, highlights some of the newest antiemetics, and finally summarizes recommendations from the evidence-based guidelines developed by the Multinational Association of Supportive Care in Cancer.

Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain

We employed an ex vivo [(3)H]rolipram binding experiment to elucidate the mechanism of emetic activity of phosphodiesterase 4 inhibitors. In Suncus murinus (an insectivore used for evaluation of emesis), emetic potential as well as ability to occupy the high-affinity rolipram binding site in brain membrane fraction in vivo were determined for phosphodiesterase 4 inhibitors. In vitro, [(3)H]rolipram bound to the membrane fraction of S. murinus brain with high affinity and its value was comparable to that for rat brain (K(d)=3.6 nM and 3.5 nM, respectively). The test compounds included denbufylline, rolipram, piclamilast, CDP840 and KF19514, each of which possessed similar affinities for the rolipram binding sites in both S. murinus and rat brain. In S. murinus, these compounds induced emesis via intraperitoneal administration. Their ED(50) values were as follows: denbufylline (1.4 mg/kg), rolipram (0.16 mg/kg), piclamilast (1.8 mg/kg), CDP840 (20 mg/kg), and KF19514 (0.030 mg/kg). In addition, these compounds occupied the high-affinity rolipram binding site in vivo as detected by dose-dependent reduction in capacity of ex vivo [(3)H]rolipram binding in brain membrane fractions. A clear correlation was observed between dose required to induce emesis and that to occupy the high-affinity rolipram binding site for individual phosphodiesterase 4 inhibitors. We conclude that the emetic effect of phosphodiesterase 4 inhibitors is caused at least in part via binding to the high-affinity rolipram binding site in brain in vivo.

Delayed Vomiting in Children With Cancer After Receiving Moderately High or Highly Emetogenic Chemotherapy

Delayed vomiting is a potentially significant adverse effect of chemotherapy used to treat childhood cancer, but little is known about the experience of delayed vomiting in children and adolescents. An exploratory study was conducted to determine the pattern of delayed vomiting in children and adolescents with cancer after highly emetic chemotherapy and to identify possible risk factors. In a sample of 82 children and adolescents who completed 117 cycles of highly emetic chemotherapy, the overall prevalence of delayed vomiting was 32%. The frequency of delayed vomiting was highest on delayed day 2, with 21% of participants experiencing vomiting. By delayed day 7, only 9% of participants still reported vomiting. The severity of vomiting was moderate to severe in 11% to 12% of subjects. Age and gender had no significant effect on delayed vomiting. The emetic potential of the agent, incomplete protection from acute vomiting, and treatment regimens that lasted 6 or more days significantly affected delayed vomiting. In addition, a history of motion sickness, lack of acute control, and 6 or more days of chemotherapy were predictive of delayed vomiting.

Emetic potential of daily oral etoposide

Chemotherapeutic agents are classified by their degree of emetogenicity. Highly and moderately emetogenic agents require antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. Intravenous etoposide is listed as having low emetic potential. However, oral etoposide is categorized as having moderate emetogenicity. Daily oral etoposide is used in refractory germ cell cancer patients. We prospectively evaluated the emetic potential of oral etoposide in this patient population. Between August 2003 and February 2006, 16 patients with refractory germ cell cancer received single-agent, daily oral etoposide 50 mg/M(2) for 21 consecutive days every 4 weeks. All patients had progressed after cisplatin combination chemotherapy and had received high-dose chemotherapy with carboplatin plus etoposide (intravenously) with peripheral blood stem cell transplant. No patient received prophylactic antiemetics. Patients completed a six-question Multinational Association of Supportive Care in Cancer (MASCC) antiemetic tool during each day of etoposide during the first 21-day course. Nausea intensity and duration were recorded. Number of emetic episodes and any antiemetic medications were recorded. All 16 patients completed the six-question MASCC form. Eleven of 16 had no nausea or vomiting and two other patients had only minimal nausea, despite absence of any prophylactic antiemetics. Only two patients required antiemetic support. Two patients experienced emesis for a single episode. One patient had nausea on days 9-20 with a MASCC rating of 3-6, and one patient had continued mild nausea (MASCC rating 1-3) for all 21 days. Daily oral etoposide has a low probability of producing chemotherapy-induced nausea and/or vomiting and, in our opinion, does not require prophylactic antiemetics.

Emetic potential of daily oral etoposide

18618 Background: Chemotherapy agents are classified by their degree of emetogenicity. Agents with high or moderate emetogenicity are treated with a 5HT3 antagonist + dexamethasone to mitigate acute and delayed chemotherapy-induced nausea and vomiting. Intravenous etoposide (E) has low probability of nausea and/or vomiting. However, at the 2004 Perugia International Antiemetic Consensus meeting, oral E was listed as a moderately emetogenic drug (Supp Care Cancer 13:80–84, 2005). Daily oral E has been used to treat refractory germ cell cancer. We prospectively evaluated the emetic potential of daily oral etoposide in this patient (pt.) population. Methods: Between 8/03 and 12/05, 13 male pts. with refractory germ cell cancer were treated with single agent daily oral E 50 mg/M2 day × 21 days every 4 weeks. All had progressed following cisplatin combination chemotherapy and had previously received high dose chemotherapy with carboplatin + E (intraveneously) with peripheral blood stem cell transplant. Median age was 35 (range 14 to 54). No pt. received prophylactic antiemetics. Pts. completed a 6 question Multinational Association Supportive Care Cancer (MASCC) antiemetic tool each day they received E. Intensity and duration of nausea were recorded, with 0 being none and 10 being most severe. Additionally, pts. were asked if they experienced vomiting. The number of vomiting episodes as well as any antiemetic medications were recorded. Data on 25 pts. will be presented and we currently have information on 13 pts. Results: 13 pts. completed the MASCC form. Only 2 pts. required antiemetic support. 1 pt. experienced emesis × 1 on day 1 and 1 pt. experienced emesis × 1 on day 11. 1 pt. experienced nausea on days 9 through 20 with a MASCC rating of 3–6. 1 pt. documented nausea day 1 through 21 with a MASCC rating of 1–3. 2 pts. experienced a MASCC rating of 1 of their nausea, 1 pt. on day 1 and 1 pt. on day 2. Overall, 8 of 13 pts. had no nausea or vomiting despite the absence of any antiemetics and 2 other patients had only minimal nausea for a single day. Conclusions: Daily oral E has only a low probability of emesis and does not require prophylactic antiemetics. [Table: see text]

The Development of Future Research Strategies from Reviewing Antiemetic Trials for Chemotherapy Induced Emesis

In reviewing the latest trials of antiemetic usage to prevent cytotoxic chemotherapy induced emesis, gaps in the literature suggest directions for future research and identify methodological approaches to be used in future investigations. The usage of molecular techniques and the identification of new receptors may allow new antiemetics to be developed and identification of the genes coding for antiemetic receptors may be used to select the appropriate antiemetics for individuals. Given the success achieved in controlling post chemotherapy vomiting, future studies should focus upon the control of nausea, and measure the impact of antiemetic control on quality of life as well as evaluating the pharmacoeconomics of these agents. Accounting for the interaction of antiemetics with cytotoxics becomes more important in trial design with the increasing complexity of antiemetic regimens. More information is needed on the emetic potential of the various combination chemotherapy regimens, multiple day chemotherapy and chemotherapy over multiple cycles. The emetic potential of prolonged administration of oral chemotherapy and newer biologicals and targeted therapies needs to be recorded. Further studies are required in specialized areas such as with high dose chemotherapy, for radiation induced emesis and in pediatrics.

婦人科がん化学療法による嘔気・嘔吐に対するｄｅｘａｍｅｔｈａｓｏｎｅの効果

Nausea and vomiting are two of the most unpleasant adverse effects associated with the use of antineoplastic agents and many patients regard them as the most stressful aspect of their disease, more stressful than even than the prospect of dying. Cisplatin, one such agent, is well known for having an emetic potential of almost 100% when administered to patients without emesis prophylaxis. The nausea it causes is the delayed-type and is hard to suppress completely with 5-HT3 antagonists. Dexamethasone (DEX) is often an effective antiemetic for cisplatin-induced nausea and vomiting, either by itself or in combination with other antiemetics. Though patients were receiving cisplatin under our regimen it did not include DEX.We therefore investigated the effects of DEX in patients with uterine cervix cancer who were being treated with a regimen including cisplatin. DEX reduced the degree of nausea and frequency of vomiting and increased appetite. It also improved the cost-effectiveness of the regimen. Based on these results, gynecologists in our hospital decided to include DEX in the cisplatin regimen.We feel that DEX should be the antiemetic drug of choice for cisplatin-regimens and in future, drug regimens should be specifically designed for each patient depending on the cause of nausea and vomiting, and the available evidence.

Update on anti‐emetics for chemotherapy‐induced emesis

The need to control chemotherapy-induced emesis has stimulated research into anti-emetics. Emesis is not only unpleasant, but negatively impacts on global quality of life. The development of two new classes of drugs has been responsible for the major advances in anti-emesis. The 5 hydroxytryptamine3 (5HT3) antagonists in combination with dexamethasone significantly improved the control of acute post chemotherapy emesis, but delayed emesis which can last for several days was still problematic, yet its incidence was underestimated by clinicians. Both the control of acute and delayed emesis was improved when the neurokinin1 (NK1) receptor antagonists were added to 5HT3 antagonists and steroids. The complete control of delayed emesis was improved by 21% with little toxicity. The triple drug combination has become the standard of care for preventing the emesis associated with cytotoxic drugs of high emetic potential.

In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration.

N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281) is a highly potent and selective phosphodiesterase 4 (PDE4) inhibitor that was designed to have a metabolic profile that was optimized for topical administration. The aim of the current study was to explore the pharmacological profile of intratracheally administered AWD 12-281 in different models of asthma and chronic obstructive pulmonary disease (COPD) in comparison with steroids. To assess the anti-inflammatory potential of AWD 12-281, the antigen-induced cell infiltration in bronchoalveolar lavage fluid (BALF) of Brown Norway rats was determined. AWD 12-281 (ID50 of 7 microg/kg i.t.) as well as beclomethasone (0.1microg/kg i.t.) suppresses late-phase eosinophilia when administered intrapulmonary. Furthermore, AWD 12-281 has also strong anti-inflammatory properties when tested in lipopolysaccharide-induced acute lung neutrophilia in Lewis rats (ID50 of 0.02 microg/kg i.t.), ferrets (ID50 of 10 microg/kg i.t.), and domestic pigs (2-4 mg/pig i.t. or 1 mg/kg i.v.). In pigs, AWD 12-281 was as effective as beclomethasone (0.4 mg/pig i.t.) and dexamethasone (0.28 mg/kg i.v.), although at 3 to 10 times the dosage. The bronchodilatory activity of AWD 12-281 was assessed in sensitized guinea pigs. AWD 12-281 (1.5 mg/kg i.t., 1-h pretreatment) inhibited allergen-induced bronchoconstriction by 68% (parameter airway resistance). In sensitized BP-2 mice AWD 12-281 abolished the allergen-induced bronchial hyperresponsiveness and eosinophilia in BALF, showing dose dependence. When given orally, i.v. or i.t., AWD 12-281 has a considerably lower emetic potential than cilomilast in ferrets and roflumilast in pigs. When given topically by inhalation, no emesis could be induced in dogs up to the highest feasible dose (15 mg/kg in 50% lactose blend). These results indicate that AWD 12-281 is a unique potential new drug for the topical treatment of asthma and COPD.

Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease.

Phosphodiesterases (PDE) belong to an important family of proteins that regulate the intracellular levels of cyclic nucleotide second messengers. Targeting PDE with selective inhibitors may offer novel therapeutic strategies in the treatment of various conditions, and in the context of respiratory disease these include asthma and chronic obstructive pulmonary disease (COPD). The rationale for such an approach stems, in part, from the clinical efficacy of theophylline, an orally active drug that is purportedly a nonselective PDE inhibitor. In addition, intracellular cyclic adenosine monophosphate (cAMP) levels regulate the function of many of the cells thought to contribute to the pathogenesis of respiratory diseases such as asthma and COPD, and these cells also selectively express PDE4. This has offered pharmaceutical companies the opportunity to selectively targeting these enzymes for the treatment of these diseases. Finally, the success of targeting PDE5 in the treatment of erectile dysfunction provides clinical proof of concept for the targeting of PDE in disease. Whether a 'Viagra' of the airways can be found for the treatment of asthma and COPD remains to be seen, but positive results from recent clinical studies examining the efficacy of selective PDE4 inhibitors such as cilomilast and roflumilast offer some optimism. However, one of the major issues to be resolved is the tolerability profile associated with this drug class that is a consequence of PDE4 inhibition. While cilomilast and roflumilast have low emetic potential they are not free from emesis and various strategies are being investigated in the hope of developing a PDE4 inhibitor without this adverse effect.

Assessing the emetic potential of PDE4 inhibitors in rats.

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey

Pre-clinical and clinical studies are currently underway to evaluate the potential of phosphodiesterase-4 (PDE4) inhibitors for the treatment of chronic obstructive pulmonary disease and other inflammatory conditions of the airways. The most common side effect associated with this class of compounds is emesis. The squirrel monkey provides a model for evaluating the efficacy of PDE4 inhibitors and their emetic potential. The distribution of three PDE4 isoforms (A, C and D) has been investigated in the squirrel monkey medulla and nodose ganglion to determine which isoform(s) could be responsible for the emetic adverse effects. The distribution of PDE4 isoforms was delineated using immunohistochemistry with antibodies specific for PDE4A, PDE4C and PDE4D and by in situ hybridization with isoform-selective riboprobes. PDE4A was present in the medulla where expression was mostly restricted to glial cells and the vasculature. PDE4C was not detected in either the medulla or nodose ganglion. Finally, the PDE4D isoform was localized to neurons in the nodose ganglion and found through many structures of medulla including the area postrema, neurons of the nucleus tractus solitarius and locus coeruleus. These data are consistent with a role for PDE4D in the emetic response.

Opioid receptor involvement in the adaptation to motion sickness in Suncus murinus

The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of 1 Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, ip) or morphine (0.1 mg/kg, ip) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, ip) revealed an emetic response to morphine ( P<.001) (1.0 mg/kg, ip) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.

Δ9-Tetrahydrocannabinol and Synthetic Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/Inverse Agonist SR 141716A

There is substantial clinical evidence that Δ9-tetrahydrocannabinol (Δ9-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB1 receptor or the cannabinoid CB2 receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB1 receptor antagonist) or SR 144528 (CB2 receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7–15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6–9 per group) administration of SR 141716A caused emesis (ED50 = 5.52 ± 1.23 and 20.2 ± 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB2 antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Δ9-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Δ9-THC which is consistent with an action on the CB1 receptor. These results suggest that the antiemetic activity of Δ9-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB1 receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Δ9-THC. On the other hand, blockade of CB1 receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.

Synthesis and biological evaluation of 2,5-dihydropyrazolo[4,3- c]quinolin-3-ones, a novel series of PDE 4 inhibitors with low emetic potential and antiasthmatic properties

A novel series of 2,5-dihydropyrazolo[4,3- c]quinolin-3-ones has been prepared. These compounds showed good PDE 4 inhibitory activity and weak affinity for rolipram's binding site. They also exhibited a good anti-inflammatory profile without emetic side effects.