Not sure why trials were never taken further, as sounded promising...
Diagnosing and treating HIV dementia.
Many studies have shown that brain infections occur early in HIV infection, usually within weeks of seroconversion. Asymptomatic seropositive persons frequently show HIV in the brain and spinal fluid. The most common presenting symptoms are memory loss, walking difficulties, mental slowing, and depressive symptoms. In patients with localized abnormalities, such as weakness, another opportunistic infection should be suspected. Most patients with HIV dementia have clear psychomotor slowing, greater than normal reflexes, and signs indicating widespread brain dysfunction. As the dementia progresses, patients develop language and attention problems, apathy, severe psychomotor slowing, and lack of insight. Delirium is a frequent side effect of the medicines used to treat dementia. Diagnosis is fairly simple, with MRI being used to rule out CMV, progressive multifocal leukoencephalopathy, and herpes. AZT and antiretrovirals offer protective effects to delay the onset and progression of AIDS dementia. The AIDS Clinical Trials Group has completed a study showing that nimodipine, a calcium-channel blocker, can lessen damage to the brain, and is safe and generally well tolerated. Combination therapies, such as antiretrovirals with cytokine blockers, will probably emerge as the treatment of choice for dementia. Posit Aware. 1996 Mar-Apr;7(2):10-1.McArthur JC. Johns Hopkins University, Baltimore, MD.
A phase I/II trial of nimodipine for HIV-related neurologic complications.
BACKGROUND: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. METHODS: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg p.o., five times daily; 30 mg p.o., three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. RESULTS: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. CONCLUSIONS: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted. Publication Types PMID: 9674806 Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA. Tufts Neurology Program and Department of Psychiatry, Tufts University School of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Neurology. 1998 Jul;51(1):221-8.
AIDS-related dementia and calcium homeostasis.
Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future. PMID: 7847672 Ann N Y Acad Sci. 1994 Dec 15;747:205-24. Lipton SA. Department of Neurology, Children's Hospital, Boston, Massachusets.
Diagnosing and treating HIV dementia.
Many studies have shown that brain infections occur early in HIV infection, usually within weeks of seroconversion. Asymptomatic seropositive persons frequently show HIV in the brain and spinal fluid. The most common presenting symptoms are memory loss, walking difficulties, mental slowing, and depressive symptoms. In patients with localized abnormalities, such as weakness, another opportunistic infection should be suspected. Most patients with HIV dementia have clear psychomotor slowing, greater than normal reflexes, and signs indicating widespread brain dysfunction. As the dementia progresses, patients develop language and attention problems, apathy, severe psychomotor slowing, and lack of insight. Delirium is a frequent side effect of the medicines used to treat dementia. Diagnosis is fairly simple, with MRI being used to rule out CMV, progressive multifocal leukoencephalopathy, and herpes. AZT and antiretrovirals offer protective effects to delay the onset and progression of AIDS dementia. The AIDS Clinical Trials Group has completed a study showing that nimodipine, a calcium-channel blocker, can lessen damage to the brain, and is safe and generally well tolerated. Combination therapies, such as antiretrovirals with cytokine blockers, will probably emerge as the treatment of choice for dementia. Posit Aware. 1996 Mar-Apr;7(2):10-1.McArthur JC. Johns Hopkins University, Baltimore, MD.
A phase I/II trial of nimodipine for HIV-related neurologic complications.
BACKGROUND: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. METHODS: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg p.o., five times daily; 30 mg p.o., three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. RESULTS: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. CONCLUSIONS: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted. Publication Types PMID: 9674806 Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA. Tufts Neurology Program and Department of Psychiatry, Tufts University School of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Neurology. 1998 Jul;51(1):221-8.
AIDS-related dementia and calcium homeostasis.
Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future. PMID: 7847672 Ann N Y Acad Sci. 1994 Dec 15;747:205-24. Lipton SA. Department of Neurology, Children's Hospital, Boston, Massachusets.
