Although leaded soil is less of a problem in countries that no longer have leaded gasoline, it remains prevalent, raising concerns about the safety of urban agriculture; eating food grown in contaminated soil can present a lead hazard. Interfacial solar evaporation has been recently studied as a technique for remediating lead-contaminated sites, which involves the evaporation of heavy metal ions from moist soil. Water
Lead from the atmosphere or soil can end up in groundwater and surface water. It is also potentially in drinking water, e.g. from plumbing and fixtures that are either made of lead or have lead solder. Since acidic water breaks down lead in plumbing more readily, chemicals can be added to municipal water to increase the pH and thus reduce the corrosivity of the public water supply. Chloramines, which were adopted as a substitute for chlorine disinfectants due to fewer health concerns, increase corrositivity. In the US, 14–20% of total lead exposure is attributed to drinking water. In 2004, a team of seven reporters from The Washington Post discovered high levels of lead in the drinking water in Washington, DC, and won an award for investigative reporting for a series of articles about this contamination. In the water crisis in Flint, Michigan, a switch to a more corrosive municipal water source caused elevated lead levels in domestic tap water.Like Flint MI and Washington DC, a similar situation affects the State of Wisconsin, where estimates call for replacement of up to 176,000 underground pipes made of lead known as lead service lines.
For example, rifampicin reduced the AUC by 60% in a study.Upadacitinib seems to be a weak inducer of CYP3A4, as it lowers concentrations of other substrates of this enzyme (such as the midazolam AUC by 26%). It has no effect on substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP2D6. Side effects
Common side effects are upper respiratory tract infections such as common cold and sinus infections (13.5% of patients in studies), nausea (3.5%), cough (2.2%), fever, and increased liver enzymes. Serious side effects include infections, including life-threatening ones, such as pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections. Pharmacology
Mechanism of action
The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. There are four JAK subtypes, each of which has overlapping receptor responsibilities. Inhibitors of this enzyme family (jakinibs) have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohns disease. However, the first generation of these drugs, tofacitinib and ruxolitinib, lacked subtype selectivity, affecting JAK1/JAK3 and JAK1/JAK2 respectively. This has led to dose-limiting side effects in this otherwise promising class of drugs. Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 (74-fold), JAK3 (58-fold) and tyrosine kinase 2 subtypes. Pharmacokinetics
After oral intake, upadacitinib reaches highest concentrations in the blood plasma after two to four hours. A fatty meal has no clinically relevant effect on its resorption.