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Explaining chemotherapy-associated nausea
By Dross at 2008-01-30 20:58
Explaining chemotherapy-associated nausea

A new study from the Monell Center increases understanding of the biological mechanisms responsible for the nausea and vomiting that often afflict patients undergoing chemotherapyterm. The findings could lead to the development of new approaches to combat these debilitating side effectsterm.

“By increasing knowledge of what causes the nausea and vomiting that accompany chemotherapy treatment, we move closer to providing patients with less traumatic and hopefully more effective drug treatment regimens,” said lead author Bart De Jonghe, PhD, a Monell physiologist.

Anorexia (loss of appetite) and cachexia (a syndrome of physical wasting and weight loss) often accompany chemotherapy-induced symptoms of nausea and vomiting. These side effects can compromise the patient’s nutritional status and impede recovery.

The research, published online in the American Journal of Physiology, uses a rat model to identify a nerve that transmits signals of chemotherapy-associated illness from the small intestine to the brain.

To explore whether sensory nerves traveling from the intestinal system to the brain contribute to nausea and illness associated with chemotherapy, the Monell researchers examined the incidence of pica in rats that received the potent chemotherapy drug cisplatin. Cisplatin treatment, widely used for a variety of cancers, is highly associated with nausea and vomiting.

Pica is the term used to describe the eating of non-food substances, such as clay or dirt. Because rats – which do not vomit – eat clay when made sick by toxins, researchers measure pica behavior as an indicator of nausea and malaise in these animals.

In the Monell study, rats given cisplatin began to eat clay, decreased their food intake, and lost body weight.

The researchers found that cisplatin-associated pica was reduced by 60 percent when they cut a nerve that transmits sensory signals from the small intestine to the brain. Cutting the same nerve, known as the common hepatic branch of the vagus nerve, also lessened the reduction of food intake and loss of body weight.

These results suggest that the upper intestine is an important site for generation of the nausea and appetite loss associated with chemotherapy drugs.

The findings also help to define the neural systems involved in nausea and malaise, which can significantly impact the nutritional status of patients receiving potent drug treatments for diseases such as cancer or AIDS.

“This nerve may be part of a natural detection system that we use to detect toxins in food, and it is possible that we are activating it with these strong medications,” comments senior author Charles Horn, PhD, a behavioral neuroscientist at Monell.

Increased understanding of this system will enable development of specific blockers to reduce nausea and improve quality of life during chemotherapy and related therapeutic regimens.

Future studies also will evaluate whether the vagus nerve contributes to other side effects associated with chemotherapy, such as altered taste perception, fatigue, and stress.



2 comments | 2875 reads

by gdpawel on Thu, 2012-12-20 09:40
Because chemotherapy is such a harsh treatment on the body, the body reacts to these poisonous chemicals and tries to rid the body of them. One way the body responds is through a vomiting action preceded by a nausea feeling.

Because the continuation of treatment is critical in chemotherapy and since nausea and vomiting is a common side effect, antiemetics are used to prevent or lessen the nausea and vomiting mechanisms. Antiemetics are compounds that prevent emesis, otherwise known as vomiting. Antiemetics function through various molecular pathways and are classified into categories by their target. A key aspect to understanding the function of antiemetics is the structure of the nervous system signaling pathway as it relates to nausea and vomiting.

The body has a vomiting center called the area postrema in the lateral medullary recticular formation in the pons, which is located at the base of the brain in the brain stem. This center contains numerous receptors which can ascertain signals carried in the blood to induce a nausea or vomiting response. This center also takes in nervous system input from throughout the body, specifically from tasting and in the gastrointestinal tract, which can produce nausea or vomiting response as well.

[url]http://en.wikipedia.org/wiki/Area_postrema
[url]http://en.wikipedia.org/wiki/Emesis

Many types of chemotherapy are known to produce chemotherapy-induced nausea and vomiting (CINV). The Multinational Association of Supportive Care in Cancer established definitions and guidelines for CINV. The drugs are grouped by risk of CINV, with high risk being 90% of patients will have CINV, moderate is 30-90%, low is 10-30%, and minimal is less than 10%.

[url]http://www.mascc.org/

Drugs in the high risk group for CINV are cisplatin, mechlorethamine, streptozocin, cyclophosphamide at doses abover 1,500 mg/m2, carmustine, and dacarbazine.

Moderate-risk drugs are oxaliplatin, cytarabine at doses above 1 gm/m2, carboplatin, ifosfamide, cyclophosphamide at doses less than 1,500 mg/m2, doxorubicin, daunorubicin, epirubicin, idarubicin, and irinotecan.

Low-risk drugs are paclitaxel, docetaxel, mitoxantrone, topotecan, etoposide, pemetrexed, methotrexate, doxorubicin HCL liposome injection, mitomycin, gemcitabine, cytarabine up to 100 mg/m2, fluorouracil, bortezomib, cetuximab, and trastuzumab.

Minimal-risk drugs are bleomycin, busulfan, 2-chlorodoxy-adenosine, fludarabine, vinblastine, vincristine, vinorelbine, and bevacizumab.

As mentioned before, antiemetics are grouped based on their function. The major groups are 5-hydroxy-tryptamine 3 (5-HT3) receptor antagonists, NK-1 receptor antagonist, corticosteroids, dopamine receptor antagonists, and cannabinoids.

The 5-HT3 receptor is a serotonin receptor, part of a family of receptors known as the Cys-loop family of receptors. This family of receptors is important for many aspects in neuronal signaling. The 5-HT3 antagonists commonly used are dolasetron (commercially Anzemet), granisetron (Kytril), ondansetron (Zofran), tropisetron (Navoban), and palonosetron (Aloxi). These compounds effectively block the normal signaling through the 5-HT3 receptor, inhibiting the signal that would normally reach the vomiting center.

Neurokinin type 1 (NK-1) receptor is found in the vomiting center and in the abdominal vagus (a nerve running along the esophagus and the stomach) and binds the neuro-peptide called substance P.

Binding of substance P elicits a neuronal signal that ultimately leads to vomiting and nausea. The antagonists of NK-1 are approved for acute as well as delayed CINV. Aprepitant (commercially Emend) is the only approved NK-1 antagonists so far.

Corticosteroids are hormones in the steroid class meaning they have the base structure of cholesterol. The corticosteroids have a range of function in the body and Wikipedia gives a good overview corticosteriods here. Dexamethasone is a synthetic corticosteroid of the glucocorticoid class and is the most commonly prescribed corticosteroid. It is given in conjunction with 5-HT3 antagonists to augment their effects.

[url]http://en.wikipedia.org/wiki/Corticosteroid

Dopamine receptor antagonists inhibit the class of receptors that binds dopamine, a hormone and neurotransmitter. Dopamine is an emetic and can induce nausea, hence blocking dopamine receptors is another treatment of CINV. Domperidone (commercially Motilium) and metoclopramide (Reglan) are the two main dopamine receptor antagonists used for antiemetic treatment. Here is an excellent review on the pharmacokenetics of dopamine receptor antagonists.

[url]http://www.pharmacorama.com/en/Sections/Catecholamines_7_4.php

Cannabinoids are drugs that bind to cannabinoid receptors (CB) found throughout the central (CB1) and peripheral (CB1 and CB2) nervous systems. There are endogenous cannabinoids produced in humans that bind weakly to these receptors. The synthetic cannabinoids nabilone (commercially Cesamet) and dronabinol (Marinol) bind more strongly to the CBs. Cannabinoids are antiemetic in that they are agonists to the CBs and partially block the release of other neurotransmitters.

While no one antiemetic is 100% effective, combinations of antiemetics are in trial producing synergistic effects between certain classes.

Here is an overview of antiemetic drugs.

[url]http://annonc.oxfordjournals.org/content/17/suppl_2/ii96.full.pdf+html

Here is a great overview of chemotherapy drugs and their associated side effects.

[url]http://www.cancersupportivecare.com/chemotherapy.html

Another good article on CINV can be found in Oncology Times 29;17: September 10, 2007 Treatment-Induced Nausea and Vomiting: Research Roundup

by gdpawel on Thu, 2012-12-20 09:47
Zyprexa (olanzapine), marketed as an antipsychotic drug, was shown to be an effective rescue medication for patients who were suffering from breakthrough chemotherapy-induced nausea and vomiting (CINV), despite having received standard prophylactic treatment.

In 80 of 205 patients who developed breakthrough CINV, Zyprexa (olanzapine) significantly outperformed the conventional antinausea drug metoclopramide.

More patients in the Zyprexa (olanzapine) group than in the metoclopramide group reported no vomiting (71% vs 32%) and no nausea (67% vs 24%).

The study was presented at the 2012 ASCO annual meeting, and so far is available only in abstract form ( J Clin Oncol. 2012;30(15 Suppl): abstract 9064).

Journal of Clinical Oncology, 2012 ASCO Annual Meeting Proceedings
Vol 30, No 15_suppl (May 20 Supplement), 2012: 9064
2012 American Society of Clinical Oncology

The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy.

Rudolph M. Navari, Cindy K Nagy and Sarah E Gray

Indiana University School of Medicine South Bend, South Bend, IN; University of Notre Dame, Notre Dame, IN

Abstract :9064

Background:

Olanzapine (OLN) has been shown to be a safe and effective agent for the prevention of CINV. OLN may also be an effective rescue medication for patients who develop breakthrough CINV despite having received guideline directed CINV prophylaxis.

Methods:

A double blind, randomized phase III trial was performed for the treatment of breakthrough CINV in chemotherapy naïve patients receiving highly emetogenic chemotherapy (HEC) (cisplatin, >70 mg/m2, or doxorubicin, >50 mg/m2 and cyclophosphamide, > 600mg/m2 ) comparing OLN to Metoclopramide (METO). Patients who developed breakthrough emesis or nausea despite prophylactic dexamethasone (12 mg IV), palonosetron (0.25 mg IV), and fosaprepitant (150 mg IV) pre chemotherapy and dexamethasone (8 mg p.o. daily, days 2-4) post chemotherapy were randomized to receive OLN, 10 mg orally daily for three days or METO, 10 mg orally TID for three days. Patients were monitored for emesis and nausea for the 72 hours after taking OLN or METO. Eighty patients (median age 56 yrs, range 38-79; 43 females; ECOG PS 0,1) consented to the protocol and all were evaluable.

Results:

During the 72 hour observation period, 30 of 42 (71%) patients receiving OLN had no emesis compared to 12 of 38 (32%) patients with no emesis for patients receiving METO (p<0.01). Patients without nausea (0, scale 0-10, M.D. Anderson Symptom Inventory) during the 72 hour observation period was: OLN: 67% (28 of 42); METO 24% (9 of 38) (p<0.01). There were no Grade 3 or 4 toxicities.

Conclusions:

OLN was significantly better than METO in the control of breakthrough emesis and nausea in patients receiving HEC.

Abstract presentation from the 2012 ASCO Annual Meeting

[url]http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/9064?sid=f61ad25c-6c84-4a08-9719-6fb7b34a510b

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