pyrimidinones and Vomiting

Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced lopinavir/ritonavir tablets.. A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period.. Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks.. The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.

Topics: Adult; Alanine Transaminase; Antibiotics, Antitubercular; Aspartate Aminotransferases; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Nausea; Pyrimidinones; Rifampin; Ritonavir; Tablets; Vomiting

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fatigue; Female; Fever; Fibrin Fibrinogen Degradation Products; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vomiting

Topics: Animals; Antineoplastic Agents; Carboplatin; Histamine Antagonists; Humans; Nausea; Neuropeptides; Paclitaxel; Pyridines; Pyrimidinones; Substance P; Vomiting

Arterially perfused, decerebrate preparations of the insectivore, Suncus murinus were made to determine whether the emetic reflex could be activated in such a preparation using a range of stimuli shown to be emetic in conscious or anaesthetised Suncus. Efferent phrenic and vagus nerve activities and electromyograms (EMGs) from the temporalis, abdominal oesophagus and trapezius muscles were recorded, as well as longitudinal shortening of the oesophagus and dorso-ventral movements of the thorax. The preparations swallowed spontaneously every 0.6 to 6.5 min. The duration of a swallow was 3.1 +/- 0.3 s (recorded as the time taken for the oesophagus to shorten and recover to its resting position) and the oesophagus shortened by 3.5 +/- 0.4 mm during a swallow. The emetic reflex was activated by electrical stimulation (30 Hz, 10-20 V, 0.2 ms pulse width, for 30 s) of abdominal vagal afferents (latency < 30 s) or by arterial perfusion with either 40 nM of the capsaicin analogue resiniferatoxin (latency 1.7 +/- 0.6 min), 6 microM nicotine (latency 1.6 +/- 0.1 min) or 1 microM of the phosphodiesterase IV inhibitor CP-80,633 (latency 8.9 +/- 3.9 min). These emetic stimuli produced somatic and visceral movements in Suncus preparations indicative of activation of the emetic reflex. There were pronounced contractions of the thorax that occurred simultaneously with oesophageal shortening and mouth opening, separated by thorax expansion and a burst of phrenic nerve activity. During emetic-like episodes, oesophageal shortenings were only 0.84 +/- 0.1 s in duration, faster than the duration of shortening observed during swallowing (cf. swallowing, 3.1 +/- 0.3 s; P < 0.0001). The shortening of the oesophagus during emetic-like episodes was 6.2 +/- 0.4 mm, which was greater than the shortening seen during swallowing (cf. swallowing, 3.5 +/- 0.4 mm; P < 0.0001). We conclude that the emetic reflex can be activated in our Suncus preparations and that this non-sentient small adult animal model can now be used to study the neurophysiology and pharmacology of swallowing and emesis.

Topics: Animals; Aorta, Thoracic; Decerebrate State; Deglutition; Disease Models, Animal; Diterpenes; Electric Stimulation; Esophagus; Female; Heart Rate; Male; Naloxone; Narcotic Antagonists; Nicotine; Nicotinic Agonists; Perfusion; Phrenic Nerve; Physical Stimulation; Pyrimidinones; Reflex; Respiratory Mechanics; Shrews; Vagus Nerve; Video Recording; Vomiting

YM976 is a novel and selective inhibitor of phosphodiesterase type 4 (PDE4) with a different chemical structure from rolipram. Orally administered YM976 showed anti-inflammatory activity (ED(50) = 2.8 mg/kg) similar to rolipram (3.5 mg/kg). On the other hand, the emetogenicity of YM976, one of the main adverse effects of PDE4 inhibitors, was lower (maximal non-emetic dose = 10 mg/kg) than that of rolipram (1 mg/kg). The reasons for this low emetogenicity of YM976 remain unclear, and the present study endeavored to elucidate the mechanisms. Candidates for the possible mechanisms included 1) PDE4 subtype selectivity, 2) binding affinity for HAR-conformation, and 3) brain penetration. YM976 exhibited affinity for high affinity for rolipram-conformation (HAR-conformation) (IC(50) = 2.6 nM) identical to that of rolipram (1.2 nM), and failed to show significant selectivity for the individual PDE4 subtype. These results suggested that neither subtype selectivity nor the affinity for HAR-conformation may be related to the low emetogenicity of YM976. YM976 showed a minor effect on reserpine-induced hypothermia, in contrast to rolipram. To estimate brain penetration, we then measured cAMP contents in peripheral tissues (peritoneal macrophages) and in the brain. YM976 increased the cAMP content of peritoneal macrophages, but caused no significant increase in brain cAMP levels, while rolipram elevated the cAMP content of both tissues at the same dose. In conclusion, YM976 shows an apparent dissociation between its anti-inflammatory effects and emetogenicity, perhaps because of the poor brain penetration.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Body Temperature; Brain Chemistry; Cyclic Nucleotide Phosphodiesterases, Type 4; Eosinophils; Ferrets; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Phosphodiesterase Inhibitors; Pyridines; Pyrimidinones; Rats; Rats, Wistar; Rolipram; Tumor Necrosis Factor-alpha; Vomiting

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC(50) of 2.2 nM. IC(50) values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED(30) values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic AMP; Ferrets; Humans; Male; Phosphodiesterase Inhibitors; Pleurisy; Pyridines; Pyrimidinones; Rats; Tumor Necrosis Factor-alpha; U937 Cells; Vomiting

Topics: Anticonvulsants; Barbiturates; Depression, Chemical; Drug Eruptions; Drug Hypersensitivity; Epilepsies, Partial; Epilepsy; Epilepsy, Absence; Epilepsy, Temporal Lobe; Epilepsy, Tonic-Clonic; Ethosuximide; Humans; Leukopenia; Nausea; Outpatient Clinics, Hospital; Phenytoin; Pyrimidines; Pyrimidinones; Sleep; Vomiting