An applicant seeking approval to market and distribute a new drug product in the U.S. must typically undertake the following:

Barbuti, A. et al. A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins. J Mol Cell Cardiol 53, 187–95 (2012).

Continuous-flow experiments Researchers in China report a continuous-flow process for the preparation of m-nitrothioanisole via diazotization of m-nitroaniline to afford a diazonium chloride intermediate, which is then subjected to azo coupling with sodium thiomethoxide to give 1-(methylthio)-2-(3-nitrophenyl)diazene, followed by dediazonization to provide m-nitrothioanisole in high yield (2). A flow process was developed to minimize accumulation of the energetic intermediate diazonium salt and enable large-scale production.

Section 102 of the Ordinance allows Israeli employees, directors and officers, who are not controlling shareholders to receive favorable tax treatment for compensation in the form of shares or options. However, under this route we are not allowed to deduct any expense with respect to the issuance of the options or shares. Israeli non-employee service providers, consultants and shareholders who hold 10% or more of our total share capital or are otherwise controlling shareholders, may be granted options pursuant to Section 3(i) of the Ordinance, which does not provide for similar tax benefits. In order to comply with the terms of the capital gains route pursuant to Section 102 of the Ordinance, the granted options as well as the ordinary shares issued upon exercise of these options and other shares received subsequently following any realization of rights with respect to such options (such as share dividends and share splits), must be granted to a trustee for the benefit of the relevant grantee and should be held by the trustee for at least two years after the date of the grant. If such options or shares are sold by the trustee or are transferred to the grantee before the end of the two-year period, then the grantee would be taxed at top marginal rates upon selling the shares.

The FDA’s standard is to be below an amount that would be expected (by their dose/response modeling) to cause 1 extra cancer case in 100,000 people who were taking the tablets at a standard dose for 70 straight years. That’s pretty stringent, considering the background rates of cancer in people who actually stay alive for 70 years in a row, especially when you factor in that no one goes on valsartan when they’re ten years old. Unfortunately, the ZHP material (according to the FDA) would be expected to cause one extra case of cancer with only 8,000 patients taking the highest dose of the drug for only four years, and that’s definitely unacceptable. It appears that the other manufacturers’ batches had contaminants at lower levels, from what I can see, although the amounts do not appear to have been specified.

Our research and development expenses amounted to approximately $8.3 million during the year ended December 31, 2018, representing a decrease of approximately $1.4 million, or approximately 14%, compared to approximately $9.7 million for the year ended December 31, 2017. The decrease primarily resulted from a decrease in research and development subcontractor expenses in connection with the completion of the ARREST Study of approximately $2.5 million; partially offset by an increase of approximately $0.5 million in salaries and benefits paid to new employees hired since the comparable prior year period. We expect that research and development expenses will significantly increase through 2019 and beyond.

Cholesterol has been shown to regulate numerous ion channels. HCN channels represent the molecular correlate of If or Ih in sinoatrial node (SAN) and neuronal cells. Previous studies have implicated a role for cholesterol in the regulation of rabbit HCN4 channels with effects on pacing in the rabbit SAN. Using electrophysiological and biochemical approaches, we examined the effect of cholesterol modulation on human HCN1, HCN2 and HCN4 isoforms. Patch-clamp experiments uncovered isoform specific differences in the effect of cholesterol on gating kinetics upon depletion by MβCD or mevastatin or enrichment using MβCD/cholesterol. Most dramatically cholesterol had isoform specific effects on mode-shifting, which has been suggested to play a key role in stabilizing firing rate and preventing arrhythmic firing in SAN cells and neurons. Mode-shifting in HCN1 channels was insensitive to cholesterol manipulation, while HCN2 and HCN4 were strongly affected. Trafficking of each isoform to the plasma membrane was also affected by cholesterol modulation differentially between isoforms, however, each isoform remained localized in lipid raft domains after cholesterol depletion. These effects may contribute to the side effects of cholesterol reducing therapies including disrupted heart rhythm and neuropathic pain, as well as the susceptibility of sinus dysfunction in patients with elevated cholesterol.

        A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired (other than method of use patents involving indications for which the ANDA applicant is not seeking approval).

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Citation:  When referring to this article, please cite as C. Challener, “Steps Closer to the Adoption of Continuous Processing," Pharmaceutical Technology 40 (6) 2016.

Mistrik, P. et al. The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. J Biol Chem 280, 27056–61 (2005).

Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. International journal of surgery 8, 336–341, doi:10.1016/j.ijsu.2010.02.007 (2010).