Dawn McGuire

Unique monocyte subset in patients with AIDS dementia

BACKGROUND 15-30% of patients infected with HIV will develop a debilitating dementia. Whilst HIV enters the brain soon after infection, presumably within monocyte-derived macrophages, not all patients with HIV become demented. Blood monocytes probably cross the blood-brain barrier and give rise ultimately to parenchyma macrophages. We looked for a specific monocyte subset in AIDS patients with dementia. METHODS Peripheral blood monocytes from three groups were compared: AIDS patients with (n = 12) and without (n = 11) dementia, and ten HIV seronegative healthy controls. We used flow cytometry to analyse monocytes, and cell lysis and apoptosis assays to examine monocyte effects on human brain cells in vitro. FINDINGS We found a unique subset of monocytes in patients with AIDS dementia. These monocytes were more dense and granular and expressed CD14/CD16 and CD14/CD69. Means (SD) for CD14/CD16 in HIV-negative controls and in AIDS non-dementia and AIDS dementia patients were 6.5% (4), 16% (13), and 37% (21), respectively (p = 0.008 between the two groups of patients). The corresponding means for CD14/CD69 were 7% (6), 8% (10), and 69% (18) (p < 0.0001). INTERPRETATION CD69 is a member of the natural-killer-cell gene complex that is expressed after activation. Supernatants from cultures containing these dense cells can trigger apoptosis of human brain cells in vitro. The monocyte subset we found in patients with AIDS dementia might enter the brain and expose neural cells to toxic factors.

Alzheimer's disease, normal‐pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis

There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-beta peptide (Abeta) from the interstitial-fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimers disease (AD) or as normal-pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Abeta in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Abeta. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH-AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.

The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects

OBJECTIVE Acute renal failure, frequently a consequence of renal vasoconstriction and subsequent renal ischemia, is a common problem for which no proven preventive or therapeutic agents exist. Fenoldopam is a new, selective, dopamine-1 receptor agonist that causes both systemic and renal arteriolar vasodilation. In hypertensive patients, fenoldopam rapidly decreases blood pressure, increases renal blood flow, and maintains or improves the glomerular filtration rate. We sought to determine a dose of fenoldopam that increases renal blood flow without inducing hypotension in normotensive patients and to explore the role of volume status (sodium replete vs. deplete) in these effects. DESIGN Randomized, double-blind, placebo-controlled, cross-over study. SETTING Clinical research unit. PATIENTS Fourteen normal male volunteers. INTERVENTIONS Renal plasma flow (para-aminohippurate clearance) and glomerular filtration rate (inulin clearance) were measured during three fixed, escalating doses of fenoldopam (0.03, 0.1, and 0.3 Lg/kg/min) on both a high-sodium and a low-sodium diet. MEASUREMENTS AND MAIN RESULTS Fenoldopam significantly increased renal plasma flow in a dose-dependent manner compared with placebo: 670 + 148 vs. 576 + 85 mUmin at 0.03 iLg/kg/min; 777 + 172 vs. 579 + 80 mUmin at 0.1 tig/kg/min; and 784 + 170 vs. 592 + 165 mUmin at 0.3 ilg/kg/min (p < .05 fenoldopam vs. placebo at all three doses). Glomerular filtration rate was maintained. At the lowest dose (i.e., 0.03 ILg/kg/min), significant renal blood flow increases occurred without changes in systemic blood pressure or heart rate. At 0.1 and 0.3 Lgl/kg/ min, systolic blood pressure did not change, but diastolic blood pressure was slightly lower in the fenoldopam group than in the placebo group: 62.5 + 6.4 vs. 63.6 + 2.6 mm Hg, respectively, at 0.3 tg/kg/min (p < .05). None of the effects of fenoldopam were altered by volume status. CONCLUSIONS Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial

Objective.  The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial.

Ziconotide, a new n-type calcium channel blocker, administered intrathecally for acute postoperative pain

Background and Objectives: Voltage‐sensitive calcium channel conductance is essential for the nervous system to signal a painful event. However, intrathecal administration of L‐type calcium channel blockers does not provide analgesia. The present investigation was designed to assess the safety and analgesic efficacy of ziconotide, a new N‐type calcium channel blocker, when administered intrathecally to patients with acute postoperative pain. Methods: This randomized, double‐blind, pilot study included patients undergoing elective total abdominal hysterectomy, radical prostatectomy, or total hip replacement. After intrathecal injection of local anesthetic and before surgical incision, a continuous intrathecal infusion of either placebo or 1 of 2 doses of ziconotide (0.7 μg/h or 7.0 μg/h) was started and continued for 48 to 72 hours postoperatively. Primary and secondary efficacy variables were the mean daily patient controlled analgesia (PCA) morphine equivalent consumption and visual analog pain intensity (VASPI) scores, respectively. Results: Thirty patients received study drug; 26 were evaluable for efficacy. Mean daily PCA morphine equivalent consumption was less in patients receiving ziconotide than in placebo‐treated patients, and the difference was statistically significant between 24 and 48 hours (P = .040). VASPI scores during the first 8 hours postoperatively were markedly lower in ziconotide‐treated than in placebo‐treated patients. In 4 of 6 patients receiving the high‐dose of ziconotide (7 μg/h), adverse events, such as dizziness, blurred vision, nystagmus, and sedation contributed to study drug being discontinued after 24 hours. After ziconotide discontinuation, these symptoms resolved. Conclusions: Ziconotide showed analgesic activity, as shown by decreased PCA morphine equivalent consumption and lower VASPI scores. Because of a favorable trend of decreased morphine consumption with an acceptable side‐effect profile in the low‐dose ziconotide group, 0.7 μg/h may be closer to the ideal dose than 7 μg/h. Large‐scale studies are required to clarify this issue.

Assessment of low-flow CSF drainage as a treatment for AD: Results of a randomized pilot study

Objective: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. Methods: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Aβ(1-42) assays at the same time intervals. Results: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group (p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment (p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Aβ(1-42). Conclusions: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade : First demonstration of N-channel function in humans

SNX-111 is the first neuronal N-type, voltage-sensitive calcium channel (VSCC) blocker to enter clinical drug development. Areas of potential therapeutic utility include treatment of nociceptive and neuropathic pain and neuroprotection after ischemic brain injury. The data presented demonstrate that SNX-111 is biologically active in humans and indicate for the first time a neurophysiologic function of N-type VSCCs in humans.

Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.

The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48‐hour period following intrathecal (IT) administration (1, 5, 7.5, or 10 μg) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24‐hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half‐life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose‐related analgesia was observed. Pharmacokinetic‐pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1‐hour IT infusion.

Continuous CSF drainage in AD Results of a double-blind, randomized, placebo-controlled study

Background: Alzheimer disease (AD) has been associated with abnormal cerebral clearance of macromolecules, such as amyloid and microtubule-associated-protein tau (MAP-τ). We hypothesized that improving clearance of macromolecules from the CNS might slow the progression of dementia. Objective: This prospective, randomized, double-blinded, placebo-controlled trial evaluated the safety and effectiveness of a surgically implanted shunt in subjects with probable AD. Methods: A total of 215 subjects with probable AD by National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria received either a low-flow ventriculoperitoneal shunt or a sham (occluded) shunt for 9 months. Longitudinal CSF sampling was performed in both active and control subjects. Primary outcome measures were the Mattis Dementia Rating Scale and the Global Deterioration Scale. CSF Aβ(1-42) and MAP-τ also were assayed. Results: After a planned interim analysis, the study was halted for futility. Using the intent-to-treat population, no between-group differences were observed in the primary outcome measures. The surgical procedure and device were associated with 12 CNS infections, some temporally associated with CSF sampling. All were treated successfully. Conclusions: We found no benefit to low-flow CSF shunting in subjects with mild to severe Alzheimer disease. CSF infections, while treatable, occurred more frequently than expected, in some cases likely related to CSF sampling. GLOSSARY: Aβ = amyloid beta-peptides; AD = Alzheimer disease; ADCS-ADL = AD Cooperative Study Activities of Daily Living; BBB = blood–brain barrier; CP = choroid plexus; FDA = Food and Drug Administration; GDS = Global Deterioration Scale; GEE = Generalized Estimating Equations; IA = interim analysis; ISF = interstitial fluid; ITT = intent-to-treat; LRP-1 = lipoprotein receptor-related protein-1; MAP-τ = microtubule-associated-protein tau; MDRS = Mattis Dementia Rating Scale; MMSE = Mini-Mental State Examination; NAART = North American Adult Reading Test; NINCDS-ADRDA = National Institutes of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Disorders Association; NPH = normal-pressure hydrocephalus; PHF = perihippocampal fissures; RAGE = receptor for advanced glycation end-products; SADAS-Cog = Standardized AD Assessment Scale–Cognitive; SAE = serious adverse events.

Continuous Intrathecal Infusion of Ziconotide for Treatment of Chronic Malignant and Nonmalignant Pain Over 12 Months: A Prospective, Open-label Study

Objectives.  This study aims to assess the safety and efficacy of long‐term intrathecal (IT) ziconotide infusion.