Robert Finn

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued its development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One worry in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients.

But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued its development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One worry in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients.

But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued its development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One worry in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients.

But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — The rise in the diagnosis of type 2 diabetes among children is calling attention to certain differences in disease characteristics between children and adults, Dr. Francine Ratner Kaufman reported at the Third World Congress on Insulin Resistance Syndrome.

In fact, some children seem to have a form of diabetes that's a hybrid between type 1 and type 2, said Dr. Kaufman of the University of Southern California, Los Angeles.

The typical child with type 1 diabetes will have a positive antibody test and low fasting C-peptide values. The situation is reversed in the typical child with type 2-negative antibodies and high fasting C-peptide. But some children have a positive antibody test along with high fasting C-peptide levels. It's those children who have the hybrid form.

Before the advent of insulin pumps and refined methods of glucose control, children with type 1 diabetes were typically underweight. Better control means that more of these children are of normal weight, and about 20% may even be obese. That means that obesity alone cannot be used to distinguish type 1 from type 2 disease, even though at least 85% of children with type 2 diabetes are overweight or obese.

Type 2 diabetes seems to take a somewhat different course in children than in adults. In adults the disease is often indolent, preceded by a long asymptomatic period. Screening reveals many adults who have undiagnosed type 2 diabetes.

In contrast, at least five studies of overweight children, who would be expected to be at high risk of type 2 diabetes, have found very low rates—6% or less—of undiagnosed type 2 diabetes. This may indicate that children progress more rapidly than do adults through progressive B-cell failure to type 2 diabetes, narrowing the window when prevention and early treatment may have benefit.

A recent study found few parameters that can help distinguish children who have impaired glucose tolerance and will go on to develop type 2 diabetes from those who will revert to normal glucose tolerance (Diabetes Care 2005;28:902–9). The two groups were similar in fasting and postprandial glucose, insulin, and C-peptide levels, for example. The best predictor turned out to be rapid increases in weight and body mass index.

Other studies have shown that the presence or absence of diabetic ketoacidosis fail to distinguish type 1 from type 2 diabetes in children.

These similarities between the two types, along with the presence of a hybrid form, argue for the “accelerator hypothesis,” which views type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds, Dr. Kaufman said.

SAN FRANCISCO — The rise in the diagnosis of type 2 diabetes among children is calling attention to certain differences in disease characteristics between children and adults, Dr. Francine Ratner Kaufman reported at the Third World Congress on Insulin Resistance Syndrome.

In fact, some children seem to have a form of diabetes that's a hybrid between type 1 and type 2, said Dr. Kaufman of the University of Southern California, Los Angeles.

The typical child with type 1 diabetes will have a positive antibody test and low fasting C-peptide values. The situation is reversed in the typical child with type 2-negative antibodies and high fasting C-peptide. But some children have a positive antibody test along with high fasting C-peptide levels. It's those children who have the hybrid form.

Before the advent of insulin pumps and refined methods of glucose control, children with type 1 diabetes were typically underweight. Better control means that more of these children are of normal weight, and about 20% may even be obese. That means that obesity alone cannot be used to distinguish type 1 from type 2 disease, even though at least 85% of children with type 2 diabetes are overweight or obese.

Type 2 diabetes seems to take a somewhat different course in children than in adults. In adults the disease is often indolent, preceded by a long asymptomatic period. Screening reveals many adults who have undiagnosed type 2 diabetes.

In contrast, at least five studies of overweight children, who would be expected to be at high risk of type 2 diabetes, have found very low rates—6% or less—of undiagnosed type 2 diabetes. This may indicate that children progress more rapidly than do adults through progressive B-cell failure to type 2 diabetes, narrowing the window when prevention and early treatment may have benefit.

A recent study found few parameters that can help distinguish children who have impaired glucose tolerance and will go on to develop type 2 diabetes from those who will revert to normal glucose tolerance (Diabetes Care 2005;28:902–9). The two groups were similar in fasting and postprandial glucose, insulin, and C-peptide levels, for example. The best predictor turned out to be rapid increases in weight and body mass index.

Other studies have shown that the presence or absence of diabetic ketoacidosis fail to distinguish type 1 from type 2 diabetes in children.

These similarities between the two types, along with the presence of a hybrid form, argue for the “accelerator hypothesis,” which views type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds, Dr. Kaufman said.

SAN FRANCISCO — The rise in the diagnosis of type 2 diabetes among children is calling attention to certain differences in disease characteristics between children and adults, Dr. Francine Ratner Kaufman reported at the Third World Congress on Insulin Resistance Syndrome.

In fact, some children seem to have a form of diabetes that's a hybrid between type 1 and type 2, said Dr. Kaufman of the University of Southern California, Los Angeles.

The typical child with type 1 diabetes will have a positive antibody test and low fasting C-peptide values. The situation is reversed in the typical child with type 2-negative antibodies and high fasting C-peptide. But some children have a positive antibody test along with high fasting C-peptide levels. It's those children who have the hybrid form.

Before the advent of insulin pumps and refined methods of glucose control, children with type 1 diabetes were typically underweight. Better control means that more of these children are of normal weight, and about 20% may even be obese. That means that obesity alone cannot be used to distinguish type 1 from type 2 disease, even though at least 85% of children with type 2 diabetes are overweight or obese.

Type 2 diabetes seems to take a somewhat different course in children than in adults. In adults the disease is often indolent, preceded by a long asymptomatic period. Screening reveals many adults who have undiagnosed type 2 diabetes.

In contrast, at least five studies of overweight children, who would be expected to be at high risk of type 2 diabetes, have found very low rates—6% or less—of undiagnosed type 2 diabetes. This may indicate that children progress more rapidly than do adults through progressive B-cell failure to type 2 diabetes, narrowing the window when prevention and early treatment may have benefit.

A recent study found few parameters that can help distinguish children who have impaired glucose tolerance and will go on to develop type 2 diabetes from those who will revert to normal glucose tolerance (Diabetes Care 2005;28:902–9). The two groups were similar in fasting and postprandial glucose, insulin, and C-peptide levels, for example. The best predictor turned out to be rapid increases in weight and body mass index.

Other studies have shown that the presence or absence of diabetic ketoacidosis fail to distinguish type 1 from type 2 diabetes in children.

These similarities between the two types, along with the presence of a hybrid form, argue for the “accelerator hypothesis,” which views type 1 and type 2 diabetes as the same disorder of insulin resistance, set against different genetic backgrounds, Dr. Kaufman said.

SAN FRANCISCO — Surrogate measures of insulin resistance, while not nearly as reliable, may be far more practical for routine clinical use than the hyperinsulinemic-euglycemic clamp and the insulin suppression test, which can take 3 hours or more.

At the Third World Congress on Insulin Resistance Syndrome, Dr. Sun H. Kim, of Stanford (Calif.) University, discussed available surrogate tests. Other speakers at the congress discussed two new instrumental measures likely to become available soon.

One problem with using any measure of insulin resistance is its continuous distribution in the general population. There is no absolute criterion by which to classify individuals as insulin resistant or insulin sensitive. Dr. Kim follows the general practice of defining individuals who fall in the upper tertile of insulin resistance as having insulin resistance syndrome.

Available surrogate measures fall into three categories—routine measures, additional measures, and calculated measures.

The routine measures include fasting glucose and components of the lipid panel, especially HDL cholesterol and triglycerides.

Compared with the steady-state plasma glucose level (SSGL) derived from an insulin suppression test, fasting glucose has a correlation coefficient of just 0.38 and HDL has a correlation coefficient of just −0.41.

Triglyceride level is a somewhat better predictor of SSGL, with a correlation coefficient of 0.60.

Further, these three routine measures have an additional complication—their correlation coefficients vary depending on the patient's level of obesity.

The additional measures include fasting plasma insulin and the area under the curve for insulin in a 2-hour oral glucose tolerance test (OGTT). Fasting plasma insulin has a fairly good correlation with SSGL—0.61—but it, too, varies with the patient's obesity.

Among the routine and additional measures, the area under the curve of insulin in an OGTT has the highest correlation with SSGL (0.79), and that correlation does not vary depending on the patient's level of obesity.

The calculated measures include the ratio between triglycerides and HDL cholesterol, the homeostasis model assessment of insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI).

A triglyceride to HDL ratio above 3 predicts SSGL with a correlation coefficient of 0.61, and this varies only modestly with obesity. This is likely to be the most frequently used measure in clinical practice. HOMA-IR and QUICKI make use of fasting insulin and fasting glucose levels. Both correlate well with insulin sensitivity, but not much better than fasting insulin alone.

The two new instrumental measures, however, promise to provide more sensitive and specific measures of insulin sensitivity.

The deuterated-glucose disposal test (

Deuterated water is measured with an isotope ratio mass spectrometer, a large instrument that costs about $250,000. But Dr. Marc Hellerstein of the University of California, Berkeley, hopes to be able to employ a smaller, less expensive laser spectrometer that would have the additional advantage of a high throughput.

The second instrumental measure is a

According to Dr. Richard Z. Lewanczuk of the University of Alberta, Edmonton, human studies have demonstrated that the breath test has a sensitivity of 78% and a specificity of 96%, compared with standard measures. The Food and Drug Administration recently approved this technique for use in clinical trials in the United States.

Dr. Lewanczuk disclosed that he is a major stockholder in Isotechnika Diagnostics, the company that hopes to market the

SAN FRANCISCO — Surrogate measures of insulin resistance, while not nearly as reliable, may be far more practical for routine clinical use than the hyperinsulinemic-euglycemic clamp and the insulin suppression test, which can take 3 hours or more.

At the Third World Congress on Insulin Resistance Syndrome, Dr. Sun H. Kim, of Stanford (Calif.) University, discussed available surrogate tests. Other speakers at the congress discussed two new instrumental measures likely to become available soon.

One problem with using any measure of insulin resistance is its continuous distribution in the general population. There is no absolute criterion by which to classify individuals as insulin resistant or insulin sensitive. Dr. Kim follows the general practice of defining individuals who fall in the upper tertile of insulin resistance as having insulin resistance syndrome.

Available surrogate measures fall into three categories—routine measures, additional measures, and calculated measures.

The routine measures include fasting glucose and components of the lipid panel, especially HDL cholesterol and triglycerides.

Compared with the steady-state plasma glucose level (SSGL) derived from an insulin suppression test, fasting glucose has a correlation coefficient of just 0.38 and HDL has a correlation coefficient of just −0.41.

Triglyceride level is a somewhat better predictor of SSGL, with a correlation coefficient of 0.60.

Further, these three routine measures have an additional complication—their correlation coefficients vary depending on the patient's level of obesity.

The additional measures include fasting plasma insulin and the area under the curve for insulin in a 2-hour oral glucose tolerance test (OGTT). Fasting plasma insulin has a fairly good correlation with SSGL—0.61—but it, too, varies with the patient's obesity.

Among the routine and additional measures, the area under the curve of insulin in an OGTT has the highest correlation with SSGL (0.79), and that correlation does not vary depending on the patient's level of obesity.

The calculated measures include the ratio between triglycerides and HDL cholesterol, the homeostasis model assessment of insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI).

A triglyceride to HDL ratio above 3 predicts SSGL with a correlation coefficient of 0.61, and this varies only modestly with obesity. This is likely to be the most frequently used measure in clinical practice. HOMA-IR and QUICKI make use of fasting insulin and fasting glucose levels. Both correlate well with insulin sensitivity, but not much better than fasting insulin alone.

The two new instrumental measures, however, promise to provide more sensitive and specific measures of insulin sensitivity.

The deuterated-glucose disposal test (

Deuterated water is measured with an isotope ratio mass spectrometer, a large instrument that costs about $250,000. But Dr. Marc Hellerstein of the University of California, Berkeley, hopes to be able to employ a smaller, less expensive laser spectrometer that would have the additional advantage of a high throughput.

The second instrumental measure is a

According to Dr. Richard Z. Lewanczuk of the University of Alberta, Edmonton, human studies have demonstrated that the breath test has a sensitivity of 78% and a specificity of 96%, compared with standard measures. The Food and Drug Administration recently approved this technique for use in clinical trials in the United States.

Dr. Lewanczuk disclosed that he is a major stockholder in Isotechnika Diagnostics, the company that hopes to market the

SAN FRANCISCO — Surrogate measures of insulin resistance, while not nearly as reliable, may be far more practical for routine clinical use than the hyperinsulinemic-euglycemic clamp and the insulin suppression test, which can take 3 hours or more.

At the Third World Congress on Insulin Resistance Syndrome, Dr. Sun H. Kim, of Stanford (Calif.) University, discussed available surrogate tests. Other speakers at the congress discussed two new instrumental measures likely to become available soon.

One problem with using any measure of insulin resistance is its continuous distribution in the general population. There is no absolute criterion by which to classify individuals as insulin resistant or insulin sensitive. Dr. Kim follows the general practice of defining individuals who fall in the upper tertile of insulin resistance as having insulin resistance syndrome.

Available surrogate measures fall into three categories—routine measures, additional measures, and calculated measures.

The routine measures include fasting glucose and components of the lipid panel, especially HDL cholesterol and triglycerides.

Compared with the steady-state plasma glucose level (SSGL) derived from an insulin suppression test, fasting glucose has a correlation coefficient of just 0.38 and HDL has a correlation coefficient of just −0.41.

Triglyceride level is a somewhat better predictor of SSGL, with a correlation coefficient of 0.60.

Further, these three routine measures have an additional complication—their correlation coefficients vary depending on the patient's level of obesity.

The additional measures include fasting plasma insulin and the area under the curve for insulin in a 2-hour oral glucose tolerance test (OGTT). Fasting plasma insulin has a fairly good correlation with SSGL—0.61—but it, too, varies with the patient's obesity.

Among the routine and additional measures, the area under the curve of insulin in an OGTT has the highest correlation with SSGL (0.79), and that correlation does not vary depending on the patient's level of obesity.

The calculated measures include the ratio between triglycerides and HDL cholesterol, the homeostasis model assessment of insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI).

A triglyceride to HDL ratio above 3 predicts SSGL with a correlation coefficient of 0.61, and this varies only modestly with obesity. This is likely to be the most frequently used measure in clinical practice. HOMA-IR and QUICKI make use of fasting insulin and fasting glucose levels. Both correlate well with insulin sensitivity, but not much better than fasting insulin alone.

The two new instrumental measures, however, promise to provide more sensitive and specific measures of insulin sensitivity.

The deuterated-glucose disposal test (

Deuterated water is measured with an isotope ratio mass spectrometer, a large instrument that costs about $250,000. But Dr. Marc Hellerstein of the University of California, Berkeley, hopes to be able to employ a smaller, less expensive laser spectrometer that would have the additional advantage of a high throughput.

The second instrumental measure is a

According to Dr. Richard Z. Lewanczuk of the University of Alberta, Edmonton, human studies have demonstrated that the breath test has a sensitivity of 78% and a specificity of 96%, compared with standard measures. The Food and Drug Administration recently approved this technique for use in clinical trials in the United States.

Dr. Lewanczuk disclosed that he is a major stockholder in Isotechnika Diagnostics, the company that hopes to market the

SAN FRANCISCO — A relatively modest amount of weight loss can normalize fasting plasma glucose and greatly improve insulin sensitivity in people with type 2 diabetes, according to a study reported by Dr. Gerald I. Shulman at the Third World Congress on Insulin Resistance Syndrome.

Eight obese patients with type 2 diabetes achieved these significant improvements after losing an average of just 8 kg (17.6 pounds), equivalent to about 8% of their body weight, said Dr. Shulman of Yale University, New Haven, Conn. Dr. Kitt Falk Petersen was the lead author of the recently published study (Diabetes 2005;54:603–8).

These results have important clinical implications for patients with poorly controlled type 2 diabetes in that a modest weight loss is a psychologically easier goal than achieving normal body weight.

The diabetic patients enrolled in the study began with an average weight of 86 kg and an average body mass index of 30 kg/m

The study diet was a liquid diet formula with 50% carbohydrate, 43% protein, 3% fat, and 12 g of dietary fiber, which was supplemented with raw fruit and vegetables to about 1,200 kcal/day. The patients continued this diet until they achieved euglycemia, which took between 3 and 12 weeks. They were stabilized on an isocaloric diet for 4 weeks before the final metabolic measurements were taken.

Following the diet, the patients weighed an average of 78 kg and had an average BMI of 27.5. Their fasting glucose averaged 6.4 mmol/L, and their fasting insulin averaged 66 pmol/L. All these values represented statistically significant decreases from baseline.

In addition, the patients achieved a marked improvement in glucose responsiveness as measured by a fourfold increase in the glucose infusion rate required to maintain euglycemia during a hyperinsulinemic-euglycemic clamp.

By measuring hepatic glucose metabolism with deuterated glucose, the investigators determined that the weight reduction improved hepatic insulin sensitivity but had no effects on peripheral insulin sensitivity.

SAN FRANCISCO — A relatively modest amount of weight loss can normalize fasting plasma glucose and greatly improve insulin sensitivity in people with type 2 diabetes, according to a study reported by Dr. Gerald I. Shulman at the Third World Congress on Insulin Resistance Syndrome.

Eight obese patients with type 2 diabetes achieved these significant improvements after losing an average of just 8 kg (17.6 pounds), equivalent to about 8% of their body weight, said Dr. Shulman of Yale University, New Haven, Conn. Dr. Kitt Falk Petersen was the lead author of the recently published study (Diabetes 2005;54:603–8).

These results have important clinical implications for patients with poorly controlled type 2 diabetes in that a modest weight loss is a psychologically easier goal than achieving normal body weight.

The diabetic patients enrolled in the study began with an average weight of 86 kg and an average body mass index of 30 kg/m

The study diet was a liquid diet formula with 50% carbohydrate, 43% protein, 3% fat, and 12 g of dietary fiber, which was supplemented with raw fruit and vegetables to about 1,200 kcal/day. The patients continued this diet until they achieved euglycemia, which took between 3 and 12 weeks. They were stabilized on an isocaloric diet for 4 weeks before the final metabolic measurements were taken.

Following the diet, the patients weighed an average of 78 kg and had an average BMI of 27.5. Their fasting glucose averaged 6.4 mmol/L, and their fasting insulin averaged 66 pmol/L. All these values represented statistically significant decreases from baseline.

In addition, the patients achieved a marked improvement in glucose responsiveness as measured by a fourfold increase in the glucose infusion rate required to maintain euglycemia during a hyperinsulinemic-euglycemic clamp.

By measuring hepatic glucose metabolism with deuterated glucose, the investigators determined that the weight reduction improved hepatic insulin sensitivity but had no effects on peripheral insulin sensitivity.

SAN FRANCISCO — A relatively modest amount of weight loss can normalize fasting plasma glucose and greatly improve insulin sensitivity in people with type 2 diabetes, according to a study reported by Dr. Gerald I. Shulman at the Third World Congress on Insulin Resistance Syndrome.

Eight obese patients with type 2 diabetes achieved these significant improvements after losing an average of just 8 kg (17.6 pounds), equivalent to about 8% of their body weight, said Dr. Shulman of Yale University, New Haven, Conn. Dr. Kitt Falk Petersen was the lead author of the recently published study (Diabetes 2005;54:603–8).

These results have important clinical implications for patients with poorly controlled type 2 diabetes in that a modest weight loss is a psychologically easier goal than achieving normal body weight.

The diabetic patients enrolled in the study began with an average weight of 86 kg and an average body mass index of 30 kg/m

The study diet was a liquid diet formula with 50% carbohydrate, 43% protein, 3% fat, and 12 g of dietary fiber, which was supplemented with raw fruit and vegetables to about 1,200 kcal/day. The patients continued this diet until they achieved euglycemia, which took between 3 and 12 weeks. They were stabilized on an isocaloric diet for 4 weeks before the final metabolic measurements were taken.

Following the diet, the patients weighed an average of 78 kg and had an average BMI of 27.5. Their fasting glucose averaged 6.4 mmol/L, and their fasting insulin averaged 66 pmol/L. All these values represented statistically significant decreases from baseline.

In addition, the patients achieved a marked improvement in glucose responsiveness as measured by a fourfold increase in the glucose infusion rate required to maintain euglycemia during a hyperinsulinemic-euglycemic clamp.

By measuring hepatic glucose metabolism with deuterated glucose, the investigators determined that the weight reduction improved hepatic insulin sensitivity but had no effects on peripheral insulin sensitivity.

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three current investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One of the worries in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this has apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients. But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

“Most people think this Pfizer case is highly, highly unlikely to be related to maraviroc, and I agree,” Dr. Deeks said. “There are a couple of reasons for the liver disease here, so all studies are going forward, at least for the Pfizer drug, for now.”

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three current investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One of the worries in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this has apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients. But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

“Most people think this Pfizer case is highly, highly unlikely to be related to maraviroc, and I agree,” Dr. Deeks said. “There are a couple of reasons for the liver disease here, so all studies are going forward, at least for the Pfizer drug, for now.”

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — Efforts to develop entry inhibitors, which constitute the first new class of anti-HIV drugs in years, have hit snags that could delay the entry of these novel agents into the pharmaceutical marketplace.

The debut of entry inhibitors has been eagerly awaited because of preclinical hints that they may be highly effective and have few side effects. But all three entry inhibitors in clinical trials have run into difficulty, and one has now been withdrawn from development, Dr. Steven W. Deeks said at a meeting on HIV management sponsored by the University of California, San Francisco.

GlaxoSmithKline has discontinued development of Aplaviroc, which appears to have caused at least five cases of liver toxicity. Schering-Plough's vicriviroc did not perform as well as efavirenz in a head-to-head comparison on treatment-naive patients, and is now being developed only for salvage therapy. And a patient taking Pfizer's maraviroc developed liver failure and required a transplant, although there are indications that other drugs the patient was taking might have been to blame.

Entry inhibitors don't attack the HIV virus directly, explained Dr. Deeks of UCSF. Instead they block a coreceptor on the surface of T cells that the virus requires for entry. Two such coreceptors are known, CCR5 and CXCR4, which are popularly called R5 and X4, respectively. All three current investigational drugs target the R5 receptor.

Some people are known to lack the R5 coreceptor because of spontaneous genetic mutations. They seem to harbor no ill effects from this, leading to speculation that agents that block that receptor are unlikely to have serious side effects. No humans are known to lack the X4 coreceptor, on the other hand, and deleting it in mice is lethal. For that reason, there has been a reluctance to develop drugs that bind to the X4 receptor.

R5 viruses are associated with slow disease progression and are common in early HIV disease. X4 viruses are associated with rapid disease progression and emerge in late disease. One of the worries in using R5 inhibitors is that they may encourage the earlier emergence of X4 viruses. Indeed, this has apparently happened in five or six patients in the clinical trials, Dr. Deeks said, and this is likely to be associated with more rapid disease progression.

The difficulties that aplaviroc, vicriviroc, and maraviroc have run into are not related to this, however. Aplaviroc has been associated with five cases of liver toxicity, all of which involved a threefold increase in ALT and a 1.5-fold increase in bilirubin. In all cases, this elevation in enzymes declined when the drug was removed, and in the one case in which the patient was rechallenged with aplaviroc, the liver toxicity recurred. Further development of aplaviroc has been stopped.

There was hope that entry inhibitors might be a good first-line therapy in treatment-naive patients. But a study comparing Combivir plus efavirenz with Combivir plus vicriviroc in patients who were treatment naive was terminated early because of the clear superiority of efavirenz. Vicriviroc is no longer being developed as a first-line therapy; its use will be only for salvage in patients who have failed earlier regimens.

The case of liver failure in a patient taking maraviroc originally caused concern that studies on this medication would have to be terminated as well. This was despite the fact that the drug has been used in hundreds of treatment-naive and salvage patients with no ill effects. But the patient, a 24-year-old woman, had also been receiving isoniazid and cotrimoxazole for HIV-associated infections. Her ALT levels increased more than fivefold during the 7-week screening period, and her AST increased as well.

On the fifth day of taking maraviroc plus Combivir the patient developed rash and fever, and maraviroc was discontinued. The next day her liver enzymes were significantly elevated (32 times normal). For some reason, despite the known potential for additional liver toxicity, she was given a high dose of acetaminophen (11 g IV) at this time. Her liver enzymes continued to worsen, and on day 16 she received a liver transplant.

“Most people think this Pfizer case is highly, highly unlikely to be related to maraviroc, and I agree,” Dr. Deeks said. “There are a couple of reasons for the liver disease here, so all studies are going forward, at least for the Pfizer drug, for now.”

Dr. Deeks disclosed relationships with several pharmaceutical companies, including being a recipient of research support from GlaxoSmithKline and working as a consultant for Pfizer.

SAN FRANCISCO — Every physician should consider how he or she would manage as the only medical professional in a mass-casualty situation, Lt. Cormac J. O'Connor, MC, USN, said at the annual meeting of the American Academy of Family Physicians.

Dr. O'Connor, a second-year resident in family medicine at Naval Hospital Camp Pendleton (Calif.), offered a mnemonic—SAGGY PRIDE—to help physicians remember the critical steps in managing mass casualties. He was assisted in his presentation by Lt. Donnelly Wilkes, M.D., MC, USN. (Dr. O'Connor emphasized that his suggestions are his own and do not represent official positions of the U.S. Navy or the Department of Defense.)

SAGGY PRIDE stands for Situational Awareness, Gather a Group and Yell, Plan Rapidly, Issue Directives, and Execute.

A “mass casualty” is any situation in which the number of casualties overwhelms the medical capabilities available. This can range from a single, critically ill person in a remote location to thousands of people in an urban area who are victims of a natural disaster or a terrorist attack.

“As a whole, civilian physicians are not trained to deal with mass casualty events,” said Dr. O'Connor, who has served in combat with the U.S. Marine Corps in Iraq.

“[Nevertheless] as a physician, you're expected to know what to do when many people are hurt, regardless of whether that falls within the nature of your practice.”

Situational Awareness

In less than 1 minute, if possible, you need to get a grasp of what has happened. What is the nature of the calamity? How many people are involved? What is the location's condition and physical layout? What resources are likely to be available?

Gather a Group and Yell

Using a loud voice, identify yourself as a physician and bring all the able-bodied people together. By definition, you will not be able to handle the situation yourself, and you will need as much help as you can muster. “You need to be the puppeteer,” Dr. O'Connor said.

“You need to be the director helping things to happen.”

Be sure to discern whether there are any other medically trained personnel available to assist you.

You need everybody's help, but you must have control and confidence, something that physicians who practice emergency medicine gain with experience, but which may not come as easily to other physicians.

Plan Rapidly

Divide the work into a short game and a long game. The short game is to do the best for the people who are going to die or suffer a serious injury if you don't act immediately. The long game is to consider how you're going to evacuate all of the injured to a higher level of care.

Triage is the first step in the short game. Don't waste time with people who are not seriously injured; conversely, don't focus your resources on those who are likely to die given the resources you have available.

In combat, as in other mass casualty situations, the two major causes of preventable death are extremity exsanguination and pneumothorax, Dr. O'Connor said. Since a physician who happens on a mass casualty is unlikely to have the equipment needed to help a patient with pneumothorax, the best thing he or she can do is to keep patients from bleeding to death from a hemorrhage of the extremity.

The best way to do this is to apply direct pressure, but even if you had a group large enough to apply direct pressure to every injured person, consider whether that is the best use of your resources.

The other alternative is to use tourniquets. While many physicians have been taught that tourniquets should never be used because they can lead to the loss of a limb, Dr. O'Connor disagrees.

He described one combat casualty he treated who had a leg wound so severe he could see the man's sciatic nerve. He applied a tourniquet that stayed on for a full 8 hours. The man lived and has full use of his leg. The truth is that peripheral muscle can stand to be deprived of oxygen for extended periods. For the long game, think first about communicating to emergency services.

These days almost everyone carries a mobile phone, but what are you going to do if cell service is down? Perhaps someone has a working BlackBerry, a CB radio, or maybe there's even a working land line.

Then think about how emergency services are going to get to the site and how they're going to leave. Plan a route that gives one way for emergency vehicles (possibly including helicopters) to get in, and another way to get out. Plan to put the people who can be helped best by being evacuated at sensible collection points and to move less seriously injured people—and the dead and dying—out of the way.

Issue Directives

Be very specific and speak directly to individuals. Don't say, “Somebody, please phone for help,” Dr. O'Connor recommended. Instead say, “Ma'am, I see you have a cell phone. Call 911 right now!”

Have able-bodied people move the dead out of the way, and preferably out of sight. Designate an assistant to move the walking wounded to another location. Say, “This is Mary. If you can walk, follow her.”

If possible, assign someone to stay with those who are likely to die within a short time. Get them to a quiet area. Find somebody who is mature, but who may not be physically very strong, to stay with these folks and comfort them during their last minutes or hours.

Execute

Have a group of worker bees search for heavy extremity bleeding and apply pressure dressings or tourniquets. Instruct them to use any available materials, including belts, shirts, and bras.

Finally, don't forget to continually reevaluate the situation. This may include retriaging the injured as their situations change.

SAN FRANCISCO — Every physician should consider how he or she would manage as the only medical professional in a mass-casualty situation, Lt. Cormac J. O'Connor, MC, USN, said at the annual meeting of the American Academy of Family Physicians.

Dr. O'Connor, a second-year resident in family medicine at Naval Hospital Camp Pendleton (Calif.), offered a mnemonic—SAGGY PRIDE—to help physicians remember the critical steps in managing mass casualties. He was assisted in his presentation by Lt. Donnelly Wilkes, M.D., MC, USN. (Dr. O'Connor emphasized that his suggestions are his own and do not represent official positions of the U.S. Navy or the Department of Defense.)

SAGGY PRIDE stands for Situational Awareness, Gather a Group and Yell, Plan Rapidly, Issue Directives, and Execute.

A “mass casualty” is any situation in which the number of casualties overwhelms the medical capabilities available. This can range from a single, critically ill person in a remote location to thousands of people in an urban area who are victims of a natural disaster or a terrorist attack.

“As a whole, civilian physicians are not trained to deal with mass casualty events,” said Dr. O'Connor, who has served in combat with the U.S. Marine Corps in Iraq.

“[Nevertheless] as a physician, you're expected to know what to do when many people are hurt, regardless of whether that falls within the nature of your practice.”

Situational Awareness

In less than 1 minute, if possible, you need to get a grasp of what has happened. What is the nature of the calamity? How many people are involved? What is the location's condition and physical layout? What resources are likely to be available?

Gather a Group and Yell

Using a loud voice, identify yourself as a physician and bring all the able-bodied people together. By definition, you will not be able to handle the situation yourself, and you will need as much help as you can muster. “You need to be the puppeteer,” Dr. O'Connor said.

“You need to be the director helping things to happen.”

Be sure to discern whether there are any other medically trained personnel available to assist you.

You need everybody's help, but you must have control and confidence, something that physicians who practice emergency medicine gain with experience, but which may not come as easily to other physicians.

Plan Rapidly

Divide the work into a short game and a long game. The short game is to do the best for the people who are going to die or suffer a serious injury if you don't act immediately. The long game is to consider how you're going to evacuate all of the injured to a higher level of care.

Triage is the first step in the short game. Don't waste time with people who are not seriously injured; conversely, don't focus your resources on those who are likely to die given the resources you have available.

In combat, as in other mass casualty situations, the two major causes of preventable death are extremity exsanguination and pneumothorax, Dr. O'Connor said. Since a physician who happens on a mass casualty is unlikely to have the equipment needed to help a patient with pneumothorax, the best thing he or she can do is to keep patients from bleeding to death from a hemorrhage of the extremity.

The best way to do this is to apply direct pressure, but even if you had a group large enough to apply direct pressure to every injured person, consider whether that is the best use of your resources.

The other alternative is to use tourniquets. While many physicians have been taught that tourniquets should never be used because they can lead to the loss of a limb, Dr. O'Connor disagrees.

He described one combat casualty he treated who had a leg wound so severe he could see the man's sciatic nerve. He applied a tourniquet that stayed on for a full 8 hours. The man lived and has full use of his leg. The truth is that peripheral muscle can stand to be deprived of oxygen for extended periods. For the long game, think first about communicating to emergency services.

These days almost everyone carries a mobile phone, but what are you going to do if cell service is down? Perhaps someone has a working BlackBerry, a CB radio, or maybe there's even a working land line.

Then think about how emergency services are going to get to the site and how they're going to leave. Plan a route that gives one way for emergency vehicles (possibly including helicopters) to get in, and another way to get out. Plan to put the people who can be helped best by being evacuated at sensible collection points and to move less seriously injured people—and the dead and dying—out of the way.

Issue Directives

Be very specific and speak directly to individuals. Don't say, “Somebody, please phone for help,” Dr. O'Connor recommended. Instead say, “Ma'am, I see you have a cell phone. Call 911 right now!”

Have able-bodied people move the dead out of the way, and preferably out of sight. Designate an assistant to move the walking wounded to another location. Say, “This is Mary. If you can walk, follow her.”

If possible, assign someone to stay with those who are likely to die within a short time. Get them to a quiet area. Find somebody who is mature, but who may not be physically very strong, to stay with these folks and comfort them during their last minutes or hours.

Execute

Have a group of worker bees search for heavy extremity bleeding and apply pressure dressings or tourniquets. Instruct them to use any available materials, including belts, shirts, and bras.

Finally, don't forget to continually reevaluate the situation. This may include retriaging the injured as their situations change.

SAN FRANCISCO — Every physician should consider how he or she would manage as the only medical professional in a mass-casualty situation, Lt. Cormac J. O'Connor, MC, USN, said at the annual meeting of the American Academy of Family Physicians.

Dr. O'Connor, a second-year resident in family medicine at Naval Hospital Camp Pendleton (Calif.), offered a mnemonic—SAGGY PRIDE—to help physicians remember the critical steps in managing mass casualties. He was assisted in his presentation by Lt. Donnelly Wilkes, M.D., MC, USN. (Dr. O'Connor emphasized that his suggestions are his own and do not represent official positions of the U.S. Navy or the Department of Defense.)

SAGGY PRIDE stands for Situational Awareness, Gather a Group and Yell, Plan Rapidly, Issue Directives, and Execute.

A “mass casualty” is any situation in which the number of casualties overwhelms the medical capabilities available. This can range from a single, critically ill person in a remote location to thousands of people in an urban area who are victims of a natural disaster or a terrorist attack.

“As a whole, civilian physicians are not trained to deal with mass casualty events,” said Dr. O'Connor, who has served in combat with the U.S. Marine Corps in Iraq.

“[Nevertheless] as a physician, you're expected to know what to do when many people are hurt, regardless of whether that falls within the nature of your practice.”

Situational Awareness

In less than 1 minute, if possible, you need to get a grasp of what has happened. What is the nature of the calamity? How many people are involved? What is the location's condition and physical layout? What resources are likely to be available?

Gather a Group and Yell

Using a loud voice, identify yourself as a physician and bring all the able-bodied people together. By definition, you will not be able to handle the situation yourself, and you will need as much help as you can muster. “You need to be the puppeteer,” Dr. O'Connor said.

“You need to be the director helping things to happen.”

Be sure to discern whether there are any other medically trained personnel available to assist you.

You need everybody's help, but you must have control and confidence, something that physicians who practice emergency medicine gain with experience, but which may not come as easily to other physicians.

Plan Rapidly

Divide the work into a short game and a long game. The short game is to do the best for the people who are going to die or suffer a serious injury if you don't act immediately. The long game is to consider how you're going to evacuate all of the injured to a higher level of care.

Triage is the first step in the short game. Don't waste time with people who are not seriously injured; conversely, don't focus your resources on those who are likely to die given the resources you have available.

In combat, as in other mass casualty situations, the two major causes of preventable death are extremity exsanguination and pneumothorax, Dr. O'Connor said. Since a physician who happens on a mass casualty is unlikely to have the equipment needed to help a patient with pneumothorax, the best thing he or she can do is to keep patients from bleeding to death from a hemorrhage of the extremity.

The best way to do this is to apply direct pressure, but even if you had a group large enough to apply direct pressure to every injured person, consider whether that is the best use of your resources.

The other alternative is to use tourniquets. While many physicians have been taught that tourniquets should never be used because they can lead to the loss of a limb, Dr. O'Connor disagrees.

He described one combat casualty he treated who had a leg wound so severe he could see the man's sciatic nerve. He applied a tourniquet that stayed on for a full 8 hours. The man lived and has full use of his leg. The truth is that peripheral muscle can stand to be deprived of oxygen for extended periods. For the long game, think first about communicating to emergency services.

These days almost everyone carries a mobile phone, but what are you going to do if cell service is down? Perhaps someone has a working BlackBerry, a CB radio, or maybe there's even a working land line.

Then think about how emergency services are going to get to the site and how they're going to leave. Plan a route that gives one way for emergency vehicles (possibly including helicopters) to get in, and another way to get out. Plan to put the people who can be helped best by being evacuated at sensible collection points and to move less seriously injured people—and the dead and dying—out of the way.

Issue Directives

Be very specific and speak directly to individuals. Don't say, “Somebody, please phone for help,” Dr. O'Connor recommended. Instead say, “Ma'am, I see you have a cell phone. Call 911 right now!”

Have able-bodied people move the dead out of the way, and preferably out of sight. Designate an assistant to move the walking wounded to another location. Say, “This is Mary. If you can walk, follow her.”

If possible, assign someone to stay with those who are likely to die within a short time. Get them to a quiet area. Find somebody who is mature, but who may not be physically very strong, to stay with these folks and comfort them during their last minutes or hours.

Execute

Have a group of worker bees search for heavy extremity bleeding and apply pressure dressings or tourniquets. Instruct them to use any available materials, including belts, shirts, and bras.

Finally, don't forget to continually reevaluate the situation. This may include retriaging the injured as their situations change.

SAN FRANCISCO — Echocardiography provides a great deal of information to help determine a patient's risk following a myocardial infarction, Dr. Thomas Ryan said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

“There are a lot of ways we can [risk stratify patients], but I think our goals should be to do it in the most efficient, the most effective, and the most cost-responsible fashion possible,” said Dr. Ryan of Duke University, Durham, N.C

Echocardiography provides a variety of perspectives on left ventricular function. It allows for a calculation of ejection fraction. Doppler plus the principle of continuity of flow allows for the measurement of stroke volume across both valves, which in turn allows for the calculation of cardiac output. The contour of the mitral regurgitation depth can be used to measure the rate of change in left ventricular pressure (dP/dt). And finally, one can generate a wall-motion score.

Together, the degree of left ventricular dysfunction and the presence and severity of mitral regurgitation are the most powerful predictors of early risk after acute MI. The results of a study of more than 3,000 patients in the Duke database show that an echo score derived from these two factors neatly stratifies patients into three categories.

Patients get no points for a good ejection fraction or good mitral regurgitation. They get 2 points each for poor ejection fraction and poor mitral regurgitation, and they get 1 point each for intermediate values. The echo score is the sum of the ejection fraction and mitral regurgitation scores.

Patients with an echo score of 0 have better than 90% 2-year survival. Those with an echo score of 3 or 4 have about a 50% 2-year survival, and those with a score of 1 or 2 have about a 75% 2-year survival.

Diastolic function has prognostic implications as well. If the deceleration time of the mitral P wave is 115 milliseconds or more, then the 30-month survival is 100%. Those with mitral deceleration times of less than 115 milliseconds have a 30-month survival rate of about 40%.

The combination of these measures means that the physician will get a great deal of information even before resorting to stress echocardiography.

SAN FRANCISCO — Echocardiography provides a great deal of information to help determine a patient's risk following a myocardial infarction, Dr. Thomas Ryan said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

“There are a lot of ways we can [risk stratify patients], but I think our goals should be to do it in the most efficient, the most effective, and the most cost-responsible fashion possible,” said Dr. Ryan of Duke University, Durham, N.C

Echocardiography provides a variety of perspectives on left ventricular function. It allows for a calculation of ejection fraction. Doppler plus the principle of continuity of flow allows for the measurement of stroke volume across both valves, which in turn allows for the calculation of cardiac output. The contour of the mitral regurgitation depth can be used to measure the rate of change in left ventricular pressure (dP/dt). And finally, one can generate a wall-motion score.

Together, the degree of left ventricular dysfunction and the presence and severity of mitral regurgitation are the most powerful predictors of early risk after acute MI. The results of a study of more than 3,000 patients in the Duke database show that an echo score derived from these two factors neatly stratifies patients into three categories.

Patients get no points for a good ejection fraction or good mitral regurgitation. They get 2 points each for poor ejection fraction and poor mitral regurgitation, and they get 1 point each for intermediate values. The echo score is the sum of the ejection fraction and mitral regurgitation scores.

Patients with an echo score of 0 have better than 90% 2-year survival. Those with an echo score of 3 or 4 have about a 50% 2-year survival, and those with a score of 1 or 2 have about a 75% 2-year survival.

Diastolic function has prognostic implications as well. If the deceleration time of the mitral P wave is 115 milliseconds or more, then the 30-month survival is 100%. Those with mitral deceleration times of less than 115 milliseconds have a 30-month survival rate of about 40%.

The combination of these measures means that the physician will get a great deal of information even before resorting to stress echocardiography.

SAN FRANCISCO — Echocardiography provides a great deal of information to help determine a patient's risk following a myocardial infarction, Dr. Thomas Ryan said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

“There are a lot of ways we can [risk stratify patients], but I think our goals should be to do it in the most efficient, the most effective, and the most cost-responsible fashion possible,” said Dr. Ryan of Duke University, Durham, N.C

Echocardiography provides a variety of perspectives on left ventricular function. It allows for a calculation of ejection fraction. Doppler plus the principle of continuity of flow allows for the measurement of stroke volume across both valves, which in turn allows for the calculation of cardiac output. The contour of the mitral regurgitation depth can be used to measure the rate of change in left ventricular pressure (dP/dt). And finally, one can generate a wall-motion score.

Together, the degree of left ventricular dysfunction and the presence and severity of mitral regurgitation are the most powerful predictors of early risk after acute MI. The results of a study of more than 3,000 patients in the Duke database show that an echo score derived from these two factors neatly stratifies patients into three categories.

Patients get no points for a good ejection fraction or good mitral regurgitation. They get 2 points each for poor ejection fraction and poor mitral regurgitation, and they get 1 point each for intermediate values. The echo score is the sum of the ejection fraction and mitral regurgitation scores.

Patients with an echo score of 0 have better than 90% 2-year survival. Those with an echo score of 3 or 4 have about a 50% 2-year survival, and those with a score of 1 or 2 have about a 75% 2-year survival.

Diastolic function has prognostic implications as well. If the deceleration time of the mitral P wave is 115 milliseconds or more, then the 30-month survival is 100%. Those with mitral deceleration times of less than 115 milliseconds have a 30-month survival rate of about 40%.

The combination of these measures means that the physician will get a great deal of information even before resorting to stress echocardiography.

SAN FRANCISCO — Cardiac MRI with late gadolinium enhancement is the imaging technique of choice when the goal is tissue characterization and infarct detection in heart failure, Dr. Christopher M. Kramer said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

Cardiac magnetic resonance (CMR) provides outstanding image quality, excellent quantification, and tissue characterization, said Dr. Kramer of the University of Virginia, in Charlottesville. In addition, Gadolinium contrast is easy to use and safe with CMR and also offers the ability to assess intramural function.

However, CMR devices are not portable, are quite expensive, and are not readily available. Physicians need to have extensive training in the use of CMR and the technique is not suitable for patients with implanted metallic devices such as pacemakers and implantable cardioverter defibrillators. Furthermore, assessment of diastolic function is not routine with CMR.

Echocardiography also has a number of advantages. The devices are portable and relatively inexpensive, and they are readily available. Generations of cardiologists have established its validity and all cardiologists become proficient in the use of echo during their training. Contrast can be added to echocardiography, and the assessment of diastolic function has become routine.

But the technique is subject to variable image quality and poor windows. The results tend to be qualitative, and quantitation can be difficult. Newer 3-D echocardiographic techniques address some of these issues, but such devices are not widely available.

Gadolinium-enhanced CMR is useful in determining if cardiomyopathy is ischemic or nonischemic. Studies have also shown the value of enhanced CMR as a marker in late-stage myocarditis, hypertrophic cardiomyopathy, amyloidosis, sarcoidosis, and Chagas disease.

Dr. Kramer noted that echocardiography is useful in several circumstances, especially for diastolic function and when “quick and easy” is adequate, but CMR is best for regional systolic function, for differential diagnosis and tissue characterization, and when quantitation is needed and 3-D echo is unavailable.

SAN FRANCISCO — Cardiac MRI with late gadolinium enhancement is the imaging technique of choice when the goal is tissue characterization and infarct detection in heart failure, Dr. Christopher M. Kramer said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

Cardiac magnetic resonance (CMR) provides outstanding image quality, excellent quantification, and tissue characterization, said Dr. Kramer of the University of Virginia, in Charlottesville. In addition, Gadolinium contrast is easy to use and safe with CMR and also offers the ability to assess intramural function.

However, CMR devices are not portable, are quite expensive, and are not readily available. Physicians need to have extensive training in the use of CMR and the technique is not suitable for patients with implanted metallic devices such as pacemakers and implantable cardioverter defibrillators. Furthermore, assessment of diastolic function is not routine with CMR.

Echocardiography also has a number of advantages. The devices are portable and relatively inexpensive, and they are readily available. Generations of cardiologists have established its validity and all cardiologists become proficient in the use of echo during their training. Contrast can be added to echocardiography, and the assessment of diastolic function has become routine.

But the technique is subject to variable image quality and poor windows. The results tend to be qualitative, and quantitation can be difficult. Newer 3-D echocardiographic techniques address some of these issues, but such devices are not widely available.

Gadolinium-enhanced CMR is useful in determining if cardiomyopathy is ischemic or nonischemic. Studies have also shown the value of enhanced CMR as a marker in late-stage myocarditis, hypertrophic cardiomyopathy, amyloidosis, sarcoidosis, and Chagas disease.

Dr. Kramer noted that echocardiography is useful in several circumstances, especially for diastolic function and when “quick and easy” is adequate, but CMR is best for regional systolic function, for differential diagnosis and tissue characterization, and when quantitation is needed and 3-D echo is unavailable.

SAN FRANCISCO — Cardiac MRI with late gadolinium enhancement is the imaging technique of choice when the goal is tissue characterization and infarct detection in heart failure, Dr. Christopher M. Kramer said at a cardiovascular imaging conference sponsored by the American College of Cardiology.

Cardiac magnetic resonance (CMR) provides outstanding image quality, excellent quantification, and tissue characterization, said Dr. Kramer of the University of Virginia, in Charlottesville. In addition, Gadolinium contrast is easy to use and safe with CMR and also offers the ability to assess intramural function.

However, CMR devices are not portable, are quite expensive, and are not readily available. Physicians need to have extensive training in the use of CMR and the technique is not suitable for patients with implanted metallic devices such as pacemakers and implantable cardioverter defibrillators. Furthermore, assessment of diastolic function is not routine with CMR.

Echocardiography also has a number of advantages. The devices are portable and relatively inexpensive, and they are readily available. Generations of cardiologists have established its validity and all cardiologists become proficient in the use of echo during their training. Contrast can be added to echocardiography, and the assessment of diastolic function has become routine.

But the technique is subject to variable image quality and poor windows. The results tend to be qualitative, and quantitation can be difficult. Newer 3-D echocardiographic techniques address some of these issues, but such devices are not widely available.

Gadolinium-enhanced CMR is useful in determining if cardiomyopathy is ischemic or nonischemic. Studies have also shown the value of enhanced CMR as a marker in late-stage myocarditis, hypertrophic cardiomyopathy, amyloidosis, sarcoidosis, and Chagas disease.

Dr. Kramer noted that echocardiography is useful in several circumstances, especially for diastolic function and when “quick and easy” is adequate, but CMR is best for regional systolic function, for differential diagnosis and tissue characterization, and when quantitation is needed and 3-D echo is unavailable.

Men and women who smoke as few as 1–4 cigarettes daily have a significantly increased risk of dying from ischemic heart disease and from all causes, according to a very large prospective study by Kjell Bjartveit, M.D., of the National Health Screening Service in Oslo, and a colleague.

Furthermore, the study, which followed 23,521 men and 19,201 women for more than 10 years, determined that women who are light smokers have an increased risk of lung cancer (Tobacco Control 2005;14:315–20).

After controlling for age, systolic blood pressure, total serum cholesterol, serum triglycerides, physical activity, body mass index, and height, the investigators calculated that light smokers had about a 50% increased risk of dying from all causes, compared with nonsmokers—a statistically significant increase in risk.

There was a clear dose-response relationship between daily cigarette consumption and adverse health outcomes. For example, men who smoked 20–24 cigarettes daily—not light smokers—had more than three times the risk of dying from all causes than nonsmokers.

Previous studies demonstrated similar dose-response curves, but in most, the lowest consumption group was set at 1–9 or 1–15 cigarettes daily. This allowed the Norwegian tobacco industry to suggest that there was a threshold level of smoking for which there were no health risks.

Participants in the study, who were residents of Oslo or one of three rural counties in Norway, were 35–49 years old when they were enrolled, between 1972 and 1978.

The investigators concluded that policymakers and health educators should emphasize more strongly that light smokers are endangering their health.

Men and women who smoke as few as 1–4 cigarettes daily have a significantly increased risk of dying from ischemic heart disease and from all causes, according to a very large prospective study by Kjell Bjartveit, M.D., of the National Health Screening Service in Oslo, and a colleague.

Furthermore, the study, which followed 23,521 men and 19,201 women for more than 10 years, determined that women who are light smokers have an increased risk of lung cancer (Tobacco Control 2005;14:315–20).

After controlling for age, systolic blood pressure, total serum cholesterol, serum triglycerides, physical activity, body mass index, and height, the investigators calculated that light smokers had about a 50% increased risk of dying from all causes, compared with nonsmokers—a statistically significant increase in risk.

There was a clear dose-response relationship between daily cigarette consumption and adverse health outcomes. For example, men who smoked 20–24 cigarettes daily—not light smokers—had more than three times the risk of dying from all causes than nonsmokers.

Previous studies demonstrated similar dose-response curves, but in most, the lowest consumption group was set at 1–9 or 1–15 cigarettes daily. This allowed the Norwegian tobacco industry to suggest that there was a threshold level of smoking for which there were no health risks.

Participants in the study, who were residents of Oslo or one of three rural counties in Norway, were 35–49 years old when they were enrolled, between 1972 and 1978.

The investigators concluded that policymakers and health educators should emphasize more strongly that light smokers are endangering their health.

Men and women who smoke as few as 1–4 cigarettes daily have a significantly increased risk of dying from ischemic heart disease and from all causes, according to a very large prospective study by Kjell Bjartveit, M.D., of the National Health Screening Service in Oslo, and a colleague.

Furthermore, the study, which followed 23,521 men and 19,201 women for more than 10 years, determined that women who are light smokers have an increased risk of lung cancer (Tobacco Control 2005;14:315–20).

After controlling for age, systolic blood pressure, total serum cholesterol, serum triglycerides, physical activity, body mass index, and height, the investigators calculated that light smokers had about a 50% increased risk of dying from all causes, compared with nonsmokers—a statistically significant increase in risk.

There was a clear dose-response relationship between daily cigarette consumption and adverse health outcomes. For example, men who smoked 20–24 cigarettes daily—not light smokers—had more than three times the risk of dying from all causes than nonsmokers.

Previous studies demonstrated similar dose-response curves, but in most, the lowest consumption group was set at 1–9 or 1–15 cigarettes daily. This allowed the Norwegian tobacco industry to suggest that there was a threshold level of smoking for which there were no health risks.

Participants in the study, who were residents of Oslo or one of three rural counties in Norway, were 35–49 years old when they were enrolled, between 1972 and 1978.

The investigators concluded that policymakers and health educators should emphasize more strongly that light smokers are endangering their health.

BLAINE, WASH. — Topical retinoids can be highly effective treatments for acne; however, they come in a bewilderingly wide variety of strengths and formulations.

Clinicians should consider effectiveness, tolerability, and the type of vehicle that would be best for an individual patient in making the choice, Robert Sidbury, M.D., said at a conference sponsored by the North Pacific Pediatric Society.

Physicians must choose among adapalene (Differin) 0.1%, which comes formulated as a gel, a cream, a solution, and as pledgets; tretinoin (Retin-A), which comes in four strengths between 0.01% and 0.1% as a cream and 0.01% and 0.025% as a gel; tretinoin micro (Retin-A Micro) gel, which comes in 0.04% and 0.1% strengths; and tazarotene (Tazorac), which comes as a gel and as a cream in 0.05% and 0.1% strengths.

Adapalene is at the top of the tolerability list, said Dr. Sidbury of the University of Washington in Seattle. Tretinoin micro comes next, followed by tretinoin. Tazarotene is the least tolerable of the retinoids.

Unfortunately, the least tolerable topical retinoid is the most effective, and the most tolerable is the least effective. Those patients who are able to tolerate tazarotene are likely to find that it works better for them than do the alternatives.

Retinoids that are formulated in creams tend to be better tolerated—but less effective in equal strengths—than those formulated in gels, Dr. Sidbury said.

There are things patients can do and things physicians can do to optimize success with topical retinoids, he said. Although all these products are intended to be used daily, patients who are particularly sensitive can apply them every other day or even just twice a week to start.

Retinoids thin the stratum corneum, and this presents as dryness, itchiness, and desquamation. However, the stratum corneum regenerates even as the patient continues to use the retinoids, so tolerability should improve with continued use.

Patients should apply topical retinoids very sparingly. A pea-sized dollop on a fingertip is enough to cover the entire acne-prone “T zone” of the face, said Dr. Sidbury.

And the physician should counsel patience, because it can take quite a long time for the patient to see improvement.

Physicians can help by matching the vehicle to the patient's skin type. Patients with oily skin will do better with a gel, whereas patients with dry skin will do better with a cream. One should start with products at the top of the tolerability scale for patients with sensitive skin, but go with something stronger in patients whose skin is not quite as sensitive, Dr. Sidbury advised.

BLAINE, WASH. — Topical retinoids can be highly effective treatments for acne; however, they come in a bewilderingly wide variety of strengths and formulations.

Clinicians should consider effectiveness, tolerability, and the type of vehicle that would be best for an individual patient in making the choice, Robert Sidbury, M.D., said at a conference sponsored by the North Pacific Pediatric Society.

Physicians must choose among adapalene (Differin) 0.1%, which comes formulated as a gel, a cream, a solution, and as pledgets; tretinoin (Retin-A), which comes in four strengths between 0.01% and 0.1% as a cream and 0.01% and 0.025% as a gel; tretinoin micro (Retin-A Micro) gel, which comes in 0.04% and 0.1% strengths; and tazarotene (Tazorac), which comes as a gel and as a cream in 0.05% and 0.1% strengths.

Adapalene is at the top of the tolerability list, said Dr. Sidbury of the University of Washington in Seattle. Tretinoin micro comes next, followed by tretinoin. Tazarotene is the least tolerable of the retinoids.

Unfortunately, the least tolerable topical retinoid is the most effective, and the most tolerable is the least effective. Those patients who are able to tolerate tazarotene are likely to find that it works better for them than do the alternatives.

Retinoids that are formulated in creams tend to be better tolerated—but less effective in equal strengths—than those formulated in gels, Dr. Sidbury said.

There are things patients can do and things physicians can do to optimize success with topical retinoids, he said. Although all these products are intended to be used daily, patients who are particularly sensitive can apply them every other day or even just twice a week to start.

Retinoids thin the stratum corneum, and this presents as dryness, itchiness, and desquamation. However, the stratum corneum regenerates even as the patient continues to use the retinoids, so tolerability should improve with continued use.

Patients should apply topical retinoids very sparingly. A pea-sized dollop on a fingertip is enough to cover the entire acne-prone “T zone” of the face, said Dr. Sidbury.

And the physician should counsel patience, because it can take quite a long time for the patient to see improvement.

Physicians can help by matching the vehicle to the patient's skin type. Patients with oily skin will do better with a gel, whereas patients with dry skin will do better with a cream. One should start with products at the top of the tolerability scale for patients with sensitive skin, but go with something stronger in patients whose skin is not quite as sensitive, Dr. Sidbury advised.

BLAINE, WASH. — Topical retinoids can be highly effective treatments for acne; however, they come in a bewilderingly wide variety of strengths and formulations.

Clinicians should consider effectiveness, tolerability, and the type of vehicle that would be best for an individual patient in making the choice, Robert Sidbury, M.D., said at a conference sponsored by the North Pacific Pediatric Society.

Physicians must choose among adapalene (Differin) 0.1%, which comes formulated as a gel, a cream, a solution, and as pledgets; tretinoin (Retin-A), which comes in four strengths between 0.01% and 0.1% as a cream and 0.01% and 0.025% as a gel; tretinoin micro (Retin-A Micro) gel, which comes in 0.04% and 0.1% strengths; and tazarotene (Tazorac), which comes as a gel and as a cream in 0.05% and 0.1% strengths.

Adapalene is at the top of the tolerability list, said Dr. Sidbury of the University of Washington in Seattle. Tretinoin micro comes next, followed by tretinoin. Tazarotene is the least tolerable of the retinoids.

Unfortunately, the least tolerable topical retinoid is the most effective, and the most tolerable is the least effective. Those patients who are able to tolerate tazarotene are likely to find that it works better for them than do the alternatives.

Retinoids that are formulated in creams tend to be better tolerated—but less effective in equal strengths—than those formulated in gels, Dr. Sidbury said.

There are things patients can do and things physicians can do to optimize success with topical retinoids, he said. Although all these products are intended to be used daily, patients who are particularly sensitive can apply them every other day or even just twice a week to start.

Retinoids thin the stratum corneum, and this presents as dryness, itchiness, and desquamation. However, the stratum corneum regenerates even as the patient continues to use the retinoids, so tolerability should improve with continued use.

Patients should apply topical retinoids very sparingly. A pea-sized dollop on a fingertip is enough to cover the entire acne-prone “T zone” of the face, said Dr. Sidbury.

And the physician should counsel patience, because it can take quite a long time for the patient to see improvement.

Physicians can help by matching the vehicle to the patient's skin type. Patients with oily skin will do better with a gel, whereas patients with dry skin will do better with a cream. One should start with products at the top of the tolerability scale for patients with sensitive skin, but go with something stronger in patients whose skin is not quite as sensitive, Dr. Sidbury advised.