Current Drug Therapy

ISSN: 1574-8855

Current Drug Therapy
Volume 2, Number 1, January 2007

Contents

Editorial Pp. 1


Prevention of Contrast Induced Nephropathy Pp. 3-9
Jeffrey W.H. Fung, Cheuk C. Szeto, Leo C.C. Kum and Cheuk M. Yu
[Abstract] [Full Text Article]


Current Status of Hormone Replacement Therapy in Post Menopausal Women Pp. 11-15
Madhur Gupta and Kamlesh Kohli
[Abstract] [Full Text Article]


Controversies of Dopamine Agonists: Somnolence, Cardiac Valvulopathy and Repetitive Behaviors Pp. 17-20
Samay Jain and Cheryl H. Waters
[Abstract] [Full Text Article]


In Vivo Effects of Topical Anti-Psoriatic Treatments on Cutaneous Inflammation, Epidermal Proliferation and Keratinisation Pp. 21-26
Peter C.M. van de Kerkhof, H. Jorn Bovenschen and John E.M. Körver
[Abstract] [Full Text Article]


Nasal Drug Delivery System-Factors Affecting and Applications Pp. 27-38
Kisan R. Jadhav, Manoj N. Gambhire, Ishaque M. Shaikh, Vilasrao J. Kadam and Sambhaji S. Pisal
[Abstract] [Full Text Article]


Coenzyme Q10 Reduction with Statins: Another Pleiotropic Effect Pp. 39-51
Hiroshi Mabuchi, Atsusi Nohara, Junji Kobayashi, Masa-aki Kawashiri and Akihiro Inazu
[Abstract] [Full Text Article]


Tacrolimus Treatment in Myasthenia Gravis Pp. 53-56
Naoki Kawaguchi
[Abstract] [Full Text Article]


Some Aspects on Comparative Efficacy Studies with Inhaled Corticosteroids in Asthma Pp. 57-54
Olof Selroos
[Abstract] [Full Text Article]


Postoperative Thoracic Epidural Anesthesia in Gastrointestinal Surgery: Outcomes, Quality of Life, and Current Controversies Pp. 75-77
Desmond C. Winter, Eric J. Dozois and John H. Pemberton
[Abstract] [Full Text Article]


Which β-Adrenoceptor Subtypes are Important in the Treatment of Overactive Bladder? Pp. 79-84
Tomonori Yamanishi, Takao Kamai, Ryuji Sakakibara, Tomoyuki Uchiyama, Tatsuya Yamamoto, Takashi Ito and Ken-ichiro Yoshida
[Abstract] [Full Text Article]


Self-Emulsifying Drug Delivery Systems: Strategy for Improving Oral Delivery of Poorly Soluble Drugs Pp. 85-93
Jing-ling Tang, Jin Sun and Zhong-Gui He
[Abstract] [Full Text Article]




Abstracts


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Editorial: Risk Benefit: Who is Responsible?

As in other issues of Current Drug Therapy, we find discussion of a wide spectrum of topics. In addition to the scope of subjects, we see a variety of philosophical approaches, particularly in regards to benefits and risks of drugs. Some articles, for example “Some aspects on comparative efficacy studies with inhaled corticosteroids in asthma” by Dr. Olof Selroos focus on efficacy, while others deal primarily with issues related to safety, for instance, “Controversies of dopamine agonists: somnolence, cardiac valvulopathy and repetitive behaviors”, by Dr. Samay Jain. Other articles, such as “Coenzyme Q10 Reduction: Another Pleiotropic Effect of Statins”, by Dr. Hiroshi Mabuchi delve into both efficacy and safety.

What this illustrates is an understanding of benefit and risk within the medical field. Unfortunately, the importance of understanding this balance is not as widely appreciated beyond the medical field as it might be. Nothing is without risk – and that includes medical therapies. While most people readily accept the risk of an auto accident in getting to work, they are often less willing to accept risk of side effects with medication, especially those more serious. There are probably many reasons for this, discussion of which is beyond the scope of this editorial. Sometimes it seems that people only want three things when it comes to drugs: 1) that they always work, 2) that they have no significant side effects, and 3) that they are cheap. Only the first two properties relate to benefit-risk considerations in the traditional sense. Clearly, no drug will work in all cases, and some patients will have side effects – occasionally serious or lethal.

Where then does the responsibility for evaluation, communication, and acceptance of benefit-risk lie? Responsibility for evaluation of risks lies primarily with manufacturers, but consumers, medical professionals and regulatory agencies have to do their part in getting information to manufacturers. Manufacturers are usually very interested in communicating benefits, but will readily describe risks. Other groups – the medical community, regulatory agencies, and the media also play an important role in communicating a balance between benefit and risk. The media can play an important role in communication of benefits and risks. While more responsible an enlightened media have addressed the issue of benefit versus risk, all too often sensational headlines only deal with safety concerns, ignoring the benefit of therapies.

Acceptance of risk is the most difficult element. Should it be the manufacturer that produced and marketed the product, regulatory agencies that approved it, physicians who prescribed it, or the consumer who chose to take it? If manufacturers make all information available, regulators evaluate all data available, and physicians discuss benefits versus risks with their patients, the final responsibility must be with consumers. Much has to change before this becomes a reality. In order to empower consumers with the ability to make informed choices, all of us in the medical community – manufacturers, regulators, and prescribers must do our part. The media can be a major force in disseminating information. Ultimately, however, the consumer must accept more responsibility.


Joachim F. Wernicke, PhD, MD
Editor in Chief
Lilly Research Laboratories
Indianapolis, IN 46285
USA
E-mail: wernicke_joachim@lilly.com


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Prevention of Contrast Induced Nephropathy
Jeffrey W.H. Fung, Cheuk C. Szeto, Leo C.C. Kum and Cheuk M. Yu

[Full Text Article]

Contrast induced nephropathy (CIN) is a well-known and serious complication in patients with chronic renal insufficiency undergoing coronary angiography or interventions. CIN is associated with significant morbidity and mortality. This complication results in prolonged hospital stay and substantially increases the cost of medical care. Various therapeutic measures have been evaluated for the prevention of CIN. Peri-procedural saline hydration, use of low osmolality contrast agents and limiting the amount of contrast administered are the preferred methods. In recent years, the efficacy of prophylactic hemofiltration and several pharmacological agents, including low dose dopamine, theophylline, N-acetylcysteine, and fenoldopam have been evaluated in randomized controlled trials. Conflicting results, rather than convincing conclusions, were observed in the studies of most of these agents. Meta-analysis suggested that the use of N-acetylcysteine and theophylline may be able to prevent the decline of renal function after contrast exposure. This review provides an update on the recent studies in this subject as well as a critical analysis on how available evidence could be translated to daily clinical practice.


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Current Status of Hormone Replacement Therapy in Post Menopausal Women
Madhur Gupta and Kamlesh Kohli

[Full Text Article]

Assessment of the risks versus the benefits of hormone replacement therapy has become a challenging task for the physicians. Controversial issues have surrounded the status of hormone replacement therapy for postmenopausal women lately. Several randomized controlled trials present contradicting evidences and have raised questions about the short-term risks of long-term benefits of HRT. Evidence from clinical trials like the WHI and HERS trial does not support HRT use for prevention of cardiovascular disease. The review also discusses the association of hormone replacement therapy and cancer, stroke, cognition, cardiovascular disease, venous thromboembolism, osteoprosis, gall bladdaer disease, and quality of life. The latest controversial results of randomized controlled trials in recent years have posed newer challenges for the physicians in prescribing HRT for postmenopausal women.


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Controversies of Dopamine Agonists: Somnolence, Cardiac Valvulopathy and Repetitive Behaviors
Samay Jain and Cheryl H. Waters

[Full Text Article]

The use of dopamine agonists has increased due to their effectiveness in treating symptoms of Parkinson disease (PD) and Restless Leg Syndrome (RLS). Recently, rare but serious adverse effects have been linked to DA agonists, including sudden somnolence, cardiac valvulopathy and repetitive behaviors. Clinicians are in a difficult situation because of insufficient information to make clear recommendations to patients. We review these controversies, discuss patho-physiology and report current practices in light of such uncertainty.


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In Vivo Effects of Topical Anti-Psoriatic Treatments on Cutaneous Inflammation, Epidermal Proliferation and Keratinisation
Peter C.M. van de Kerkhof, H. Jorn Bovenschen and John E.M. Körver

[Full Text Article]

Classical antipsoriatic treatments reduce T-cell subsets, inhibit epidermal proliferation and affect keratinisation. These changes either can be primary or secondary to the resolution of the psoriatic lesion during treatments.

During the last decade various studies described the effect of classical and innovative treatments on the various aspects of the psoriatic lesion.

The aim of the present review is a critical evaluation of studies describing the response to psoriatic treatment at T-cells, NK-T cells and epidermal growth and differentiation. In particular the questions will be answered whether the profile of changes is treatment specific and which changes can be considered as early or late therapeutic effects.


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Nasal Drug Delivery System-Factors Affecting and Applications
Kisan R. Jadhav, Manoj N. Gambhire, Ishaque M. Shaikh, Vilasrao J. Kadam and Sambhaji S. Pisal

[Full Text Article]

The nasal route is a potential alternative route for systemic availability of drugs restricted to intravenous administration, such as peptide and protein drugs and vaccines. This route is also advisable for drugs undergoing extensive first pass effect .Besides this, intranasal route has also been successfully exploited for bypassing the blood brain barrier [BBB] and subsequently delivering drug molecules to central nervous system [CNS]. The present article highlights the advantages, barriers, physicochemical factors and formulation related parameters affecting the nasal drug delivery. It also includes a note on nasal absorption enhancers. Also, the applications of nasal route for delivery of peptides and proteins, non-peptide drugs, vaccines and drug molecules to CNS have been summarized in depth.


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Coenzyme Q10 Reduction with Statins: Another Pleiotropic Effect
Hiroshi Mabuchi, Atsusi Nohara, Junji Kobayashi, Masa-aki Kawashiri and Akihiro Inazu

[Full Text Article]

Hypercholesterolemia is a major coronary risk factor, and extensive epidemiological data have shown that the higher the serum cholesterol level the higher the incidence of coronary heart disease (CHD). Over the past decade, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as one of the most effective means of reducing risk for CHD. A number of clinical trials have demonstrated that statins are not only safe and well tolerated but also significantly decrease CHD morbidity and mortality in hyper- and normo-cholesterolemic patients in both primary and secondary prevention studies. These findings support “the lower the cholesterol, the better” concept.

HMG-CoA reductase converts HMG-CoA to mevalonate, and inhibition of this enzyme results in decreased synthesis of cholesterol and other products downstream of mevalonate. Sometimes clinical results from treatment with statins are not fully explained by reduction in serum cholesterol levels. These effects of the statins that go beyond the clinica0l effects brought about by cholesterol reduction are called “pleiotropic effects”. Many of these so-called pleiotropic effects have been shown to be secondary to inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway, and, thus, are completely independent of intracellular cholesterol biosynthesis. Although statins have been known to be safe, fatal cases of rhabdomyolysis in connection with this drug has raised major concerns about the possibility that certain pleiotropic effects of statins could also be harmful.

Mevalonate is a precursor of coenzyme Q10 (CoQ10) which is a central compound of the mitochondrial respiratory chain, and is a potent lipophilic antioxidant present in nearly all human tissues and plasma lipoproteins. Decreased content of CoQ10 found in the patient’s plasma could therefore increase its potential to oxidize. Supplementation of CoQ10 may restore tissue and plasma CoQ10 concentrations in patients treated with statins. Inhibitors of cholesterol biosynthesis beyond mevalonate may reduce cholesterol synthesis without inhibiting the biosynthesis of CoQ10 and dolichol. Here, we have reviewed CoQ10 metabolism in patients treated with statins, and the correlation with the possible side effects of statins.


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Tacrolimus Treatment in Myasthenia Gravis
Naoki Kawaguchi

[Full Text Article]

Tacrolimus (FK506) is a new macrolide immunosuppressant isolated from Streptomyces tsukubaenesis that acts by a variety of different mechanisms, including inhibition of calcineurin. Although the mechanism of action of tacrolimus is similar to that of ciclosporin A, tacrolimus is 10 to 100 times more potent. Tacrolimus also has an effect on glucocorticoid receptor-mediated gene expression. The therapeutic efficacy of tacrolimus in primary immunosuppression has been evaluated in numerous clinical trials in patients receiving hepatic, renal, heart, lung, pancreas, intestinal, or bone marrow transplantation. Because tacrolimus displays a variety of different mechanisms of action and shows a synergism with corticosteroids, it is presumed that tacrolimus provides a new and useful therapeutic approach for autoimmune diseases, including myasthenia gravis.


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Some Aspects on Comparative Efficacy Studies with Inhaled Corticosteroids in Asthma
Olof Selroos

[Full Text Article]

This review evaluates dose–response and comparative studies with inhaled corticosteroids (ICS) in asthma. A dose–response relationship for lung function variables has been demonstrated for some ICS, but not for all. Measurements of anti-inflammatory properties, e.g. bronchial challenge with adenosine 6’-monophosphate, may provide better possibilities to detect dose–response relationships and differences between ICS.

Studies with the same ICS delivered by different inhalers with different lung deposition characteristics show that efficacy is strongly related to the amount of drug deposited in the airways. Comparative studies with different ICS using different inhalers have often used doses resulting in effects at the top of the dose–response curve. However, a lack of statistically significant difference between treatments does not mean therapeutic equivalence.

Comparative clinical studies should be performed with dose–response curves of both products and the relative dose ratio should be estimated. The minimum criterion is to use one dose of one product and fit the result of that treatment to a dose–response curve of the other. Down titration represents an alternative, clinically reliable study design.

Clinically relevant differences between doses and treatments should be defined prior to the study; a proper power calculation has to be performed; and comparisons should be made on the dose scale rather than the effect scale.


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Postoperative Thoracic Epidural Anesthesia in Gastrointestinal Surgery: Outcomes, Quality of Life, and Current Controversies
Desmond C. Winter, Eric J. Dozois and John H. Pemberton

[Full Text Article]

Introduction: Quality of Life (QoL) may be reduced by postoperative pain and improving analgesic techniques, including local and regional techniques, may impact on this important healthcare measurement. This study focused on the QoL issues surrounding thoracic epidural analgesia used in patients undergoing gastrointestinal surgery.

Methods: A review of the published literature (English language, electronic search) was undertaken using the terms: quality of life, analgesia, epidural, thoracic epidural, regional anesthesia, gastrointestinal surgery, colon and rectal surgery, abdominal surgery, major surgery, complications, pain scores. There were no exclusions and all relevant literature was included in the breadth of discussion.

Results: Epidural analgesia may improve pain, sedation scores, pulmonary function, tissue oxygenation, and QoL but there may be little impact on overall patient morbidity and mortality. The relative paucity of data and diminutive power of many clinical studies represent a challenge to establishing superiority or equivalence of epidurals over patient-controlled opiate analgesia but emerging evidence suggests an improved QoL, perhaps through less sedation and faster recovery of gastrointestinal function.

Conclusions: The benefits of postoperative thoracic epidural analgesia include better analgesia and overall well-being in addition to the intuitive advantages of less sedation and improved pulmonary function following gastrointestinal surgery.


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Which β-Adrenoceptor Subtypes are Important in the Treatment of Overactive Bladder?
Tomonori Yamanishi, Takao Kamai, Ryuji Sakakibara, Tomoyuki Uchiyama, Tatsuya Yamamoto, Takashi Ito and Ken-ichiro Yoshida

[Full Text Article]

For the pharmacological treatment of frequency, urgency and/or urge incontinence due to bladder overactivity, anticholinergics have been used as first-choice drugs. However, these drugs can exert severe side effects (accommodation paralysis, constipation, tachycardia, dry mouth and blurred vision) and some patients are refractory to their actions. Thus there is a need for new drug therapies with novel mechanisms of action.

β-Adrenoceptors are found in the body of the bladder, where they mediate relaxation of the detrusor muscle. It has been reported that β₃-adrenoceptor subtypes are predominantly present in the smooth muscles of bladder and urethra in the pig and human. Recently, β₃-adrenoceptors have been reported to predominantly mediate relaxation of the bladder smooth muscle. However, the relaxant effects of β₃-adrenoceptor agonists are half of those of (±)isoproterenol, a non-selective β-adrenoceptor agonist, and the antagonist affinity of β₃-adrenoceptor antagonists varies according to the drugs tested. It has also been suggested that both β₂-, and β₃-adrenoceptors are involved in relaxation of the human bladder, but the involvement of the β₃-adrenoceptor may be greater than that of β₂-adrenoceptor. Another possibility is that other β-adrenoceptors, possibly β₄-adrenoceptor and/or atypical β-adrenoceptors, may coexist and play a functional role in mediating the relaxation of the bladder.


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Self-Emulsifying Drug Delivery Systems: Strategy for Improving Oral Delivery of Poorly Soluble Drugs
Jing-ling Tang, Jin Sun and Zhong-Gui He

[Full Text Article]

Drugs are most often administered by the oral route. However, more than 40% of new chemical entities exhibit poor aqueous solubility, resulting in unsatisfactory oral drug delivery. Recently, much attention has been focused on self-emulsifying drug delivery systems (SEDDS) to improve the oral bioavailability of poorly aqueous soluble drugs. SEDDS are isotropic mixtures of oil, surfactants, solvents and co-solvents/surfactants. The principal characteristic of these systems is their ability to form fine oil-in-water (o/w) emulsions or microemulsions upon mild agitation following dilution by an aqueous phase. For lipophilic drugs, which display dissolution rate-limited absorption, SEDDS may be a promising strategy to improve the rate and extent of oral absorption.

This article gives an overview of the new excipients used in SEDDS and biopharmaceutical aspects of SEDDS. The application of SEDDS and closely related lipid-based systems as drug delivery vehicles is also introduced, with particular emphasis being placed on the application of SEDDS in traditional Chinese medicine (TCM).