Distal side effects

The same model and computational protocol was used in another MD study of the distal side effects [74]. Three distal side mutants were studied. The His64Gln mutation resulted in a conformation similar to that of the wild-type 64N5H tautomer, the His64Leu mutant showed little interaction with the ligand, while... 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

To avoid the side effects of sulfapyridine, various preparations to target 5-ASA directly to sites of disease have been formulated. Also known as mesalamine, 5-ASA has been formulated in oral forms (Pentasa, Asacoi). Pentasa is a time-release capsule that releases the drug throughout the GI tract. Asacoi is a pH-dependent-release preparation that delivers drug to the distal small bowel and colon. The response of ulcerative colitis to this formulation appears to be identical to that seen with sulfasalazine. Mesalamine can also be administered as a suppository (Canasa) or enema (Rowasa) for distal colonic disease. 

The most common side effects are Raynaud s phenomenon with cold or even cyanotic distal extremities and digits, tiredness or weakness, bradycardia, and sexual impotence. Less common side effects are depression and dysphoria, bronchoconstriction, congestive heart failure, hallucinations, hypotension, vomiting or nausea, diarrhea, insomnia and nightmares, dizziness, and hypoglycemia. When due attention is paid to contraindications and the treatment is carefully monitored, the side effects of beta-blocker treatment are generally mild. 

It is an antisecretory drug. It is 5-ami-nosalicylic acid with linked sulfapyridine through azo bond. The drug is poorly absorbed from the intestine and the azo linkage is broken down by the bacterial flora in the distal ileum and colon to release 5-ami-nosalicylic acid (5-ASA) and sulfapyridine. 5-ASA inhibits locally prostaglandin synthesis, decreases mucosal secretion. It is used in rheumatoid arthritis and ulcerative colitis. Side effects include fever, rashes, blood dyscrasias, nausea, vomiting and headache. 

Oral or subcutaneous administration is usually associated with more side effects. However, when administered orally or subcutaneously, beta agonists may reach the more distal branches of the airway to a greater extent. The bronchioles are usually constricted during an asthmatic attack, and the drug may not reach the distal respiratory passages when administered by inhalation. 

As mentioned above, both the point-mutation on the distal side of the Mb and the modification of the heme-propionate side chains are effective to convert the Mb into peroxidase and peroxygenase. Thus, one can imagine that the combination of an amino acid mutation and a modified-heme reconstitution may more effectively allow us a new catalyst by oxygen storage. Recently, two examples, which demonstrated the hybrid modification of Mb, have been reported. One is the T67R/S92D Mb reconstituted with the modified hemin where a histidine is linked at the terminal of the heme-propionate side chain (108). The peroxidase activities toward p-hydroxyphenylpropionic acid and tyramine oxidations by the reconstituted mutant Mb are increased by 24- and 2.3-fold, respectively, based on the kciJKm value compared to those observed for the native Mb. 

Comparisons between R- and T-state hemoglobins on the one hand and a variety of synthetic model compounds on the other have allowed an evaluation of the possible occurrence and importance of electronic, proximal-base tension, and distal-side steric effects on the kinetics of ligation of CO and 02. Although all of these effects could influence the reactivities of hemoproteins, we conclude that hemoglobin reactivity and cooperativity are controlled predominantly by the presence or absence of proximal-base tension. 

B. Redesign of Nonheme Iron Proteins. In heme protein redesign described above, the heme prosthetic group largely dictates the active site structure. Redesign focuses mainly on the proximal and distal sides of the heme, causing minimal effects on the overall protein scaffolds. This is not necessarily the case for nonheme metalloproteins in which metal sites are not as dominant and small changes may have more dramatic effects on the protein folds and stability. 

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