以下文章引自《复方蒿甲醚历程 -- 庆贺军事医学科学院成立60周年和复方蒿甲醚项目国际合作20周年纪念册》，2011年出版。（如需原书，请留言）

POLTERA A A , MD,DTM&H (Liverpool)                                                                              

46 WIRTSGARTENWEG                                                                                                          

CH-4123 ALLSCHWIL

21st ofAugust 2010

SWITZERLAND

a2poltera@gmail.com

EARLYCO-DEVELOPMENT OF ARTEMETHER PLUS BENFLUMETOL BETWEEN AMMS AND CIBA-GEIGY LIMITED

SOME ANECDOTES AND CONTRIBUTIONS BY A APOLTERA, RETIRED MD

A POTENTIAL SOURCE FOR THEPLANNED COMMEMORATIVE BOOK CELEBRATING 20 YEARS OF CO-DEVELOPMENT (1991-2011)

INTRODUCTION

I am Anton Alexander Poltera, a Swiss doctorfor Tropical Medicine who worked for Ciba-Geigy Limited from 1982 to 1994 asproject leader for the clinical development of anti-parasitic agents. In 1990 Itravelled with a delegation of Ciba-Geigy in April to Beijing to meet members of AMMS with the aimto license-in Artemether for the international market. Because of difficultiesin spelling my name the Chinese partners preferred to call me Toni and alsogave me the name of Green Mountain, including itswriting in Chinese.

THE DISCOVERY

At the end of the negotiations, theCiba-Geigy delegation rejected the Chinese offer for licensing-in ofArtemether, because it was no more patentable and as a monosubstance it showedsome relapses.

In a gesture to bridge over thegeneral deception I asked the Inventor of the artemisinines, late PorfessorZhou Keding (*13.October 1927 - 8.January 2008), whether they had something elseto offer, which we did not know?

There was a long debate among theChinese partners and then Professor Zhou Keding answered me: Yes, we have acombination drug.

I thanked him for his confidence andtold him: If you have a combination drug, then we will come back afterestablishing new confidentiality agreements and please do NOT reveal me now itscomposition.

AN “EXPERIMENTAL” MISUNDERSTANDING

However, he allowed me a secondquestion, in asking him to comment on the stage of development. He answered,that they were in “experimental testing”. To my understanding “experimental”meant animal testing. Therefore I commented: There is no other animal model forPlasmodium falciparum than the Aotus monkey and to my understanding suchmonkeys were not available in China,because they are a highly protected species from Latin America. Late Professor Zhou Keding, after some consultation withhis collaborators, answered that they were conducting clinical trials in China.Subsequently I asked him, whether he would like to specify in which stage ofdevelopment they were? He replied “Phase IV”. This meant extreme urgency, if apatent application was to be filed internationally.

THE PATENT

In August 1990 the Ciba-Geigydelegation and I met again in Beijingwith the AMMS members and Professor Zhou Yiqing revealed the composition ofCoArtemether (Artemether plus Benflumetol, the latter is now calledlumefantrine due to international standardisation). During this session thepatentability was checked in Basel, Switzerland bytelefaxing, and the answer was positive for artemether-benflumetol. However allother combinations of known antimalarials with artemisinines had been patentedby a German pharmaceutical company. Therefore AMMS and Ciba-Geigy have beenvery fortunate. As a consequence they signed a contract and deposited a patent intheir names in 1991, which was granted in 1992. Most of this work had beenaccomplished by late Dr Hanspeter Schluep, †2002, together with our Chinesepartners and Professor W H Wernsdorfer (see SYNERGISM below and my OverviewTable of 21^st of June 2010, #2, 2^nd line, 1^stfoto).

“THE GOLDEN EGG”

In 1990 after the late professorZhou Keding had revealed to Dr A A Poltera the existence of a up to thentop-secret arteminsinin combination drug, Dr Poltera made a comparison to theChinese Partners: In Beijing you honoured us with wonderful food and I likedthe Pekinese duck. However the “Pekinese duck” had already produced wonderfuleggs, meaning the non-patented artemisinines. This time you should protect yourinvention of a combination drug by a patent. Please take care that this GoldenEgg can grow undisturbed.

By May1994 the project had developedsubstantially and the Chinese partners wanted to meet me despite my forceddeparture from the company in January. So we met in Basel and the Chinesepartners received my Golden Egg as a symbolic present, a chocolate egg filledwith the best pralinés in town (see foto taken by Mrs Jean Heimgartner,Overview Table of 21^st of June 2010, #2, 2^nd line , 3dfoto).

“PROJECT GIN-TONIC”

In August 1990 the composition ofthe combi-drug was revealed: Artemether plus Benflumetol.

It was hot in Beijing and we gathered after the officialmeetings in the hotel for a drink. What would you like to drink? Gin Tonic wasserved. One member of the Chinese Partners was concerned and said: we have aproblem spelling your names, for instance Mrs Heimgartner and Dr Poltera. LookI am Li and I am suggesting that we call you Jean and Toni? Of course, we allagreed. But there was a further concern for the secret protection of theproject: the need of a cover-name. So the project was called “Project GinTonic”, up to the time, when the patent application had been filed and theproduct had received the official Ciba-Geigy Pharma code number “CGP 56697”.

“GREEN MOUNTAIN”

Apparently the Chinese partnersliked my way of communicating with them. At one gathering a Chinese partnerinformed us all that they gave me a new name by which I was well characterised:Green Mountain. Of course I thanked themcordially and was very pleased. Mrs Professor Mao Jujing was so kind to writeand explain me its Chinese characters, which I kept and published it recently(see my Overview Table of 21^st of June 2010, #9, 2^nd fotoon page 1).

“YELLOW FLOWER”

The Chinese Partners wanted me toreturn to Beijing in November 1990, but I wasvery busy with my official antiparasitic drugs projects against worms in Latin America. I told them that I will return when theProject Gin Tonic is showing Yellow Flowers in allegation to Artemisia annua.But for the meantime I realised, we needed expert help from outside and so Isuggested Professor W H Wernsdorfer, from the University of Vienna, Austria. Idid return to Chinain

April 1993 (Sanya and Beijing) (see my OverviewTable #2, Prof Wernsdorfer is 2^nd to Professor Zhou Yiqing on 2^ndline, 2^nd foto). I planted an Artemisia plant from my home mountainsin my garden in Allschwil near Baselto remind me annually of the Yellow Flower (see my letter to you with fotodated 1^st of August 2010).

SYNERGISM

For a combination drug it must beproven to the authorities, that the bringing together of two active components hasan advantage over the single components. Due to the urgency of filing a patent,the in vitro experience of Prof Wernsdorfer was crucially welcome. With hisexperiments, using laboratory isolates and field strains of Plasmodiumfalciparum, he corroborated the clinical claim of synergism of Artemether andBenflumetol and this was accepted for the patent claim (1991/92).

“THE ACID TEST”

In Ciba-Geigy not all participantswere happy with the perspective of co-developing a combination drug,particularly testing three components generated some uneasiness. Enormous costsfor toxicology were calculated and used as an argument against this unscheduledproject. Malaria had been cancelled as a company’s priority since theseventies. So I phoned the head of the medical department, late Dr med JustusGelzer, †1998, at 7 am to meet him urgently. In his office I explained him myconcept: We repeat in Chinain 100 malaria patients with Plasmodium falciparum the administration ofArtemether plus Benflumetol according to international standards, undersurveillance and monitoring of Ciba-Geigy Limited. If it provides the sameresults as already obtained by the Chinese we have the clearance for thego-ahead, if it fails we must stop. Great idea, he commented and supported itstrongly. We called the trial “the acid test” due to its function of “go” or“no go”.

With Professor Wernsdorfer and DrSeet from Ciba-Geigy Limited, Singapore,we designed the appropriate trial plan and corresponding case record forms. Theresults after 28 days in the in-patients of the screened hospital at Sanya, Hainan, were clear cut: 96% cure rate and excellenttolerability (see my Overview Table 21^st of June 2010, # 2, Trial ABMO1, 3d line square 1 and 2, 1993). Of course, we had also designed a trial inPlasmodium falciparum patients to prove the synergism of this combination drug(see my Overview Table 21^st of June 2010, # 2, Trial AB MO2, 4^thline square 1 and 2, 1994), which proved the superiority of Artemether plusBenflumetol over the single components of Benflumetol and Artemether in thisorder. The cornerstones for further international development had been laid.

GAMETOCYTOCIDAL EFFECT

In August 1990 in Beijing, I asked our Chinese partners,whether Artemether plus Benflumetol would also act on the gametocytes ofPlasmodium falciparum? The answer was evasive. For this reason we designed inTrial AB MO1 the observation of gametocytes before and after treatment, theresult being a net decline, which was subsequently confirmed in other trials.This gametocytocidal effect is an unexpected further asset of the uniqueness ofArtemether plus Benflumetol and contributes to its success by reducing themortality and the morbidityof endemic malaria.

PHARMACOKINETICS

From my experience withanthelminthic drugs (amocarzine and triclabendazole) I knew that postprandialadministration did enhance the absorption of the active substance in patients.

When the chemists reported thatartemether as well as benflumetol were poorly watersoluble, a similaradministration of the combination drug after food intake was considered. WithProfessor Wernsdorfer we initiated appropriate studies in volunteers andplanned it for patients. Today, the doses after the first dose are recommendedto be taken after food intake for optimizing drug absorption.

Dr Peter Degen and collaboratorsfrom Novartis could report on the pharmacokinetic results via Mrs JeanHeimgartner, and so could Dr Peter Wirz and collaborators from Novartis on thechemistry or Dr Alan Chalmers for the early coordination of the joint effortsof registering this combination drug.

I am not qualified to comment on thecontracts, marketing or production of Coartem™, but Mrs Jean may have thenecessary contacts.

CHINESE HAT and GREEN MOUNTAIN

For the 20^th anniversaryof my discovery of the existence of Artemether plus Benflumetol, kindlyrevealed by late Professor Zhou Keding in April 1990, I put on the Chinese Hat,which Professor Zhou Yiqing had given me on the Great Wall to protect my headfrom the burning sun (August 1990). My wife took a foto of me with this hat. Iam also wearing a necklace of rhodonite stones from my home mountainsrepresenting 25 years of participating to the Engadine Ski Marathon (42km)which kept me fit, now reduced to half the distance (09/10/?11?) (see myOverview Table of 21^st of June 2010, #9, 1st foto on page 1).

IN SUMMARY

The small but appropriate questionsof Dr A A Poltera were honoured by the initial answers of

• the late Professor Zhou Keding, the     inventor of the Artemisinines,

• and subsequently by Professor Zhou Yiqing,     the inventor of Artemether plus Benflumetol

• as well as by other Chinese partners.

These answers opened the way for thesuccessful co-development of Artemether plus Benflumetol (1990-94).

This antimalarial combination drugwith unique properties was further developed by Novartis Limited (founded in1996) in collaboration with the Chinese partners and registered in 1999. It is marketedunder the names of Coartem™/Riamet™, Benflumetol having changed its name forLumefantrine due to international standardisation.