L'Italo-Americano

THURSDAY, MAY 28, 2020 www.italoamericano.org 16 L'Italo-Americano C o V i D - 1 9 p a n - demic as of 20 M a y 2 0 2 0 : Globally - Con- f i r m e d C a s e s : 5 , 0 3 9 , 6 0 0 + ; F a t a l i t i e s : 326,900+. Cases/million: 647; Deaths/million: 42 Italia - Confirmed Cases: 2 2 7 , 3 0 0 + ; F a t a l i t i e s : 3 2 , 3 3 0 + . C a s e s / m i l l i o n : 3,760; Deaths/million: 535 US - Confirmed Cases: 1 , 5 7 7 , 9 4 0 + ; F a t a l i t i e s : 9 3 , 8 9 0 + . C a s e s / m i l l i o n : 4,770; Deaths/million: 284 California - Confirmed Cases: 83,870+; Fatalities: 3 , 4 2 5 . C a s e s / m i l l i o n : 2,122; Deaths/million: 87 L o s A n g e l e s C o u n t y - Confirmed Cases: 39,570+; F a t a l i t i e s : 1 , 9 1 3 . V i l l a S c a l a b r i n i C o n f i r m e d Cases: 7 Residents, 11 Staff (publichealth.lacounty.g ov) The careful production of new drugs and vaccines to fight any virus, including the 2 nd virus of the Corona f a m i l y t o p r o d u c e t h e Severe Acute Respiratory S y n d r o m e ( S A R S - C o v 2 ) , the causative agent of the C o r o n a V i r u s D i s e a s e o f 2 0 1 9 ( C o V i D - 1 9 ) , i s a process that consists two p r i n c i p a l c o m p o n e n t s : development and test- ing. C o n s i d e r i n g t h e a d v a n c e s i n c h e m i s t r y , physiology and molecular biology of the past decades, the first phase of develop- ment can be relatively fast: m o n t h s , w e e k s , p e r h a p s e v e n d a y s . T h e s e c o n d phase is a bit more compli- cated as it entails scaling up production at industrial levels and world-wide dis- tribution. H o w e v e r , b e t w e e n t h e first phase of development a n d i t s d i s t r i b u t i o n , t h e new drug or vaccine must be tested for toxicity, safety and efficacy. The testing component can be complex and lengthy. Testing for toxicity is rel- atively quick. It is called a Phase 0 trial, and is per- f o r m e d e i t h e r o n h u m a n cells in culture or in ani- m a l s , s o m e t i m e s e v e n i n b o t h . I f t h e n e w d r u g o r v a c c i n e k i l l s t h e c e l l s o r harms the animals, the new drug or vaccine is rejected as toxic. If it passes that initial test, then a Phase 1 trial is done to test its safe- ty in a small group of care- fully selected healthy vol- unteer subjects. They are randomly divided into two groups: one receives the new drug or vaccine, and t h e o t h e r a g r e e s ( L a t i n , placebo, I will please) to receive an inert control. If the subjects given the new drug or vaccine manifest or complain of unwanted side- e f f e c t s , t h e n e w d r u g o r vaccine is shelved for revi- sions, fine-tuning and re- test. S o m e t i m e s , a s i n t h e r e c e n t r e p o r t f r o m M o d e r n a , I n c . a P h a s e 0 and a Phase 1 trial can be run contemporaneously to test a new vaccine: it can be dangerous for the sub- jects in the Phase 1 trial, b u t i t c a n b e d o n e . Moderna did, and reported that their new anti- SARS- Cov2 vaccine was safe for mice and for humans, and that it produced immunity capable of neutralizing the SARS-Cov2 virus in mice (note: no reports to date has indicated that SARS- Cov2 is pathogenic in mice; that is to say, it seems that mice are quite capable of neutralizing that virus on their own – the choice of animal species by Moderna f o r t h e P h a s e 0 t r i a l i s arguable). Be that as it may, when a new drugs or vaccine pass- es the Phase 0 and Phase 1 trials, as this vaccine has reportedly done, it must be tested in a Phase 2 trial to preliminarily establish its efficacy in a small num- b e r o f p a t i e n t s a n d matched control subjects, again distributed randomly i n a t e s t a n d a p l a c e b o group. The better Phase 2 trials are extended in time in what is called a longitu- d i n a l s t u d y b e c a u s e t h e y p r o d u c e m o r e c e r t a i n t y that the findings are in fact true. If the Phase 2 is suc- cessful, then it is repeated in an expanded format that uses many more patients across many study sites in what is called a Phase 3 trial. Again, the more reli- able Phase 3 trials are the ones that are longitudinal in design. If the Phase 3 is successful, then the efficacy of the new drug or vaccine is almost confirmed. What r e m a i n s t o b e d o n e i s t o test it in a population-wide P h a s e 4 t r i a l , w h i c h , because of the large sample size, is the best and most s e n s i t i v e w a y w e h a v e t o d e t e c t u n d e s i r a b l e s i d e - effects in a small propor- t i o n o f t h e p o p u l a t i o n . Again, a longitudinal Phase 4 trial is best because it has more power to reveal true e f f e c t s . C u t t i n g c o r n e r s may shorten the process, but it can be dangerous and even life-threatening. M a n y n e w d r u g s a n d vaccines are discarded at the Phase 3-Phase 4 trial because serious side-effects are noted. Case in point, Merck voluntarily withdrew rofecoxib (Vioxx) from the m a r k e t a f e w y e a r s a g o , because of increased risks of heart attack and stroke associated with long-term, high-dosage use, based on 88,000 to 140,000 cases followed long-term at the Phase 4 stage. Taken together, Phase 0 and 1 are relatively fast ini- tial tests. Phase 2 and 3 are methodical and take time, lest they lead to catastroph- i c o u t c o m e s i n P h a s e 4 . That, in a nutshell, is why we cannot expect to safely h a v e n e w d r u g s a n d n e w vaccines against the SARS- Cov2 virus to treat patients w i t h C o V i D - 1 9 a n y t i m e soon. It must take the time Per Saperne Di Più: CoViD-19, a word with Francesco Chiappelli Issue 5, Dott. Francesco Chiappelli, Prof. Emerito UCLA Center for the Health Sciences that it takes to test toxicity, safety, and efficacy. As we Italians would say: dai tempo al tempo, give t i m e t o t h e t i m e i t m u s t take. Certainly, in the case of drugs, we can jump-start t h e p r o c e s s : w e c a n t e s t whether drugs we already k n o w a r e n o n - t o x i c , s a f e a n d e f f e c t i v e f o r r e l a t e d d i s e a s e s c a n b e u s e f u l against SARS-Cov2 virus infection. Since this virus is an RNA virus (cf. Issues 1 & 4), like Ebola virus or HIV, we can try to use antivi- rals developed and tested for patients with Ebola or H I V / A I D S . S o m e m i g h t w o r k , o t h e r m i g h t n o t . Remdisivir (cf., Issue 4), a broad-spectrum antiviral medication that is effective in Ebola, and that seems to interfere with the replica- tion cycle of the virus such t h a t i t a c c e l e r a t e s t h e recovery-time from infec- tion – despite some impor- tant side-effects, including liver inflammation, nausea, and blood pressure drop – seems to benefit patients with CoViD-19. Phase 3 and Phase 4 trials will have to confirm these initial obser- vations. O t h e r d r u g s m a y d o n o t h i n g a g a i n s t S A R S - Cov2, but may work to con- t a i n t h e ' c y t o k i n e s t o r m ' (cf., Issue 4). Case in point, h y d r o x y c h l o r o q u i n e ( H C Q ) , a n a n t i - m a l a r i a medication, whose impor- tant side-effect is to contain cytokine over-production in c e r t a i n c o m p l e x a u t o i m - m u n e d i s e a s e s , s u c h a s L u p u s e r y t h e m a t o s u s , rheumatoid arthritis, and porphyria cutanea tarda. But, importantly, the fact that HCQ works in certain a u t o i m m u n e p a t h o l o g i e s does not imply that it will e f f e c t i v e l y s h u t d o w n cytokine over-production in every autoimmune disease ( i n f a c t , i t d o e s n o t ) , l e t alone the 'cytokine storm' in patients afflicted with C o V i D - 1 9 . T o b e c l e a r , cytokine over-production in Continued to page 18 NEWS & FEATURES TOP STORIES PEOPLE EVENTS

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