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Nerve growth factor promising in diabetic neuropathy
SCIENCE AND MEDICINE
NEWS Nerve growth factor promising in diabetic neuropathy esults from the first randomised trial of recombinant human nerve growth factor (rhNGF) in diabetic neuropathy suggest that the therapy is safe and may prevent onset and progression of neuropathy, says lead author Stuart Apfel (Albert Einstein College of Medicine, New York, NY, USA). “Our results are very exciting because right now we only have palliative treatment—nothing to help the nerves become more resistant to injury and function better”. But, warns Apfel, everything will depend
on the results of European and US phase III trials now underway. In the US phase II study, 250 patients with symptomatic diabetic neuropathy received either placebo or rhNGF 0·1 g/kg or 0·3 g/kg three times a week for 6 months via selfadministered subcutaneous injection. Improved response to heat and cold, and trends toward improvement in other sensations, were seen in treated patients. 75% of patients given rhNGF but only 49% patients given placebo reported symptom improvement, suggesting “a beneficial . . . and in HIV-1-related neuropathy effect of rhNGF overall”. The In the first use of rhNGF in HIV-1-infected authors acknowledge, however, a patients, 271 patients with neuropathy major drawback in their study, received 0·1 or 0·3 g/kg rhNGF or namely, that it became unblinded placebo two times a week for 18 weeks. because of injection site reacPatients noted a decrease in pain intensity, tions. This led most patients— and neurological tests showed improved and the investigators examining sensation, reported Justin McArthur (Johns them—to correctly guess who Hopkins University, Baltimore, MD, USA) was receiving rhNGF (Neurology earlier this year at the Geneva AIDS 1998; 51: 695–702). Conference. “The study was a full The unblinding problem is success”, comments Al Kerza, head of the being dealt with in the phase III US National Institutes of Health consortium trials “by making the placebo a that funded the phase II trial. “We’re hypertonic solution, so you have pleased Genentech has picked up it up and injection site tenderness in all is running with it.” patients”, explains Apfel. In the US phase III trial, 500 patients
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are receiving placebo and 500 rhNGF 0·1 g/kg three times a week. In the European trial, 500 patients are receiving placebo, 500 are taking 0·3 g/kg rhNGF once a week, and 500 are taking 0·1 g/kg three times a week. Results from these trials are expected by mid-1999. But does rhNGF provide benefits in addition “to those achieved by rigorous control of a patient’s hyperglycaemia”, asks an editorial? “In theory, it should do”, says Apfel. “There are tremendous advantages to tight control, but it’s probably not the entire answer. And tight control is very difficult to achieve. For many patients it’s not a realistic option.” Patients with earlier, less severe neuropathy seem to respond more strikingly and more quickly to rhNGF, notes Apfel. The drug will, therefore, be most likely to be used “with patients who are beginning to present with signs and symptoms, such as loss of reflexes and vibratory sensation in the feet”. Physicians “would need to be more attentive to these signs, which right now are often overlooked”, he warns. Marilynn Larkin
Green coffee beans may yield new class of anti-HIV-1 agents
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esearchers from the University of California, Irvine (CA, USA) report that chicoric acid extracted from green coffee beans inhibits HIV-1 replication in CD4 T cells by inhibiting HIV-1 integrase, one of three enzymes needed for HIV-1 infection of healthy cells (J Virol 1998; 72: 8420–24). Cocktails of drugs acting against two viral enzymes—HIV-1 protease and HIV-1 reverse transcriptase— are currently the most effective way to combat AIDS. But these mixtures are cytotoxic and have unpleasant side-effects. “With the eventual addition of chemicals that inhibit the integrase, we can attack the three main enzymes used by HIV-1 to spread throughout the body”, says researcher Peter King.
THE LANCET • Vol 352 • September 26, 1998
“Chicoric acid can inhibit HIV-1 integrase at doses that are not toxic to cells”, adds co-author Edward Robinson. “And, if chicoric acid is effective, it could benefit HIV-1 therapy without adding more toxic chemicals to the cocktails”, although a more potent chemical that acts like chicoric acid may need to be made. In selection experiments, a single aminoacid mutation in HIV-1 integrase conferred resistance to chicoric acid. For this reason, chicoric acid and other integrase inhibitors may have to be used in combination with other anti-HIV-1 agents. Extracts of green coffee beans have been used for more than 1500 years by Bolivian shamans to treat
fungal infections, cancer, and liver disorders. “Many plants and plant constituents have antiviral activity”, notes Edzard Ernst (Exeter University, UK). “The results with chicoric acid are encouraging, but whether they will lead to a clinically useful drug remains to be seen.” Dorothy Bonn
1039
NEWS Nerve growth factor promising in diabetic neuropathy esults from the first randomised trial of recombinant human nerve growth factor (rhNGF) in diabetic neuropathy suggest that the therapy is safe and may prevent onset and progression of neuropathy, says lead author Stuart Apfel (Albert Einstein College of Medicine, New York, NY, USA). “Our results are very exciting because right now we only have palliative treatment—nothing to help the nerves become more resistant to injury and function better”. But, warns Apfel, everything will depend
on the results of European and US phase III trials now underway. In the US phase II study, 250 patients with symptomatic diabetic neuropathy received either placebo or rhNGF 0·1 g/kg or 0·3 g/kg three times a week for 6 months via selfadministered subcutaneous injection. Improved response to heat and cold, and trends toward improvement in other sensations, were seen in treated patients. 75% of patients given rhNGF but only 49% patients given placebo reported symptom improvement, suggesting “a beneficial . . . and in HIV-1-related neuropathy effect of rhNGF overall”. The In the first use of rhNGF in HIV-1-infected authors acknowledge, however, a patients, 271 patients with neuropathy major drawback in their study, received 0·1 or 0·3 g/kg rhNGF or namely, that it became unblinded placebo two times a week for 18 weeks. because of injection site reacPatients noted a decrease in pain intensity, tions. This led most patients— and neurological tests showed improved and the investigators examining sensation, reported Justin McArthur (Johns them—to correctly guess who Hopkins University, Baltimore, MD, USA) was receiving rhNGF (Neurology earlier this year at the Geneva AIDS 1998; 51: 695–702). Conference. “The study was a full The unblinding problem is success”, comments Al Kerza, head of the being dealt with in the phase III US National Institutes of Health consortium trials “by making the placebo a that funded the phase II trial. “We’re hypertonic solution, so you have pleased Genentech has picked up it up and injection site tenderness in all is running with it.” patients”, explains Apfel. In the US phase III trial, 500 patients
R
are receiving placebo and 500 rhNGF 0·1 g/kg three times a week. In the European trial, 500 patients are receiving placebo, 500 are taking 0·3 g/kg rhNGF once a week, and 500 are taking 0·1 g/kg three times a week. Results from these trials are expected by mid-1999. But does rhNGF provide benefits in addition “to those achieved by rigorous control of a patient’s hyperglycaemia”, asks an editorial? “In theory, it should do”, says Apfel. “There are tremendous advantages to tight control, but it’s probably not the entire answer. And tight control is very difficult to achieve. For many patients it’s not a realistic option.” Patients with earlier, less severe neuropathy seem to respond more strikingly and more quickly to rhNGF, notes Apfel. The drug will, therefore, be most likely to be used “with patients who are beginning to present with signs and symptoms, such as loss of reflexes and vibratory sensation in the feet”. Physicians “would need to be more attentive to these signs, which right now are often overlooked”, he warns. Marilynn Larkin
Green coffee beans may yield new class of anti-HIV-1 agents
R
esearchers from the University of California, Irvine (CA, USA) report that chicoric acid extracted from green coffee beans inhibits HIV-1 replication in CD4 T cells by inhibiting HIV-1 integrase, one of three enzymes needed for HIV-1 infection of healthy cells (J Virol 1998; 72: 8420–24). Cocktails of drugs acting against two viral enzymes—HIV-1 protease and HIV-1 reverse transcriptase— are currently the most effective way to combat AIDS. But these mixtures are cytotoxic and have unpleasant side-effects. “With the eventual addition of chemicals that inhibit the integrase, we can attack the three main enzymes used by HIV-1 to spread throughout the body”, says researcher Peter King.
THE LANCET • Vol 352 • September 26, 1998
“Chicoric acid can inhibit HIV-1 integrase at doses that are not toxic to cells”, adds co-author Edward Robinson. “And, if chicoric acid is effective, it could benefit HIV-1 therapy without adding more toxic chemicals to the cocktails”, although a more potent chemical that acts like chicoric acid may need to be made. In selection experiments, a single aminoacid mutation in HIV-1 integrase conferred resistance to chicoric acid. For this reason, chicoric acid and other integrase inhibitors may have to be used in combination with other anti-HIV-1 agents. Extracts of green coffee beans have been used for more than 1500 years by Bolivian shamans to treat
fungal infections, cancer, and liver disorders. “Many plants and plant constituents have antiviral activity”, notes Edzard Ernst (Exeter University, UK). “The results with chicoric acid are encouraging, but whether they will lead to a clinically useful drug remains to be seen.” Dorothy Bonn
1039