Pulmonary Arterial Hypertension, November 2005

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Pulmonary Arterial Hypertension, November 2005 Journal Scan

FromThe New England Journal of MedicineNovember 17, 2005  ( Volume 353, Number 20 )

Sildenafil Citrate Therapy for Pulmonary Arterial HypertensionGalie N, Ghofrani H, Torbicki A, et al. 
The New England Journal of Medicine.  2005;353(20):2148-2157

The pathophysiology of pulmonary hypertension involves an increased production of vasoconstrictors (endothelin-1) and a decrease in prostacyclin and nitric oxide, which are vasodilators.[1] Over time, this pulmonary endothelial dysfunction causes strain on the right ventricle, leading to right ventricular failure. The end result is eventually death. Long-term therapies have consisted of prostanoids, oxygen, diuretics, and endothelin receptor antagonists (ERAs). Yet treatment is problematic. The prostanoids are often associated with many potential side effects. Routine liver enzyme testing is required when using the ERAs.[2] The role of the nitric oxide pathway has been studied, and inhaled nitric oxide has been used for some time in vasoreactivity testing. Phosphodiesterase type-5 (PDE-5) metabolizes cyclic guanosine monophosphate (cGMP), causing vasoconstriction and the growth of vascular smooth muscle cells. In patients with pulmonary hypertension, PDE-5 is upregulated. The inhibition of PDE-5 enhances the cGMP, allowing for dilation of pulmonary vessels and possibly exerting antiproliferative effects on the vascular smooth muscle cells in the lungs.[3]

This large 12-week study conducted in 53 centers between October 2002 and November 2003 evaluated the effects of 3 different doses of sildenafil (a PDE-5 inhibitor) on patients with pulmonary arterial hypertension, mostly New York Heart Association (NYHA) classes II and III. The patients included in the study had either idiopathic pulmonary arterial hypertension, pulmonary hypertension associated with connective tissue disease, or repaired congential heart disease. Patients were randomized according to distance walked on a 6-minute walk (< 325 m or > 325 m) and the cause of the pulmonary hypertension. Treatment groups received either 20-, 40-, or 80-mg doses of sildenafil or placebo. In the extension study, 80 mg of sildenafil was studied. The primary endpoint was the 6-minute walk distance (6MWD). Also evaluated was NYHA functional class, time to clinical worsening, hemodynamic parameters (mean pulmonary artery pressures), and Borg dyspnea scale. A total of 278 patients were randomized to 1 of the 4 treatment groups, with 265 completing the 12 weeks of study. Idiopathic pulmonary arterial hypertension was the most common type noted, with NYHA class of III for 58% of the patients. All patients receiving sildenafil exhibited an increase in 6MWD at the end of 12 weeks. The 20-mg group demonstrated an increase of 45 m and the 80-mg group improving by 50 m. Hemodynamics varied considerably among the 3 sildenafil groups and the control group. The placebo group demonstrated an increase in hospitalizations for worsening pulmonary hypertension compared with the treatment group. WHO functional class improved to a greater degree in the sildenafil groups.

Overall, an improvement was noted in exercise capacity for the patients taking sildenafil regardless of the cause of PAH evaluation. The improvement in 6MWD compares to that noted with epoprostenol (47 m) and bosentan (44 m). This effect was noted up to 1 year in the extension study.ReferencesHumbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:(Suppl 12):13S-24S.Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol. 2005;100:131-138.

Abstract

This is a part of article Pulmonary Arterial Hypertension, November 2005 Taken from "Levitra Versus Viagra" Information Blog

Austin Powers III: Your views

Monday, 29 July, 2002, 10:12 GMT 11:12 UK Austin Powers III: Your views
The film boasts some new faces along with old favourites
Mike Myers returns for his third incarnation as the dandy spoof spy, this time joining forces with old flame Foxxy Cleopatra (Beyoncé Knowles) in the fight against Dr Evil.

The film opens with a James Bond-style set piece which enlists a bevvy of A-list Hollywood stars.

"Myers' scriptwriting skills and performance have sharpened since The Spy Who Shagged Me. At times, there are even flashes of genius, reminiscent of Peter Sellers at his legendary best," wrote BBC News Online's Rebecca Thomas.

But what do you think?

Has the Powers persona run out of steam? Or is Goldmember the best yet?

I'm still reeling and getting flash backs. Will have to see it again as I know I missed bits from laughing. A much needed pick me up, just what the doctor ordered.
sheila, UK

Definitely not as good as the second installment. Beyonce was fantastic as Foxxy Cleopatra and the cameos were a great touch. The Dutch villian had his grossly funny moments but all in all, this is best for the DVD player and not the big screen.
Jason, USA

I loved the film! Not as funny as the first, but it was still a good laugh. Mike Myers is a comedy genius and I hope he continues to make films well into the future.
Amanda, Scotland

This movie is groovy baby. The cameo roles are really funny - I was nearly in tears. The Goldmember character was really funny and also, to live up to tradition, some of the character names are really funny.
Dr Evil aka Neil, Scotland

Very disappointing. Without question the weakest instalment in the trilogy. The character of Goldmember is devoid of any humour and really grates. He's perhaps even less funny than Fat Bastard - and certainly more irritating. The rehashed gags were simply not funny the third time round and there were genuinely few moments past the opening 20 minutes where I laughed.

Myers still shows his comedic genius through his use of subtle and not-so-subtle facial expressions in the characters of Evil and Powers, but seemed fresh out of inspiration for any new and funny gags.

A sequel too far.
Stavros, England

Don't believe the hype - see the film and see what a genius Mike Myers is. Anyone who could come up with a Dutch villain with such imagination has much to offer the world. Laugh a second, particularly the first 20 minutes. The film does have a human side, particularly as Myers lost his father in the same way that his screen character did (in reality he died when Myers was young). No-one else can pull off a film like that other than Myers. Well done to great casting.
Paul Rowley, UK

Austin Powers 3 was a great film overall, some really funny moments - Austin Power's fight with Mini-Me, Austin accidently unplugging the fountain and the medical aboard Dr Evil's ship to name a few. There where however some dull moments in between, but this just gave time for the audience to recover. Myer's certainly is a comedy genius, not sure there is enough mileage for a fourth Austin Powers though!
Mini Me, UK

Grooovy baby yeah! Myres never fails to deliver, true there's nothing original here but why would you want to change a formula which already works?
Mike Harwood, UK

I went to see it last night and at times I had stomach ache where I laughed so much. The opening is brilliant, great use of cameos without interfering with the storyline. I thought it was supremely better than 'The Spy Who Shagged Me. I thought Goldmember was such a weird but entertaining character, where does Mike Myers get his ideas from? I loved the development of Dr Evil's character. Allowing time for a proper story. Will definitely go and see it again
Kat, England

The third time is definitely not the charmer. With the exception of Ms. Knowles, the whole escapade was a crushing bore.
Robert del Valle, USA

There was the odd good gag, but on the whole I left with the impression they had made another movie for the sake of it (and for loads of cash).
Laura, UK

Great film. Laughed so much my sides ached. Beyonce would benefit from acting lessons.
Phil, England

Complete rubbish. Goldmember was just not funny. It lacked all of the wit and novelty of the first two. Myers is under the impression that his observations are accurate, but the accents are awful and stilted, and quite often his characters just leave you cold, lacking subtlety and humour. He has taken Austin Powers one stage too far. Wayne¿s World and Wayne¿s World 2 were fantastic, and Austin Powers 2 was excellent. Maybe Myers should have a "two strikes and out" rule, as AP 3 was a load of tripe.
Jasper, UK

Goldmember is an excellent film, at times it was like watching Peter Sellers in the Pink Panther, and the bit where Austin beats up Mini-Me is truly gut busting. Better than the second but not as good as the first, but a top rate comedy that I'll definitely be watching again and again.
MatFlat, UK

I laughed and laughed and laughed… And on rare occasions, realised that the rest of the audience wasn't laughing with me. This was due to the number of UK/US gags, many of which the North Carolina audience didn't get (and I'm guessing the Brits didn't get some of the US gags - like the Subway diet one). Hilarious, just the pick-me-up I need, baby.
Melissa, US, ex-pat UK

The film was excellent. It was undeniably funny. But the humour went more for qauntity than quality. Which is better? Laughing a lot? Or really laughing every now and then? Whetever you come out saying things like "what about when Dr.Evil….." so yeah go see it. It's the culture.
Terry, england

Total self-indulgent rubbish, this film suffers from the success of the previous films.

It now appears that everyone wants in on the Austin Powers phenomenon. It was as if numerous stars have just turned up on set and been obliged with a distracting cameo.

Part of the charm of the other films is that you could suspend reality and loose yourself in a wonderfully brash comic environment. This film, however, is far too aware of its own humour. It is as if the whole franchise has become one big in-joke to which you are presumed to be a part. But lines annoyingly played straight to camera are no substitute for plot.

What story there is serves little purpose other than to act as a tenuous link to the next ill-conceived, recycled, or just plain laboured gag.

The whole experience was like looking forward to meeting some old friends, only to find that success had made them big-headed and boorish.

Brian, UK

Oh dear, what a tired concept. There were so many moments in the film where the actors paused for audience laughter, but laughter came there none. Even Myers seemed to be cringing. Relying on age-old gags - "meat and two veg", "you're a tripod", and the Viagra stiff neck joke - is beyond lame, it's embarrassing. The script was terrible. Only Mini-Me could provoke the mildest of titters, and even then, the violence towards him was at times unpalatable.
Andrew Davies, UK

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Yeah baby BBCi Films Austin Powers quiz and interviews See also:

25 Jul 02 | EntertainmentMyers recharges Powers' pencil
23 Jul 02 | EntertainmentStars turn out for Goldmember
09 Apr 02 | EntertainmentLast hope for Goldmember
14 Nov 99 | UKAustin Powers stunt not groovy
24 Jul 02 | EntertainmentWalk Of Fame honour for Myers
23 Jul 02 | EntertainmentKnowles nervous about Foxxy role
06 Sep 99 | EntertainmentMyers voted hottest star
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This is a part of article Austin Powers III: Your views Taken from "Levitra Versus Viagra" Information Blog

Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medicine: A Single-Dose, Dose-Escalation Safety and Pharmacokinetic Study

Tomoo Kuge, Ph.D.; Takashi Shibata, M.D., Ph.D.; Michael S. Willett, Pharm.D.

Abstract and Introduction

Abstract

Study Objective: To assess the safety, tolerability, and pharmacokinetics of escalating single doses of wood creosote, an herbal antidiarrheal and antispasmodic agent.
Design: Randomized, double-blind, placebo-controlled study.
Setting: Clinical research center.
Subjects: Forty (32 men, 8 women) healthy volunteers aged 19-42 years.
Intervention: By random assignment, 22 men and 8 women received escalating single doses of wood creosote (45, 90, 135, 180, and 225 mg) and 10 men received placebo (for each of the five dose levels, 6 subjects received active substance and 2 subjects received placebo).
Measurements and Main Results: Vital signs, laboratory tests, and electrocardiograms were assessed; no dose-related or clinically significant changes were noted. Serial blood samples were obtained to determine the pharmacokinetics of four major active components of wood creosote: total (conjugated plus free) guaiacol, creosol, o-cresol, and 4-ethylguaiacol. The most common adverse events were mild headache and dizziness, with no dose-related trends being apparent. Area under the concentration-time curve from time zero to infinity increased in a dose-proportional manner for total guaiacol, creosol, and o-cresol and was not assessed for total 4-ethylguaiacol owing to lack of data at the low dose level. No apparent differences by sex were noted for any of the four active components. All four components were rapidly eliminated.
Conclusion: Single oral doses of wood creosote up to 225 mg were safe and well tolerated in healthy men and women. Also, the doses of wood creosote were rapidly absorbed, conjugated, and eliminated. Such a rapid onset and short duration of action would appear desirable in the treatment of acute nonspecific diarrhea.Introduction

Diarrhea is recognized as a major health problem and one of the leading causes of infant mortality in developing countries.[1-3] Diarrheal illness is also common in developed countries but usually is viewed as an inconvenience rather than a medical hazard. In developed countries, most episodes of diarrhea are mild and are either self-limiting or self-treated with over-the-counter drugs or home remedies. Nonetheless, acute diarrhea significantly affects the United States population through restriction in activity and loss in productivity.[4] In addition, there are certain high-risk populations (e.g., infants, elderly patients with concomitant medical conditions, immunocompromised patients) for whom diarrhea can be severely debilitating. Traveler's diarrhea, although often self-limiting, can also be severe. In some developing countries, the frequency of traveler's diarrhea can exceed 50%.[5, 6]

The cause of acute diarrhea in the United States most often is thought to be infectious; however, in clinical practice, a pathogen is identified less than 50% of the time. Diarrhea in infants and children in the United States is usually associated with infections caused by rotavirus. In adults in the United States, the causative agent may be a bacterial or viral pathogen or may be noninfectious. In clinical trials, traveler's diarrhea is caused by bacterial pathogens in more than half of the cases.[7]

Diarrhea, having many different causes and therefore different effects on the gastrointestinal system, can be categorized based on potential mechanisms of altered fluid and electrolyte movement.[8] The pathophysiologic manifestations of acute diarrhea often include increased luminal osmolality, increased intestinal secretion, inflammation of the intestinal lining, and altered intestinal motility. The goal in management is to correct the underlying pathophysiologic problem when feasible and to provide symptomatic relief.

Available treatments, including prescription and over-the-counter drugs, have several disadvantages. Antibiotic treatment is generally not recommended for most cases of mild-to-moderate, acute, nonspecific diarrhea because the risks of overuse may outweigh the benefits. Other drugs used to treat diarrhea, such as those containing diphenoxylate hydrochloride and atropine, can have central nervous system adverse effects and may be contraindicated in some patients.[9] Loperamide, the most commonly administered drug to treat acute diarrhea, is safe and effective, but it can cause other gastrointestinal adverse effects, such as constipation and abdominal cramps.[10]

Wood creosote is an herbal medicine that has been used as an antidiarrheal and antispasmodic agent in Japan and in other countries in the Pacific Rim under the brand name Seirogan (currently marketed by Taiko Pharmaceutical Company, Ltd., Osaka, Japan) for the past century. Wood creosote also has been used for medicinal purposes in Europe since the early 1800s.[11] Approximately 1.16 billion Seirogan tablets (wood creosote 45 mg/tablet) are sold worldwide each year, representing approximately 42.8 million patient treatment courses, estimated based on a 3-day treatment course of three tablets/dose taken 3 times/day (27 tablets/course). Seirogan recently has been marketed in the United States as an over-the-counter herbal product and is approved in Canada as an over-the-counter drug (drug identification number 02243423). Total Seirogan sales in North America account for less than 5% of worldwide sales at the present time. Seirogan typically is taken for up to 3 days as an acute antidiarrheal agent, and patients typically report relief of symptoms after one to two doses. There are no known drug-drug interactions or contraindications with Seirogan.

Wood creosote (CAS-8021-39-4), also referred to as medicinal creosote, is a mixture of simple phenolic compounds, including guaiacol, creosol, o-cresol, and 4-ethylguaiacol as major active components,[12] and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. A long-term safety study in rats documented a lack of oncogenicity for wood creosote.[13]

Wood creosote has been shown to suppress gastrointestinal motility, with a consequent increase in intestinal transit time and increase in net fluid absorption from the intestine in in vivo and ex vivo animal models.[14-16] Clinical experience in humans indicates that wood creosote relieves acute diarrhea, often within one or two doses; suppresses intestinal hypermotility; and produces an antispasmodic effect in the setting of acute diarrhea. Also, decreased stool volume and frequency have been observed by clinicians in anecdotal reports.

Despite many years of postmarketing experience with Seirogan, in Asia in particular, rigorously controlled clinical studies evaluating the safety and efficacy of wood creosote are lacking. The objective of our study was to assess the safety, tolerability, and pharmacokinetics of escalating single doses of wood creosote in a rigorous manner with a double-blind, placebo-controlled study design. The Seirogan tablet formulation marketed worldwide contains wood creosote plus other herbal ingredients, including gambir, philodendron bark, glycyrrhiza, and citrus unshiu peel. The formulation evaluated in this study is a sugar-coated tablet that contains wood creosote 45 mg as the principal active ingredient without the other herbal components.

Section 1 of 5 Tomoo Kuge, Ph.D., Takashi Shibata, M.D., Ph.D., and Michael S. Willett, Pharm.D.

From Taiko Pharmaceutical Company, Ltd., Osaka, Japan (Drs. Kuge and Shibata); the Department of Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (Dr. Kuge); and Advanced Biomedical Research, Inc., Pennington, New Jersey (Dr. Willett).
Pharmacotherapy 23(11):1391-1400, 2003. © 2003 Pharmacotherapy Publications
This is a part of article Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medicine: A Single-Dose, Dose-Escalation Safety and Pharmacokinetic Study Taken from "Atropine Sulfate" Information Blog

Ghrelin: More Than a Natural GH Secretagogue

Biological Actions of Ghrelin

Ghrelin and Hypothalamus–Pituitary Endocrine Functions

GH-Releasing Activity. Ghrelin, as well as synthetic GHS, possesses a strong and dose-related GH-releasing effect (Kojima et al., 1999; Arvat et al., 2000, 2001; Peino et al., 2000; Seoane et al., 2000; Takaya et al., 2000; Wren et al., 2000; Broglio et al., 2003a). Ghrelin and GHRH have a synergistic effect indicating that they act, at least partially, via different mechanisms (Arvat et al., 2001; Hataya et al., 2001; Cunha & Mayo, 2002). Nevertheless, GH secretagogues need GHRH activity to fully elicit their GH-releasing effect and probably act by triggering GHRH-secreting neurones, being strongly inhibited by a GHRH antagonist as well as by a hypothalamus–pituitary disconnection (Pandya et al., 1998; Tannenbaum & Bowers, 2001; Popovic et al., 2003; Tannenbaum et al., 2003; Kamegai et al., 2004).

Ghrelin probably also acts as a functional somatostatin antagonist at both the pituitary and the hypothalamic level (Tannenbaum et al., 2003). In humans the GH response to ghrelin is partially refractory to exogenous somatostatin or cortistatin (Broglio et al., 2002a; Di Vito et al., 2002). The GH response to ghrelin and GHS is also partially refractory to other factors known to affect somatotroph secretion, such as glucose, lipids, arginine, cholinergic agonists and antagonists, IGF-I and GH itself (Broglio et al., 2002b,c; van der Lely et al., 2004). The GH-releasing action of ghrelin and GHS undergoes homologous desensitization under prolonged exposure to these molecules in both animals and humans (Micic et al., 2002; Orkin et al., 2003; Camina et al., 2004).

The GH-releasing effect of ghrelin and GHS is influenced by pharmacological doses of oestrogens; however, the somatotroph response to ghrelin administration is independent of gender while it undergoes marked age-related variations (Broglio et al., 2003a; van der Lely et al., 2004). As a reduced expression of the hypothalamic GHS receptors has been demonstrated in the aged human brain, an impairment of the ghrelin system could theoretically have a role in the age-related decrease of GH secretion (Muccioli et al., 1998; van der Lely et al., 2004).

Interestingly, the GH response to ghrelin has been reported to be clearly reduced not only in obesity, where it was expected due to the functional hyposomatotropism commonly present in this condition, but also in anorexia nervosa, a condition in which both spontaneous and GHRH-stimulated GH secretion have been reported to be increased (Tassone et al., 2003; Broglio et al., 2004a; varez-Castro et al., 2004). These findings suggest that in anorexia nervosa, chronic hyperghrelinaemia could induce some desensitization to exogenous ghrelin actions.

Ghrelin is likely to play a role in the GH response to fasting and energy restriction; the GH hyper- and hyposecretion that connote anorexia and obesity, respectively, could reflect the ghrelin hyper- and hyposecretion that have been demonstrated in these clinical conditions (Ariyasu et al., 2001; Tschop et al., 2001b; Shiiya et al., 2002). However, a feedback link between GH and ghrelin secretion has never been demonstrated and ghrelin does not play a role in mediating the GH response to the majority of pharmacological stimuli of somatotroph secretion such as insulin-induced hypoglycaemia, arginine, glucagon and cholinergic agonists (Lucidi et al., 2002; Broglio et al., 2004c,d).

PRL- and ACTH-releasing Activity. The stimulatory effect of ghrelin and GHS on PRL secretion in humans is slight, independent of both gender and age and probably involving both direct action on somatomammotroph cells and indirect hypothalamic actions (Arvat et al., 2001; Broglio et al., 2003a; Korbonits et al., 2004).

The acute stimulatory effect of ghrelin and GHS on the activity of the hypothalamic–pituitary (HPA) axis in humans is similar to that after naloxone, AVP and even corticotrophin-releasing hormone (CRH) but prolonged GHS administration apparently does not lead to an HPA axis hyperfunction (Korbonits et al., 2004; van der Lely et al., 2004). In physiological conditions, the ACTH-releasing activity of GHS depends totally on CNS-mediated mechanisms and probably involves CRH, AVP, neuropeptide Y (NPY) and Gamma-Aminobutyric Acid (GABA) neurones (Korbonits et al., 2004; van der Lely et al., 2004).

The ACTH response to GHS is generally sensitive to the negative feedback control by cortisol (van der Lely et al., 2004). However, the stimulatory effect of ghrelin and GHS on corticotroph secretion is surprisingly enhanced and higher than that of hCRH in patients with pituitary ACTH-dependent Cushing's disease, probably reflecting an action on the pituitary tumoral corticotroph cells where both ghrelin and GHS-R are expressed (Leal-Cerro et al., 2002). Ghrelin and GHS-R expression have also been shown in some ectopic ACTH-releasing tumours and, accordingly, enhanced ACTH and cortisol responses to ghrelin has been reported in some patients with ectopic Cushing's syndrome (Korbonits et al., 2001a, 2004; Leal-Cerro et al., 2002).

Influence on Gonadotroph Secretion. Intracerebroventricular injection of ghrelin has been reported to be able to decrease the frequency of pulsatile LH secretion leading to a decrease in LH concentration (Furuta et al., 2001; Fernandez-Fernandez et al., 2004). These findings probably reflect a modulation of the activity of the GnRH pulse generator and indicate that ghrelin also plays a role in the central control of gonadotroph function (Furuta et al., 2001). Overall, this neuroendocrine action of ghrelin would fit well with the hypothesis that ghrelin, in collaboration with leptin, plays a role in the prompt turn-off of the gonadal axis that, coupled with the amplification of somatotroph and corticotroph functions, occurs during starvation. Ghrelin could, however, also play a role in the control of the gonadal axis at the peripheral level (see below).  Printer- Friendly Email This

Clin Endocrinol.  2005;62(1):1-17.  ©2005 Blackwell Publishing
This is a part of article Ghrelin: More Than a Natural GH Secretagogue Taken from "Atropine Sulfate" Information Blog