A-8-TETRAHYDR0-CANNABIN0L AS ANTIEMETIC

FIELD OF THE INVENTION

The present invention relates to antiemetic pharmaceutical compositions for use in human medicine, and more particularly in pediatric oncologic medicine. The drugs are of special value as antiemetic in pediatric oncology.

BACKGROUND OF THE INVENTION

Cannabis has been used for millenia as antiemetic. After the identi ication of delta-9-tetrahyd o-cannablnol (delta-9-THC), as the psychoactive constituent of cannabis, it was evaluated as ant 1-vo i t ing agent. It was found useful as antiemetic in the chemotherapy of cancer, and is marketed today commercially under the name of Dronabinol. It has a limited effectivity, and prevents vomiting and nausea in about 20 to 30 per cent of treated patients, and reduces such symptoms in another 40 to 50 per cent, having little or no effect in the rest. Pronounced side effects are drowsiness, dizziness and in some cases - anxiety. Such symptoms are pronounced with elderly patients, while younger ones undergo mainly mood changes.

SUMMARY OF THE INVENTION

The invention relates to pharmaceutical antiemetic compositions for use mainly in pediatric oncology.

The compositions of the invention comprise as active ingredient an effective quantity of delta-8-THC, of the formula

This compound is an isomer of delta-9-THC, and has been found to be at least as effective for the intended use as delta-9-THC, but has considerably reduced side-e ects, especially in pediatric medicine. The compound delta-8-THC is considerably more stable towards various chemicals than the delta-9 isomer, and is less prono to oxidation. Furthermore, it can be produced easily and is less expensive than the delta-9-THC isomer .

There administ ation is per os, and various dosage forms were prepared.

The compositions of the invention were tried on patients, mainly children, before the administration of a variety of anti-cancer drugs. In all of these causes of nausea and vomiting, the compositions proved highly effective, and had negligible undesired side-e fects. The experiments were carried out in the framework of an open label evaluation and results indicate that this composition is by far superior to existing ones.

The dosage administered is in the range of from about 5 mg to 20 mg, and preferably in the range of from 6 mg to about 15 mg. In oncology (pediatrics) the dosage is about 4 mg/m* to about

30 mg/m ² , and preferably about 18 mg/m ²

It was found that there can be administered to children doses which are larger than those which causes pronouced side-effects in adults. In pediatric use, essentially no side effects of significance wre encountered. Doses of the order of 18 mg/m* did not cause undesired side-ef ects.

The effective component is generally administered in a vehicle such as an edible oil.

In a trial, with 8 children of 3 to 13 years age, with various blood cancers, treated with a variety of antineoplast ic drugs, 18 mg/m', in edible oil, p.o. of delta-8-THC was given two hours before the ant ineoplast ic drug, and repeated every 6 hours of 24 hours. Vomiting was completely prevented, with negligible side effects. So far these children have received Δ -THC nearly 500 times (see Table).

PATIENTS AND METHODS

Eight children with various blood cancers were administered delta-8-THC at a dose of 18 mg/m* p.o. two hours before the start of the anticancer treatment. The drug wad dissolved in corn or olive oil (6 mg/ml ) . The same dose was repeated every 6 hrs for 24 hrs. The treatment for each child is presented in the Table.

Whenever additional cycles of ant ineoplastic therapy were required, delta-8-THC was administered following the same time procedure desribed above. Children received delta-8-THC only during days when emetogenic drugs were administered.

Established anticancer drug protocols were followed with all pat lents .

Λ study on vomiting due to ant ineoplast ic therapy was carried out with 8 patients. Details of their ant ineoplast ic treatment and side effects of the antiemetic therapy are presented in the Table. Chemotherapy protocols of the types indicated in the Table almost invariable cause intense vomiting, which starts about 2 hrs after the initiation of chemotherapy and gradually ends over a 24 hr period, in prelimary trials we tried to end the antiemetic therapy after the first or second dose of the cannabinoid, i.e. after 6 or 12 hrs. Vomiting started in most cases. Hence, in the recorded trial, all children were given 4 doses over 24 hrs. When antiemetic protocol described above was strictly followed no emesis was noted. In

one case (patient D.E.) delta-8-TIIC therapy Initially was refused. The patient experienced debilitating vomiting for 24 hrs after the ant ineoplast ic treatment. During the second treatment cycle (which took place after 8 days), at the patient's family request, delta-8-TIIC treatment was initiated. No vomiting occurred .

As Indicated in the Table the side effects observed with delta-8-THC were minor: some irritability as slight euphoria. No anxiety or hallucinogenic effects were noted in spite of the high doses administered.

The LDDO values for Fischer rats treated orally with single doses of delta-9-THC and delta-8-THC, and observed for 7 days, are 1910 mg/kg and 1980 g/kg (for males) respectively and 860 mg/kg (for females). The histopathological changes caused by these extremely high doses were essentially the same for both delta-8- and delta-9-THC. LDβo could not be determined in either rhesus monkeys or dogs as single oral doses of up to 9000 mg/kg of either delta-8- or delta-9-THC in dogs or monkeys were non lethal. Hi stopathological alterations did not occur in either dogs or monkeys

We found that infants and young children with different blood cancers, who were treated with a variety of anticancer drugs protocols could be administered doses of delta-8-THC considerably higher than the doses of delta-9-THC generally administered to adult cancer patients without the occurence of major side effects (5-10 mg/m* of delta-9-THC generally recommended for adult patients versus 18 mg/m* of delta-8-THC used by us in children). Our antiemetic protocol for cancer patients, to which we strictly adher, consists of one dose of delta-8-THC (18 mg/m*) 2 hours before chemotherapy, followed by the same dose every 6 hours for a total of 4 doses per day. As mentioned above, the prevention of vomiting was complete regardless of the ant ineoplast ic protocol followed.

Table, ϋel ta-8-TBC Administered to Chi l dren Treated for Various Blood Cancers . ³

Age, Number and

Effect of antiemetic treatments

(32) , no side effects

(64), slight irritability during first 2 cycles

(76), slight irritability and euphoria

(30) , no side effects

(24) , no side effects

(114) , no side effects

(64) , no side effects

(76), no side effects

Metoclopromide (0.3 mg/kg) p.o. Treatment during remission after 2nd or i.v. in previous treatment relapse and during 3rd relapse. failed to prevent vomitting

** During first cycle, refusal to take THC caused profuse vomiting

Footnotes to Table

a. Λ -THC. 18 mg/m ² b. A.L.L. - acute lvmphoblastic anemia c . Cvtarabine and asparaginase d. Includes vincristine. procarbazine. doxorubicin, bleomycin, vinblastine e. Includes vincristine. daunorubicine. asparaginase, cyclophos- phamaide. cvtarabine. 6-meracaρtoρurine etoposide, methotrex¬ ate f. Includes vincristine, doxorubicin. dactinomycin g. Cvtarabine and amsacrine h. Includes vincristine, doxorubicin. cvclophosphamide, metho¬ trexate i. Includes ό-mercaptopurine. vincristine. methotrexate, cytara- bine. teniposide, asparaginase