Discussion

Diabetic peripheral neuropathy is a common and diverse complication that adversely affects the quality of life and life expectancy of diabetes patients. The key to the pathology is hyperglycemia, but the cascades that bridge the metabolic state with the secondary pathological changes still represent boundless challenges to basic research and clinical intervention.

Symptom management typically requires careful use of a combination of agents. Current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications for the treatment of diabetic sensorimotor neuropathy. Citalo-pram, NSAIDs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxe-tine, levodopa, and α-lipoic acid are alternative considerations. The evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal, and their risks are generally better defined than their benefits. Transcutaneous electrotherapy and percutaneous electrical nerve stimulation are alternative therapies that have demonstrated efficacy and may represent a hope for patients with severe, refractory pain.

Diabetic autonomic neuropathy is extremely difficult to treat, and the risks and adverse effects frequently outweigh the benefits of most pharmacologic therapies. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, ACE inhibitors, and β-blockers. Gastroparesis may be improved with metoclopramide or erythromycin, but glycemic control is perhaps the best long-term treatment. Erectile dysfunction may respond to phosphodiesterase inhibitors, vacuum-constriction devices, and intracavernosal injections.

It is critical that all clinical recommendations be based on a thorough patient review to minimize potentially severe adverse effects. Further, all medications should be initiated at low dosages and adjusted to individual efficacy and adverse effects. Ruboxistaurin represents the current hope for future disease-modifying therapies. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment of diabetic neuropathy.

Conclusion

Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.

Reprint Address

Address correspondence to Dr. Duby at 1347 N. Euclid Avenue, Tucson, AZ 85719.Previous PageSection 6 of 6Am J Health-Syst Pharm 61(2):160-176, 2004. © 2004 American Society of Health-System Pharmacists
This is a part of article Diabetic Neuropathy: An Intensive Review Taken from "Tadalafil Cheap" Information Blog

SLI381 (Adderall XR), a Two-Component, Extended-Release Formulation of Mixed Amphetamine Salts: Bioavailability of Three Test Formulations and Comparison of Fasted, Fed, and Sprinkled Administration

from Pharmacotherapy
Posted 11/20/2002

Simon J. Tulloch, M.D., Yuxin Zhang, Ph.D., Angus McLean, Ph.D., Kathleen N. Wolf, B.A.

Abstract and Introduction

Abstract

Study Objectives: To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food.
Design: Randomized, open-label, crossover study.
Setting: Clinical research unit.
Patients: Forty-one healthy adults.
Interventions: Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce.
Measurements and Main Results: The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition.
Conclusion: SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.Introduction

Attention-deficit-hyperactivity disorder (ADHD) is a neurobehavioral condition characterized by various degrees of developmentally inappropriate inattention, hyperactivity, and impulsivity.[1] It is diagnosed most commonly in childhood, and prevalence rates vary from 4-12% in school-age children.[2] In addition, 50-65% of children with ADHD continue to display behavioral problems and symptoms into their adult lives. The disorder is associated with considerable disability, and the negative impact can be felt not only in academic and vocational settings, but also in social situations and recreational activities.[3-5] Psychostimulant agents (methylphenidate, amphetamine) are well tolerated and effective in treating core symptoms of ADHD.[6-8] However, therapy can be problematic because of the need for several daily doses in most individuals, which can lead to poor compliance and decreased satisfaction with treatment. In-school dosing in children may lead to diversion of drug, ridicule by peers, and negative impact on self-esteem. Thus, a more effective once-daily dosage form of stimulant drugs that lasts throughout the school day and into the evening is necessary.

Amphetamine compounds and other psychostimulants are first-line treatments for ADHD. Although the precise mechanism of action is not fully elucidated, the agents both accentuate release and block reuptake of neurotransmitters dopamine and norepinephrine in presynaptic neurons.[9] The pharmacokinetic and pharmacodynamic effects of amphetamine are described in adults[10, 11] and children.[12, 13] Amphetamine's absorption is rapid and complete from the gastrointestinal tract, and maximum plasma concentrations are reached in 3-4 hours. The agent undergoes hepatic metabolism by side-chain deamination and ring hydroxylation; most is excreted unchanged in urine.[14] Clinical behavioral effects are most apparent during the absorption phase and decrease after peak plasma concentrations are reached.[10-13] Food has little effect on plasma amphetamine levels, although gastrointestinal acidifying agents (e.g., ascorbic acid) may lower absorption and decrease bioavailability.

Adderall (Shire US Inc., Florence, KY) is a mixture of neutral salts of dextroamphetamine sulfate, amphetamine sulfate, the dextro isomer of amphetamine saccharate, and d, l-amphetamine aspartate. For each Adderall tablet, the combination of salts and isomers results in a 3:1 ratio of dextroamphetamine:levoamphetamine. The efficacy and tolerability of this product in treating children and adults with ADHD were proven in clinical trials.[15-21]

Historically, the efficacy of Adderall was attributed to the chemical composition of d- and l-amphetamine salts. Several small studies in the 1970s explored different effects of d- versus l-amphetamine in children with ADHD.[22-24] The results indicated that both isomers are pharmacologically active and efficacious, with most children responding well to either isomer. However, some children responded only to the d- and some only to the l- isomer. No further investigations have evaluated the different pharmacodynamic activity of the isomers.

SLI381 (Adderall XR; Shire US Inc.) is a new extended-release capsule for treatment of ADHD designed to produce a therapeutic effect that lasts throughout the day, with one morning dose. The capsule contains the same active ingredients as immediate-release Adderall and is composed of two types of beads combined in a 50:50 ratio. Immediate-release beads are designed to release drug content in a time course similar to Adderall. Delayed-release beads are designed to release drug content approximately 4 hours after administration. With the delayed-release component, the capsule, taken once/day, is expected to produce similar pharmacokinetic and pharmacodynamic effects to immediate-release Adderall taken twice/day.

We conducted two studies to address several issues. The primary objective of the first trial (study A) was to assess the bioavailability of a single dose of three different test formulations of extended-release Adderall 20-mg capsules compared with two Adderall 10-mg immediate-release tablets administered 4 hours apart to determine the optimal formulation to take into final development. The purpose of the second trial (study B) was to assess whether the contents of a single 30-mg dose of the chosen extended-release Adderall capsule formulation (SLI381) administered in applesauce is bioequivalent to the same dose administered as an intact capsule with or without food, and to determine the effect, if any, on bioavailability of a single dose of a SLI381 30-mg capsule administered with a high-fat breakfast compared with the same dose administered in the fasted state.

This is a part of article SLI381 (Adderall XR), a Two-Component, Extended-Release Formulation of Mixed Amphetamine Salts: Bioavailability of Three Test Formulations and Comparison of Fasted, Fed, and Sprinkled Administration Taken from "Generic Benzac (Benzoyl Peroxide)" Information Blog

A new review of existing research suggests that group therapy can help men with erectile dysfunction even if they are already using popular drugs like Viagra. Group therapy could even be a feasible alternative to some treatments for impotence.

While the number of men studied overall was small, the reviewers found that group therapy appeared to be about as successful as suction devices and injections in terms of promoting erections. One analysis showed therapy worked for nearly two-thirds of participants.

The findings spotlight the importance of "integrating sex therapy and other psychological techniques into office practice" to help impotent patients, said lead author Tamara Melnik, professor of psychiatry at the University of São Paulo in Brazil.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Before the days of Viagra and its sibling drugs, many considered erectile dysfunction to be a difficult-to-treat psychological disorder. Now, drugs allow millions of men to achieve normal erections by allowing blood to flow more freely to the penis; the more serious side effects are rare.

However, drugs are not always an automatic cure for men with erectile dysfunction, especially those whose impotence relates to psychological factors.

A 2001 study of 115 impotent men found that psychological factors were responsible for the problems in 43 percent of the men and physical factors were responsible for problems in another 43 percent. In the rest of the men, researchers blamed impotence on a combination of mental and physical factors.

In the new review, Melnik and colleagues examined 11 studies from the last 32 years to compare the value of group therapy to other treatments such as oral drugs, injections and suction devices.

The review studies nearly 400 men: 141 received group therapy, 109 took drugs, 68 took drugs and took part in psychotherapy, 20 used "vacuum" (suction) devices and 59 were in control groups that did not receive any treatment.

Half of the men in the studies were from the United States and the average age of the men was 47.4 years.

By pooling data from five of the studies, the researchers found that 36 of 55 men who took part in group therapy reported successful intercourse compared with 5 of 45 who were on waiting lists and had no treatment, Melnik said.

The researchers also combined data from two similar studies from 2000 and 2005 and found that men who took Viagra in conjunction with group therapy were more likely to report successful intercourse than those who took the drug alone.

The total number of men in the two studies was small just 71.

The review authors did not find much difference in erection success rates between those who tried injections or suction devices and those who took part in group therapy alone.

According to Melnik, the goal of group therapy is to help men gain confidence and reduce anxiety. Most men feel comfortable in the setting of group therapy because they can share their difficulties with other men who have the same problem, Melnik said.

"Most people only wonder about the easiest and most rapid way to reach remission of erectile dysfunction," Melnik said. "Group therapy takes more time than using medication, but in some cases dealing with psychological aspects is fundamental to achieving a successful outcome and maintaining the results."

The review does not examine issues of cost nor how group therapy expenses compare to those of other treatments. The review authors did not look at the availability of group therapy for erectile dysfunction patients.

Hossein Sadeghi-Nejad, M.D., a New Jersey urologist, said psychological factors play a role in some cases of impotence. While drugs like Viagra can help people with erectile dysfunction caused by mental factors, the medications "do not work unless the patient is in the right frame of mind," said Sadeghi-Nejad, director of the Center for Male Reproductive Medicine at Hackensack University Medical Center.

Indeed, while some people assume that Viagra and other drugs cause erections on their own, sexual stimulation is still necessary. Moreover, as generations of psychologists have discovered, mental issues can wreak havoc on a person's sexual thoughts and sensations.

Sadeghi-Nejad added that stress, in particular, could cause problems and reduce the effectiveness of erectile dysfunction drugs.

Melnik T, Soares BGO, Nasselo AG. Psychosocial interventions for erectile dysfunction (Review). Cochrane Database of Systematic Reviews 2007, Issue 3.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.

Health Behavior News Service
Center for the Advancement of Health 2000 Florida Ave. NW, Ste 210
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http://www.hbns.org
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Aaron I. Vinik, M.D., Ph.D.; Roy Freeman, M.B., Ch.B.; Tomris Erbas, M.D.

Abstract and Introduction

Abstract

Diabetic autonomic neuropathy is the most common and troublesome complication of diabetes mellitus. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. Complications of diabetic autonomic neuropathy contribute greatly to the morbidity, mortality, and reduced quality of life of the person with diabetes and are the major source of increased costs of caring for the diabetic patient. Factors in the pathogenesis of these complications are altered metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of nerves in a visceral and cutaneous distribution. The clinical manifestations and the complications of diabetic autonomic neuropathy are reviewed. Future therapeutic strategies that are developed from a better understanding of the pathogenetic processes underlying this disorder can be directed at the cause rather than the manifestations. There are studies in progress that suggest that autonomic nerves can be induced to regenerate, and the future for patients with diabetic autonomic neuropathy is brighter.Introduction

Diabetic neuropathy is a heterogeneous disorder that encompasses a wide range of abnormalities affecting both proximal and distal peripheral sensory and motor nerves, as well as the autonomic nervous system (ANS). Diabetic autonomic neuropathy is among the least recognized and understood complications of diabetes despite its significant negative impact on survival and quality of life in people with diabetes.[1-3] Many organs are dually innervated, receiving fibers from the parasympathetic and sympathetic divisions of the ANS. Diabetic autonomic neuropathy typically occurs as a systemwide disorder affecting all parts of the ANS. Diabetic autonomic neuropathy manifests first in longer nerves. The vagus nerve (the longest of the ANS nerves) accounts for ~75% of all parasympathetic activity; as such, even early affects of diabetic autonomic neuropathy are widespread. The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the pupil, sweat glands, genitourinary system, gastrointestinal tract system, adrenal medullary system, and the cardiovascular system (Table 1).[4] The availability of sensitive, specific, and reproducible noninvasive tests of autonomic function has enhanced our understanding of the prevalence, pathophysiology, and clinical manifestations of this disorder.[1,5-6] Clinical symptoms of autonomic neuropathy generally do not occur until long after the onset of diabetes. Subclinical autonomic dysfunction, however, can occur within a year of diagnosis in type 2 diabetic patients and within 2 years in type 1 diabetic patients.[7]

Estimates of the prevalence of diabetic autonomic neuropathy are dependent on the criteria used for diagnosis and the specific population under study. The prevalence of symptoms of autonomic dysfunction and abnormal tests of autonomic nervous system function in diabetic clinic-based populations and tertiary referral centers is considerably higher than in general clinic-based populations. For example, symptomatic visceral autonomic neuropathy had a prevalence of 5.5% in a population-based study of diabetic patients in Rochester, Minnesota.[8] In a community-based population study of diabetic neuropathy in Oxford, England, the prevalence of autonomic neuropathy as defined by one or more abnormal heart rate variability (HRV) test results was 16.7%.[9] In a study that evaluated the prevalence of cardiovascular autonomic neuropathy in 1171 diabetic patients randomly recruited from 22 diabetic centers in Germany, Austria, and Switzerland, 25.3% of patients with type 1 diabetes and 34.3% of patients with type 2 diabetes had abnormal findings in more than two of six autonomic function tests.[10]

Section 1 of 9 Aaron I. Vinik, M.D., Ph.D.,1 Roy Freeman, M.B., Ch.B.,2 and Tomris Erbas, M.D.1

1Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, Norfolk, Virginia; and 2Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Semin Neurol 23(4):365-372, 2003. © 2003 Thieme Medical Publishers
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Thursday, 27 May, 1999, 09:14 GMT 10:14 UK Doctors: Why we oppose Viagra rationing
Doctors say the Viagra restrictions are arbitrary
Doctors say the government's decision to ration Viagra is arbitrary, "bizarre" and unfair.

Health Secretary Frank Dobson has set out guidelines which limit the prescription of Viagra on the NHS to people with certain physical problems and severe psychological distress.

Dr John Dean, a GP specialising in erectile dysfunction, said: "This is arbitrary and does not go anywhere to meeting clinical need for the majority of impotent men."

He said only about 20-25% of patients he saw with impotence were covered by Mr Dobson's categories.

If coronary artery disease, including high blood pressure, was included, this would lift the number to 80%.

Fifty per cent of diabetics become impotent as a result of their illness compared with 40% of people with coronary artery disease.

"They are just as likely to suffer and they did not choose their problem," he said.

Psychological causes

He added that it was very difficult to draw a line between physical and psychological causes of impotence in many cases.

A quarter of cases of diabetic impotence were caused by psychological rather than physical reasons, he said.

"There is not a guaranteed diagnostic test which can show whether impotence is due to physical or psychological factors," he said.

Moreover, Viagra did not work as well for diabetics as for people with coronary artery disease.

Only 55-60% of diabetics responded to Viagra, he claimed. Men with coronary heart disease were more likely to respond and the drug was effective for 80% of men with psychological problems.

"He has chosen a group which is likely to respond the least well to the drug," said Dr Dean.

He believes the decision to leave out some physical causes of impotence is due to cost.

More people have coronary artery disease than diabetes and it was more difficult to diagnose borderline vascular disease than diabetes.

More expensive treatments

Doctors also believe it is illogical to restrict Viagra while still allowing more expensive treatments for impotence which are less safe and more expensive, for example, injection therapy.

Dr Angela Coulter: the NHS has to set priorities

And they predict that hospital specialists will be inundated with patients who say their impotence is due to severe psychological problems.

Dr Dean said GPs were better equipped to decide if a person's impotence was due to psychological problems as they knew the person's history and personal circumstances.

He said specialists in urological problems would not necessarily be skilled in psychology.

Dr John Chisholm of the British Medical Association has also hit out at the "unjustifiable" restrictions on Viagra prescription.

The BMA's meeting on the subject on Thursday morning forced the government's hand after months of delay.

But NHS managers have backed the decision. Stephen Thornton, chief executive of the NHS Confederation, said: "Setting limits to healthcare is never easy. The government has been very brave with these proposals."

Dr Angela Coulter, director of policy and development for the King's Fund charity, also welcomed "clear rules" on Viagra.

She said: "There does have to be some control. The NHS has to set priorities. It cannot afford to provide everything people might want."

She added that previously doctors and health authorities had had to decide where to draw the line, but said the government had now recognised that this could not go on.

The government is setting up the National Institute for Clinical Excellence later this year which will decide on similar cases in the future.

Patients group backs Dobson

Roger Goss, of the Patients' Association, said Mr Dobson's stance was "eminently responsible and sensible".

Roger Goss backed the government

He said: "Doctors are going to be able to treat people who have deep emotional problems which if they did not get treatment might cause them even more trouble and make them a bigger cost to the health service.

"But for people like me, 50-year-olds who might see this as an opportunity to have a bit more fun in life, it is not realistic to allow me to subsidised."

Mr Goss said the Patients' Association wanted the government to consult the public on what the priorities for the health service should be.

However, a spokeswoman for the Impotence Association said it was "extremely disappointed" by Mr Dobson's announcement.

She stated: "These are extremely restrictive guidelines.

"They don't take into account people suffering impotence from the side effects of medicines or high blood pressure and they make up a huge majority of impotence sufferers."

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