Friday, March 29, 2019

Professor Longo's Advice to future Biology Phd students don’t worry, be happy

 What advice would you give to PhD students and postdocs who are now starting off their scientific careers?

 1) find something you would do even if they did not pay you
 2) dedicate all of your time to it
 3) work with both a simple model organism and mice or human cells
 4) do regular presentations of your work but not too many 
5) start an experiment every day or as often as possible 
6) don’t believe anything you hear and half of what you see 
7) doubt your own results
8) don’t worry, be happy
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what a person can do but won’t VS what a person wants to do but can’t

There is a basic, common-sense distinction between
 what a person can do but won’t (because they are not motivated)
 and what a person wants to do but can’t (because they lack the ability)

 Normal people can ignore heroin ... even when it is plentiful in their environment, and they can use these drugs with little likelihood of addiction ... Rats from Rat Park seem to be no less discriminating.

 prevalence of drug addiction in USA

 Illicit drug use in the United States has been increasing. In 2013, an estimated 24.6 million Americans aged 12 or older—9.4 percent of the population—had used an illicit drug in the past month. This number is up from 8.3 percent in 2002.

 Survey results suggest between 2.5 and 2.9 million Afghans use drugs – 11% of the population – and 1.9 and 2.3 million use opiates – about 7% of the population.  Approximately 0.9-1.1 million use cannabis, about half the rate of opioid users.[1]  
The evidence shows that the majority of addicts have the ability
to refrain from use in many ordinary circumstances. But it does not demonstrate they have

the ability in all possible circumstances.
This evidence is strong, but we need nonetheless to be careful in drawing conclusions.
There is a basic, common-sense distinction between what a person can do but won’t (because
they are not motivated) and what a person wants to do but can’t (because they lack the ability)
(Pickard 2012, 2017a). The evidence shows that the majority of addicts have the ability
to refrain from use in many ordinary circumstances. But it does not demonstrate they have
the ability in all possible circumstances. The attribution of an ability to refrain from use is
consistent with there being occasions where, due to any variety of constraints, it cannot be
exercised. Nor does the evidence demonstrate beyond doubt that the minority of addicts who
do not respond to incentives have the ability to refrain but don’t exercise it, rather than not
having the ability at all. In the absence of any clear marker between different sub-groups of
addicts that would explain the difference between the majority who refrain and the minority
who don’t, the evidence suggests the latter are like the former in having the ability and
unlike them in not exercising it, but it does not conclusively establish this. Finally, there is
the important question of how to understand conflicting self-reports from addicts, who often
oscillate both intra- and inter-personally between using the language of compulsion and the
language of choice (for discussion see Booth Davies 1992; Pickard 2012, 2017a). For all these
reasons, caution is needed in interpreting the evidence. Nonetheless, our understanding of
addiction should reflect what the evidence clearly does show, namely that, for many addicts,
on many occasions, they are not compelled to use. For this reason, an appeal to compulsion
understood as irresistible desire cannot be the fundamental explanation of the puzzle of
persistent use despite negative consequences. It is simply not true, of too many addicts, too

much of the time.
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Yet another Instance of Pharma company Greed_Pharma companies Like Actelion tinker with the chemical molecule

Macitentan is the second nonselective endothelin receptor antagonist approved for PAH. It is a derivative of bosentan (Tracleer), which is also manufactured by Actelion

Pharma companies Like Actelion tinker with the chemical molecule to obtain  another 10 years of time to  Suck the Money out of the  patient Population  by  misrepresentation by stating the  new drug to be  more  powerful.

Med Lett Drugs Ther. 2014 Feb 17;56(1436):15-6
The FDA has approved macitentan (ma" si ten' tan; Opsumit – Actelion), for oral treatment of pulmonary arterial hypertension (PAH). Macitentan is the second nonselective endothelin receptor antagonist approved for PAH. It is a derivative of bosentan (Tracleer), which is also manufactured by Actelion, and is scheduled to become available generically in 2015. Riociguat (Adempas), another new drug for this indication, will be reviewed in a future issue.
DRUGS FOR PAH — Current management of PAH usually includes warfarin (Coumadin, and others) and furosemide (Lasix, and generics). Oral drugs approved specifically for PAH include the phosphodiesterase 5 (PDE5) inhibitors sildenafil (Revatio, and generics) and tadalafil (Adcirca),1bosentan, and ambrisentan (Letairis), a selective endothelin type A receptor antagonist.2 Patients with more advanced disease can be treated with multiple daily inhalations of a systemic prostacyclin such as iloprost (Ventavis) or treprostinil (Tyvaso), or continuous intravenous infusions of epoprostenol (Flolan, and generics) or treprostinil (Remodulin); treprostinil can also be given as a continuous subcutaneous infusion.3
MECHANISM OF ACTION — Macitentan prevents the binding of endothelin (ET)-1 to both ETA and ETBreceptors. Macitentan has high affinity for ET receptors in human pulmonary arterial smooth muscle cells and may cause less liver toxicity than bosentan.3-5
CLINICAL STUDY — Approval of macitentan was based on a clinical trial (SERAPHIN) in 742 patients randomized to placebo or to 3 mg or 10 mg of the active drug once daily. The composite primary endpoint was time from treatment initiation to the first occurence of death, atrial septostomy, lung transplantation, use of injectable prostanoids, or worsening of pulmonary hypertension. More than 60% of patients were on stable PAH therapy, primarily with oral PDE5 inhibitors.6
After a median treatment duration of 115 weeks (the incidence of death was followed to 129 weeks), 31.4% of patients taking macitentan 10 mg/day experienced a primary endpoint event, compared to 46.4% of patients taking placebo (P<0 .001="" 6-minute="" a="" additional="" alone.="" an="" and="" as="" attributable="" authors="" beneficial="" but="" clinical="" defined="" did="" distance="" effect="" for="" in="" incidence="" lower="" macitentan="" morbidity="" mortality="" mostly="" need="" not="" of="" on="" p="" pah="" reduced="" reduction="" show="" significantly="" state="" symptoms="" that="" the="" to="" treatment.="" trial="" walk="" was="" which="" worsening="">
At 6 months, the secondary endpoint of 6-minute walk distance had increased by 7.4 meters and 12.5 meters in the 3-mg and 10-mg groups, respectively, and had decreased by 9.4 meters with placebo.
ADVERSE EFFECTS — Adverse events that occurred at a rate at least 3% higher with macitentan 10 mg than with placebo included headache, nasopharyngitis, bronchitis, and anemia. Decreases in hemoglobin and hematocrit have also occurred in patients taking other endothelin receptor antagonists. Macitentan is not recommended for patients with severe anemia.
Aminotransferase elevations, hepatotoxicity and liver failure have also occurred with other endothelin receptor antagonists. In the macitentan clinical trial, the incidence of elevated aminotransferases >3× the upper limit of normal (ULN) was similar with both doses of macitentan and with placebo, but the incidence of elevated aminotransferases >8x ULN was 2.1% with macitentan 10 mg and 0.4% with placebo.
A decrease in sperm count has occurred with other endothelin receptor antagonists and may also occur in men taking macitentan.
PREGNANCY — Macitentan is teratogenic in animals. It is contraindicated for use during pregnancy (category X) and is available for women only through a restricted access program. Pregnancy should be excluded before starting treatment and prevented during treatment and for one month afterwards.
DRUG INTERACTIONS — Strong CYP3A4 inducers such as rifampin can lower serum concentrations of macitentan, and strong CYP3A4 inhibitors such as ketoconazole and ritonavir can increase them. Concomitant use of macitentan with strong CYP3A4 inducers and inhibitors should be avoided.7
DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of macitentan is 10 mg once daily. Aminotransferases should be monitored before starting macitentan and as needed during treatment. The drug should be discontinued for clinically significant aminotransferase elevations or when elevations are accompanied by an increase in bilirubin >2x ULN or by symptoms of hepatotoxicity. Patients with pulmonary veno-occlusive disease should not take macitentan.
The cost of 1 month's treatment with macitentan is $6840.8

CONCLUSION — Macitentan (Opsumit) can decrease morbidity in patients with pulmonary arterial hypertension, but the claim that it has been shown to decrease mortality is misleading
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Monday, March 25, 2019

CCH_Adolescent Medicine Topics

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