BACKGROUND:

Chemotherapy regimens for breast cancer containing anthracycline and cyclophosphamide are classified as highly emetogenic. Aprepitant (A), palonosetron (P), granisetron (G), or dexamethasone (D) are recommended antiemetic drugs. However, it is uncertain which combination is most effective. We retrospectively examined the efficacy of these antiemetic drugs.

PATIENTS AND METHODS:

We reviewed the medical records of 454 patients with breast cancer treated in our facility with regimens containing anthracycline and cyclophosphamide between August 2009 and September 2010.

RESULT:

The number of patients treated with GD, AGD, and APD was 147, 150, and 157, respectively. Complete response (CR) in the acute (0-24 h) and delayed (24-120 h) phases was 68.7 and 76.2 %, respectively, for GD, 90.0 and 92.7 %, respectively, for AGD, and 89.8 and 90.4 %, respectively, for APD. Complete control (CC) in the acute and delayed phases for each regimen was 60.5 and 64.6 %, respectively, for GD, 62.7 and 88.7 %, respectively, for AGD, and 84.1 and 87.3 %, respectively, for APD. In the acute and delayed phases CR for AGD or APD was significantly superior to that for GD (P < 0.01). It worth noting that CC for APD in the acute phase was significantly superior to that for AGD (P < 0.01). In the delayed phase CC for AGD or APD was significantly superior to that for GD.

CONCLUSION:

A combination of aprepitant, palonosetron, and dexamethasone is an antiemetic treatment of choice for patients treated with regimens containing anthracycline and cyclophosphamide.

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT3 receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first-generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

BACKGROUND:

Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron.

METHODS:

Chemotherapy-naïve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h).

RESULTS:

The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0 %, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7 %, respectively. The most common adverse event was grade 1 or 2 constipation.

CONCLUSIONS:

Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.

Chemotherapy-induced nausea and vomiting (CINV) is a concern for many cancer patients. It can have an enormous impact on quality of life. CINV occurring in the first 24 hours after treatment is considered acute, and CINV occurring on days 2 through 5 after treatment is considered delayed. Anticipatory nausea and depression can also occur when patients are reminded of their chemotherapy treatment. CINV can lead to weight changes, fatigue, and the need for additional medications. Even mild to moderate CINV can increase health care utilization and costs, as well as delay treatment. Nausea and vomiting are separate events, although their mechanisms are entwined. Drugs that stop vomiting do not necessarily treat nausea. Control of CINV allows patients to complete treatment and to minimize use of health care resources and additional medications. Current antiemesis agents, such as 5-hydroxytryptamine-3 (5-HT3) antagonists and neurokinin-1 (NK-1) antagonists, have markedly decreased hospitalization for chemotherapy and have nearly eliminated acute emesis. The second-generation 5-HT3 receptor palonosetron has a unique pharmacology that makes it especially effective at preventing delayed emesis.

Chemotherapy-induced nausea and vomiting (CINV) is a concern for many cancer patients. It can have an enormous impact on quality of life. CINV occurring in the first 24 hours after treatment is considered acute, and CINV occurring on days 2 through 5 after treatment is considered delayed. Anticipatory nausea and depression can also occur when patients are reminded of their chemotherapy treatment. CINV can lead to weight changes, fatigue, and the need for additional medications. Even mild to moderate CINV can increase health care utilization and costs, as well as delay treatment. Nausea and vomiting are separate events, although their mechanisms are entwined. Drugs that stop vomiting do not necessarily treat nausea. Control of CINV allows patients to complete treatment and to minimize use of health care resources and additional medications. Current antiemesis agents, such as 5-hydroxytryptamine-3 (5-HT3) antagonists and neurokinin-1 (NK-1) antagonists, have markedly decreased hospitalization for chemotherapy and have nearly eliminated acute emesis. The second-generation 5-HT3 receptor palonosetron has a unique pharmacology that makes it especially effective at preventing delayed emesis.

Chemotherapy-induced nausea and vomiting (CINV) is a concern for many cancer patients. It can have an enormous impact on quality of life. CINV occurring in the first 24 hours after treatment is considered acute, and CINV occurring on days 2 through 5 after treatment is considered delayed. Anticipatory nausea and depression can also occur when patients are reminded of their chemotherapy treatment. CINV can lead to weight changes, fatigue, and the need for additional medications. Even mild to moderate CINV can increase health care utilization and costs, as well as delay treatment. Nausea and vomiting are separate events, although their mechanisms are entwined. Drugs that stop vomiting do not necessarily treat nausea. Control of CINV allows patients to complete treatment and to minimize use of health care resources and additional medications. Current antiemesis agents, such as 5-hydroxytryptamine-3 (5-HT3) antagonists and neurokinin-1 (NK-1) antagonists, have markedly decreased hospitalization for chemotherapy and have nearly eliminated acute emesis. The second-generation 5-HT3 receptor palonosetron has a unique pharmacology that makes it especially effective at preventing delayed emesis.

Chemotherapy-induced nausea and vomiting (CINV) is a concern for many cancer patients. It can have an enormous impact on quality of life. CINV occurring in the first 24 hours after treatment is considered acute, and CINV occurring on days 2 through 5 after treatment is considered delayed. Anticipatory nausea and depression can also occur when patients are reminded of their chemotherapy treatment. CINV can lead to weight changes, fatigue, and the need for additional medications. Even mild to moderate CINV can increase health care utilization and costs, as well as delay treatment. Nausea and vomiting are separate events, although their mechanisms are entwined. Drugs that stop vomiting do not necessarily treat nausea. Control of CINV allows patients to complete treatment and to minimize use of health care resources and additional medications. Current antiemesis agents, such as 5-hydroxytryptamine-3 (5-HT3) antagonists and neurokinin-1 (NK-1) antagonists, have markedly decreased hospitalization for chemotherapy and have nearly eliminated acute emesis. The second-generation 5-HT3 receptor palonosetron has a unique pharmacology that makes it especially effective at preventing delayed emesis.

5-hydroxytryptamine 3 (5-HT3) receptors have been known to be associated with the modulation of nociceptive transmission. However, it is uncertain whether 5-HT3 plays a role in the antinociceptive or pronociceptive pathway for incisional pain. In this study, we evaluated the effects of palonosetron, a 5-HT3 receptor antagonist, on incisional pain in rats when administered intrathecally or intraplantarly.An intrathecal catheter was implanted through the cisterna magna and placed in the intrathecal space of rats. An incision in the plantaris muscle of the right hind paw was done under anesthesia with sevoflurane. Withdrawal thresholds were evaluated with the von Frey filament after 2 hours. Palonosetron (0.5 and 0.1 µg intrathecally; 0.5 µg intraplantarly) was administered and the thresholds were observed for 4 hours.Mechanical hypersensitivity developed after the incision. Intrathecal palonosetron (0.5 µg and 0.1 µg) did not alter the paw withdrawal threshold. Intraplantar palonosetron (0.5 µg) also did not change the paw withdrawal threshold.Intrathecal and intraplantar palonosetron (0.5 µg) had no effect on modulating the mechanical hypersensitivity in the incisional pain model of rats.

BACKGROUND AND PURPOSE:

The 5-HT3 receptor antagonist palonosetron is an important pharmacotherapy for the treatment of emesis and nausea during cancer therapy. Its clinical efficacy is thought to result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT3 receptors in order to better understand its clinical efficacy. EXPERIMENTAL APPROACH: Cell surface receptors (recombinantly expressed 5HT3A or 5HT3A/B in COS-7 cells) were monitored using [(3) H]granisetron binding and ELISA after exposure to palonosetron. Receptor endocytosis was investigated using immunofluorescence microscopy. KEY

RESULTS:

Chronic exposure to palonosetron reduces the number of available cell surface [(3) H]granisetron binding sites. This downregulation is not sensitive to either low temperature or pharmacological inhibitors of endocytosis (dynasore or nystatin) suggesting that internalisation does not play a role. This was corroborated by our observation that there is no change in cell surface 5-HT3 receptor levels or increase in endocytic rate. We find that palonosetron exhibits slow dissociation from the receptor over many hours, with a significant proportion of binding sites being occupied for at least 4 days. Furthermore, our observations suggest that chronic receptor downregulation involves interactions with an allosteric binding site.

CONCLUSIONS

AND

IMPLICATIONS:

Our results indicate that palonosetron acts as a pseudo-irreversible antagonist causing prolonged inhibition of 5-HT3 receptors due to its very slow dissociation. In addition, an irreversible binding mode persists at least four days. Allosteric receptor interactions appear to play a role in this phenomenon.

A specific and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric method was developed for the quantification of imatinib and its primary metabolite N-desmethyl imatinib in human plasma. Protein precipitation with methanol was used for sample preparation. High-performance liquid chromatographic separation was performed on a Thermo BDS Hypersil C18 column (4.6 × 100 mm, 2.4 µm) with methanol-water (55:45, v/v) containing 0.1% formic acid and 0.2% ammonium acetate as the mobile phase, using isocratic elution at a flow rate of 0.7 mL/min. Detection was conducted with positive electrospray ionization multiple reaction monitoring of the ion transitions at m/z 494 → 394 for imatinib, 480 → 394 for N-desmethyl imatinib and 297 → 110 for the internal standard (palonosetron). The assay was validated in the concentration ranges of 8-5,000 ng/mL for imatinib and 3-700 ng/mL for N-desmethyl imatinib. The quantification limits for imatinib and N-desmethyl imatinib were 8 and 3 ng/mL, respectively. The intra-day and inter-day precision values of the assay (expressed as percentage relative standard deviation) were less than 15% at all concentration levels within the tested range, and the accuracy values were between 85 and 115%. The established method was successfully applied to the pharmacokinetic study of imatinib mesylate capsules in 24 healthy Chinese volunteers.