PDE5 is a dimeric enzyme that is composed of two identical 100 kD
proteins. There are four known isoforms of PDE5 ( PDE5A 1-4 ) ACC . No
: NM _ 03343I : these isoforms are products of a single gene and are
formed by alternative splicing of mRNA . The enzymatic characteris-
tics of the PDE5A1-3 appear to be quite similar although there may be
some selectivity in their tissue distributions ; PDE5A3 is largely
expressed in smooth muscle. The enzymatic properties of PDE5A4 have not
been character- ized . Each of the monomers in PDE5 is a chimeric
protein that contains two major functional domains that are
approximately equal in size , i . e ., a catalytic domain ( C domain )
located in the more C-terminal portion of the protein and a regulatory
domain ( R domain ) located in the more N-terminal portion. The single
catalytic site located in the C domain is the target for sildenafil.
The R domain of PDE5 contains allosteric cGMP-binding sites that
contribute importantly to regulation of enzyme functions and to potency
of these PDE5 inhibitors . However , the allosteric cGMP-binding sites
in PDE5 are evolutionarily and biochemically distinct from that of the
catalytic site . These sites are highly specific for cGMP : and do not
interact with sildenafil. The catalytic site binds cGMP in a shallow
pocket along the sur- face of the enzyme . When cGMP occupies this site
, the cyclic phosphate bond of cGMP is brought into proximity with the
catalytic machinery of the enzyme , which involves an array of amino
acids and divalent cations including Zn2 +. This arrangement provides
for the rapid hydrolysis of the cyclic phosphate bond of cGMP to form 5
‘ -GMP , which has low affinity for the enzyme and rapidly dissociates
from PDE5 . 5 ‘ -GMP is inactive in the cellular cGMP-signaling pathway
. Other cellular phosphohydrolases do not hydrolyze the novel cyclic
phosphate bond of eGMP or cAMP . Because the structure of sildenafil
resembles that of eGMP , it can occupy the PDE5 catalytic site , thus
blocking access to eGMP . In addition , sildenafil is stable and is not
inactivated by the catalytic machinery ; nor is it metabolized
significantly in the smooth muscle cell . For these reasons ,
occupation of the PDE5 catalytic site by sildenafil competitively
inhibits eGMP breakdown since eGMP cannot gain access to the catalytic
machinery . In the face of ongoing synthesis of eGMP in any tissue
containing PDE5 , this will cause eGMP to accumulate and to increase
cGMP signaling through PKG . In the penile corpora cavernosa , this
contributes to improved erectile function . Although the C domain of
PDE5 is the direct target of PDE5 inhibitors, functions of the R domain
enhance the PDE5 inhibitor actions on the enzyme . Allosteric
cGMP-binding is provided by sites in the R domain ; whether one or two
eGMP molecules are bound per subunit is still unclear . In addition ,
there is a single consensus phosphorylation site for PKG or PKA near
the N-terminus . Phosphorylation of this site activates PDE5 catalytic
function and thereby provides for negative feedback regulation of cGMP
levels. Phosphorylation of this serine is tightly controlled by cGMP
levels since occupation of the PDE5 allosteric cGMP-binding sites is
required for phosphorylation to occur , and the site is preferentially
phosphorylated by PKG compared to PKA . Therefore , it is likely that
the site is only phosphorylated when cGMP is elevated in the cell .
When cGMP binds to the allosteric sites , cGMP is not degraded as it is
in the catalytic site , but PDE5 enzyme functions are altered . Cyclic
GMP binding to the allosteric sites in the R domain pro- duces a
conformational change that exposes the serine allowing it to be rapid-
ly phosphorylated , thereby increasing PDE5 catalytic activity. Cyclic
GMP occupation of the allosteric sites also increases the affinity of
the catalytic site for cGMP , thereby further activating PDE5 catalytic
site func- tions. However , in the presence of a PDE5 inhibitor and
ongoing syn- thesis of cGMP , cellular cGMP is elevated , which fosters
increased binding of cGMP to the allosteric sites and phosphorylation
of the serine by activated PKG ; as a result , the affinity with which
PDE5 inhibitors bind at the catalytic site is increased . Therefore ,
due to its molecular mechanism , the potency of sildenafil is actually
greater than would occur in the absence of the R domain . This property
of the enzyme translates into greater clinical efficacy and poten- cy
of sildenafil and other PDE5 inhibitors . Following ingestion of a PDE5
inhibitor tablet , any elevation of cGMP in smooth muscle cells should
increase the avidity with which the PDE5 catalytic site binds that
inhibitor . That is , the PDE5 inhibitor , by fostering increased
binding of cGMP to PDE5 allosteric sites , stimulates its own efficacy
and potency.
Don’t allow food to spoil, but if it does, discard it immediately, then wash and dry receptacles thoroughly. Use a fan or open the windows to remove excess steam when cooking. Look out for mold on cutting boards and sponges, in sink and disposal stoppers, refrigerator gaskets and drip pans, washing machines, garbage containers, and places where fresh food is stored. Watch for dust and mildew atop, behind, and under sinks, stoves, refrigerators, and other hard-to-reach places.
All Rooms
Bare is beautiful. The fewer objects lying around, the better. Books, magazines, light fixtures, shelves of knickknacks, TV sets, even clothes collect dust. Move small objects to drawers and cabinets and keep the furniture 3 to 5 inches from the wall, so you can vacuum behind them. Store all garments in clean closets with closed doors. If you must dust the room yourself, use damp rather than dry dusting, and wear a disposable face mask. To get to hard-to-reach places atop refrigerators or behind headboards, wrap a moist rag around a pole or yardstick. Painted walls are preferable to wallpaper because the flour in wallpaper paste has a high content of mold spores. So do fabric hangings and tapestries. If practical, replace upholstered chairs and sofas with. canvas, metal, plastic, or simple wood furniture. Decorative pillows and stuffed animals attract dust. One mother tells her daughter she’s taking her teddy bear for a ride, then pops him into the dryer for a half-hour spin at high heat. An alternative is to put Teddy in an airtight plastic bag and place him in the freezer for two to three days. It takes that long for the cold temperature to kill the mites, although it doesn’t remove their debris. A third possibility is to cut open the toy, replace the stuffing with old nylon stockings or polyester fill, and sew up the seam.
New carpet loses its strong chemical odor over time, but as it ages, it becomes a haven for microorganisms-dust mites, mold spores, animal dander, and the like. A University of Virginia study found that carpets accumulate allergens at one hundred times the rate of a bare floor. If possible, carpets should be replaced. The ideal nonallergenic floor is a hardwood, tile, or vinyl surface that can be cleaned with a wet mop-twice a week, at least-and covered with small washable rugs. Don’t use brooms; they stir up too much dust.The best vacuum to buy is a tank-type with strong suction and an extension on the hose so that the canister can sit outside the room during vacuuming. Dust-filtering bags are available from allergy supply companies for $ 6 to $ 10 for a set of five. Leave the task of changing them to someone else. Many new and more expensive ($ 400 and up ) vacuum cleaners come equipped with HEPA ( high efficiency particulate arresting ) filters specially designed to trap fine particles as small as . 3 microns. ( A micron is ”/, mw of a millimeter .) Consumer Reports studied vacuum cleaners in 1997 and reported : ” If someone in your family has asthma or allergies, consider using one of the high-performing models as your regular vacuum cleaner. Many airborne allergens-notably pollens-are much larger than the particle sizes we tested, so cleaners that performed well on our tests will also trap the larger particles effectively. But don’t expect a high-filtration vacuum cleaner to substitute for longer-lasting environmental controls, such as removing carpeting or encasing bedding in mite-proof covers .”
The Windows
Roll-down shades and. unlined washable curtains are preferable to dust-catching blinds and draperies. Keep windows closed during pollen season and at peak pollen hours, usually 5 A. M. to 10 A. M. Use central or room air conditioning switched to the ” recycle ” or ” recirculate ” setting. Air conditioners are great pollen traps, so clean them and change filters scrupulously. If possible, avoid heavy draperies and Venetian blinds in favor of light cotton or synthetic curtains that can be washed regularly. Shades are fine if dusted at least once a week.
The Bathroom
Prevent molds from growing by wiping down shower curtains, walls, tub, toilet, tile, and all damp areas with a mixture of cup of bleach to 1 gallon of water ( or one part bleach to ten parts water ) at least once a month. Four times a year use Zephiran ( benzalkonium chloride ), 1 fluid ounce to 1 gallon of water, to further inhibit mold growth. Allow plenty of ventilation, and let surfaces air-dry-or better yet, install an exhaust fan. Keep as few toxic cleaning products and pesticides in the kitchen as possible. ( See chapter 17 for nontoxic substitutes .)
Outdoor allergens are almost impossible to control. In your home, however, you rule the atmosphere. The cleaner the air you breathe, and the more dust, pollens, molds, and dander you can banish from your indoor environment, the better your chances of getting good results from pills, sprays, or shots. Your eventual goal is to live and work in settings so free of irritants and allergens that you won’t need any medication.
CLEANING HOUSE
Dust reduction is your main priority. Begin in the bedroom, be- cause it ‘ s where adults spend one-third of their time and children spend half their time. It’s also home to the greatest number of dust mites. Once you’ve done the bedroom, apply the same principles to the rest of the house, including closets.
The Bed
Not a pretty picture, but do you realize that thousands of tiny dust mites share your bed and bedding every night? If you weren’t so hospitable, they’d starve-and that’s exactly what you want to happen. The little beasties can’ t crawl through plastic, so encase your mattress and box spring in airtight zippered covers, then apply tape over the zippers. Mattresses not only draw mites ; many contain allergenic materials such as horsehair. Allergy specialty stores like Gazoontite ( see appendix D ) sell protective mattress covers, not only in heavy-duty vinyl but also in machine-washable blends of cotton and polyester. Some are fortified with an antibacterial agent to protect against molds. The bed should, be made of wood or metal. Try to avoid wool, down, feather, kapok, and ( moldattracting ) foam rubber products. Polyester, linens, or cottons are fine for most people, although one 1999 British study compared dust mite levels in feather and synthetic pillows and found higher levels of dust mite allergens in the synthetic pillows. Studies show that the average year-old pillow houses no fewer than 250, 000 mites, and that up to 20 percent of a pillow’ s weight can come from mites and their waste. Perhaps the answer is to buy inexpensive new pillows and replace them annually-or, as one enterprising mother does, make your own pillows out of soft white towels. Then, once a week, toss the whole thing into the washer. Blankets, sheets, and cotton or polyester pillowcases should be machine-washed in very hot water ( 140 degrees Fahrenheit ) every seven to fourteen days. Eliminate such dust collectors as quilts and comforters, and in general, keep your bed simple. If you can’ t bear to part with Grandma’ s quilt or your rose-patterned comforter, wash them first, then dry them in the dryer. An hour of dry heat dramatically reduces the dust mite population. Canopies, padded headboards, bunk beds, and ruffles are far too hospitable to the critters. Don’ t overlook your clothes, especially outerwear such as jackets, wool caps, mittens, and sweaters. Wash in cold water, then dry for fifteen minutes at a high temperature or stash in the freezer overnight. Incidentally, dust mites don’ t much care for mothball fumes. A Connecticut study found that mothballs, mothball crystals, and mothball oil packets destroy dust mite eggs. The bad news is that mothball vapors can be irritating to humans, especially asthmatics or anyone sensitive to chemicals. The Journal of Allergy and Clinical Inimunologil recently reported that Australian researchers added eucalyptus oil to laundry and found it killed 95 percent of mites that survived the high temperatures.
Viagra is a recent invention , but sex is not . And for as long as humans have engaged in sexual activity , there has been impotence . The word impotence first appeared in the fifteenth century , but today it has been abandoned in politically correct circles in favor of the term erectile dysfunction , or more colloquially , ED . Incredibly , it took a panel of experts to meet and decide on the name change . In 1993 , at the Consensus Meeting of the National Institutes of Health , participants agreed that the failure of the penis to achieve and sustain adequate rigidity for sexual intercourse was equivalent to other types of organ failures , such as hepatic dys- function for liver disease . Moreover , the experts recognized that the word impotence had negative connotations that should not be invoked just because a man ‘ s penis did not work properly . To be impotent , after all , means that someone lacks power , force , or effec- tiveness . Since we would not attribute such qualities to someone whose liver did not work well , the meeting attendees agreed that the term impotence should not be applied to men with erectile dysfunction . Nevertheless , unlike men with liver disease , kidney disease , or rhythm disturbances of the heart , men with erectile dysfunction do in fact feel impotent , in the full sense of the word . For this reason , I continue to use the word interchangeably with erectile dysfunc- tion . Depression , embarrassment , a diminished sense of masculin- ity-these are some of the feelings men experience when erectile dysfunction occurs . Women are often surprised at the depth of despair men exhibit when the erection fails . Of course , it can be disappointing at the moment for both partners . But when it first happens to a couple , many women describe an ” oh , well ” attitude about it , with the expectation that there will be other opportunities later . Only rarely do men have such a response . Typically , they expe- rience a frenzy of anxiety and despair when they go soft during a sexual encounter . The experience is mocked in the first of the Austin Powers movies , when the comic sleuth Austin temporarily loses his ” mojo .” The cocky , sexually aggressive aspect of his per- sona disappears until he gets it back . On a much more serious note , many a young man fantasizes about being a great lover-a Casanova or Don Juan-but if his penis will not cooperate enough even to get started , then what hope of sexual greatness can he entertain ? A torrent of questions rushes in on him when he expe- riences erectile dysfunction for the first time : ” What is happening ?” ” Why ?” ” Why now ?” ” Does this mean that my penis is broken for good ?” ” Will I never be able to have sex again ?” ” Will she laugh at me ?” ” Will she leave me ?” ” Will she tell everyone and shame me ?” Since a normal erection occurs as if by magic , the failure of the penis to respond appropriately in a sexual situation can be an unpleasant mystery for the affected man . An erection is one of the few things in life that is not improved by greater determination and willpower . A woman may roll over and say nonchalantly , ” Let ‘ s just sleep on it , and I bet things will be great in the morning .” The man will probably not sleep a wink .
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