Gene: Here are the answers to your questions and more:
Which organs receive the majority of blood flow and how does this influence drug distribution?
Although it accounts for only 2% of the total weight of the body, the brain receives the largest proportion of cardiac output (16-20% of the body's blood). After a drug is absorbed into the bloodstream, it rapidly circulates through the body (avg. time: 1 minute).The initial distribution of drug will reflect the cardiac output including well-perfused organs such as the brain, heart, liver, and kidney. Drugs penetrate different tissues at different speeds, depending on their ability to cross membranes. Final patterns of drug distribution reflect the particular physiological and physicochemical properties of the drug.
Once absorbed, most drugs don't spread out evenly through the body. Some drugs do not bind to blood proteins . They escape the bloodstream and attach to cells by means of receptors on the cell surface. A receptor has a specific configuration which allows only a drug that fits precisely to attach to it. The proper analogy would be a key that fits into a lock.
A drug's selectivity can be explained by how selectively it attaches to only one type of receptor. Some drugs only attach to one type of receptor; others are like a master key and can attach to several types of receptors throughout the body. In addition to cell receptors, the other important targets for drugs are enzymes which serve to transport vital chemicals, regulate chemical reactions, or serve other transport, structural, or regulatory functions.
Drugs targeted at enzymes are either inhibitors or activators.
The "key "analogy to enzyme selectivity applies here as well.
What is the PDE System?
Nonselective phosphodiesterase (PDE) inhibitors such as the theophylline have been extensively used since 1958. In the 1970s, various selective PDEs were identified. During the past 5 years, molecular biology has revealed a superfamily of selective PDE inhibitors.
Currently there are 7 PDE isoenzyme families. Each the product of distinct but related gene families. Products within each family are distinct and have different effects within the body. Comparing one PDE inhibitor to another is the equivalent of trying to open your neighbor's house with your house key. It just doesn't fit.
Importantly, the specificity of selective PDE inhibitors is restricted to a relatively narrow concentration range with inhibition evident at higher concentrations.
What is the distribution of these PDE enzymes?
Many organs in the bodies contain members of known PDE families. There is a higher concentration of PDE in a particular organ depending of its function.
There are distinct functional effects resulting from the inhibition of isoenzymes for each PDE family including:
PDE-I: CNS modulation
PDE-III: Positive inotropism
PDE- IV: Airway smooth muscle relaxation
PDE- V: Penile erection
PDE-VI: Photoreceptor
PDE-VII: Skeletal muscle
What are the effects of systematically inhibiting PDEs?
The primary use of the PDE-III inhibitors is in the treatment of heart failure. Drugs include: Inocor (amrinone) and Primacor (milrinone). Persantine (dipridamole) is an example of a PDE inhibitor that has been used extensively as a vasodilator without major adverse effects.
As with MUSE, long-term Viagra studies over 5 years are not available.
How does sildenafil work?
cAMP and cGMP are fundamental second messengers for the development of cavernosal smooth muscle relaxation and are inactivated by PDEs. If the action of the PDE is inhibited, the cAMP and cGMP activities would be enhanced. The main PDE activity in human corpora cavernosa was due to PDE-V with PDE-II and PDE-III also identified.
Sildenafil has found to be a particularly active inhibitor of cGMP-specific PDE-V.
Is sildenafil specific to PDE-V sites only and no other PDE inhibition will occur?
Sildenafil has been shown to be 70 fold selective for PDE-V as compared to other PDE families ncbi.nlm.nih.gov
Dr. Tom Lue, author of the MUSE monograph on the Vivus website, has commented at the 1997 AUA meeting: "It's remarkable because we didn't really think a pill would actually work for this problem. Because normally, you take a pill, it goes to all parts of the body. And this particular one actually works on the penis."
How do you reconcile Dr. Padma-Nathan's dramatic change of opinion concerning MUSE after Pfizer started paying for studies?
First of all, I believe you are misrepresenting the lead author of the NEJM MUSE study Dr. Padma-Nathan's position. You stated: Dr. Padma-Nathan " verbally blasted (MUSE) therapy as being only 10% effective."
Dr. Padma-Nathan was quoted as saying in Barrons (2/24/97)" Only 5-10% of the patients are opting for it (MUSE)."
In the a CNBC interview , Dr. Padma-Nathan said "There is a role for each therapy, be it injection, transurethral, topical or a pill."
Insight into Dr. Padma-Nathan's current position was provided on this Board at www3.techstocks.com
I also believe Dr. Padma-Nathan provides unbiased opinions about ED drugs. Fortunately, he does not have royalty agreements with any ED drug.
What is the effect of trazodone on ED?
Trazodone exhibits adrenoceptor antagonistic activity in the human cavernosal tissue. It was fortuitously found to induce priapism leading to its application as an ED drug. Kurt et al found it to be effective in a study described in the Journal of Urology, 1994; 152, 407-409.Trazadone is used at different doses of 50-200mg daily, most commonly 100mg at bedtime. Adverse effects include drowsiness, nausea and , rarely, urinary retention. . Here is a recent study:
Oral trazodone as empirical therapy for erectile dysfunction: a retrospective review.AUTHOR: Lance R; Albo M; Costabile RA; Steers WDAUTHOR AFFILIATION: Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307, USA.SOURCE: Urology 1995 Jul;46(1):117-20NLM CIT. ID: 95328174ABSTRACT: OBJECTIVES. Anecdotal reports of increased libido and sexual function in patients taking trazodone have led to its empirical use in patients with erectile dysfunction. A retrospective review of patient-reported responses to trazodone was performed to outline the efficacy and side-effect profile of this agent. METHODS. Between 1989 and 1994, 182 patients were placed on oral trazodone as empirical therapy for erectile dysfunction. Patients ranged in age from 26 to 85 years, with a mean of 60 years. Patients were evaluated before receiving trazodone with a thorough medical history and physical examination. Known risk factors for erectile dysfunction were assigned based on historical information and the findings of the examination. Patients received trazodone for at least 2 consecutive months, with daily doses starting at 25 mg. RESULTS. One hundred twenty-seven patients were available for follow-up by a standardized questionnaire regarding perceived improvement in erectile function, sexual function, and side effects. In patients less than 60 years of age, with no known risk factors for erectile dysfunction, 21 of 27 (78%) showed significant improvement in erectile ability. Smokers and patients older than 60 years with a history of significant peripheral vascular disease responded poorly to trazodone therapy. The duration of erectile dysfunction was inversely related to a response to trazodone. Of patients with a duration of impotence less than 12 months, 48% reported a positive response. Only 16% of patients with duration of erectile dysfunction greater than 60 months reported improvement in erections and sexual function. Trazodone was well tolerated by this population, with 62% reporting no side effects. CONCLUSIONS. Despite the limitations of a nonrandomized, retrospective study, trazodone appears to benefit younger patients with erectile dysfunction with few known risk factors. A prospective, placebo-controlled trial is needed to confirm the observations of this pilot study.
Have a great week!
BigKNY3 |
