Neuroinflammation, its Role in Alzheimer's Disease and Therapeutic Strategie.

Neuroinflammation precedes the clinical onset of various neurodegenerative diseases, including Alzheimer's disease (AD), by years or frequently even decades (1-3). In terms of the underlying physiology, there is a great need for understanding and controlling interactions between the central nervous system (CNS) and the immune system in an attempt to develop approaches to prevent or delay the disease's progression. Nerve cells have limited motion capability, whereas immune cells can migrate freely via circulation. This difference raises a variety of questions in the context of senile plaque formation and phagocytosis. Broad-scale unbiased genomic studies bring several genetic variants such as sialic acid binding Ig-like lectin 3 (CD33), triggering receptor expressed on myeloid cells 2 (TREM2) or complement receptor type 1 (CR1) into the focus of researchers' attention as potential risk factors for neuroinflammation. In addition, advanced proteomic analyses have been revealing links between these genetic contributors and complex, malfunctioning signaling pathways (including the upregulation of factors like tumor necrosis factor TNF-α, tumor growth factor TGF-ß and interleukin IL-1α) that promote proinflammatory mechanisms via intracellular signaling and trafficking, synaptic function, and cell metabolism/ proliferation. In AD, the brain's microglia and astrocytes, which are normally responsible for maintaining the homeostasis of synaptic transmission and its remodeling by pruning, are the initiators of neuroinflammation and toxic tau and amyloid-ß (Aß) accumulation. Thus, they drive the CNS into a state of sustained or even self-accelerated deterioration. Here we aim to review the cell types and mediators involved in neuroinflammation and AD, the symptom manifestation in clinical settings, and potential candidates for improving diagnosis and treatment.

Inflammation: planning for a source of pharmacokinetic/pharmacodynamic variability in translational studies.

The impact of inflammation on variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs should be considered in the design, analysis, and interpretation of clinical pharmacology studies. Data suggest that the metabolism and transport of drugs, as well as the expression of receptors, may change in the presence of inflammation. The clinical implications of these changes are not straightforward; they may vary depending on whether the inflammation is active or controlled and may change with time and successful treatment of the inflammation.

Effects of inflammation on pharmacokinetics/pharmacodynamics: increasing recognition of its contribution to variability in response.

Inflammation is an interesting phenomenon that crosses many disciplines as part of the host response to disease, whether it is the acute response to an infectious, traumatic, or surgical event or the more chronic responses to systemic disease such as malignancy, rheumatoid arthritis, asthma, inflammatory bowel disease, or diabetes. The impact of inflammatory states on the variability in drug response should be an integral part of research conducted across disciplines within clinical pharmacology.

Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.

Alvimopan, a mu-opioid antagonist without anti-analgesic effects, is being developed to manage postoperative ileus. We characterized the population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

Pharmacokinetic profile of epidurally administered methylnaltrexone, a novel peripheral opioid antagonist in a rabbit model.

Methylnaltrexone (MNTX) is the first peripheral opioid receptor antagonist used in man to treat acute and chronic opiate-mediated side-effects. We describe in a rabbit model the pharmacokinetics of epidurally administered MNTX 0.66 mg kg(-1), and we tested the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space. There were minimal concentrations of MNTX (40 ng ml(-1)) detected in the CSF at 10 and 20 min and none thereafter in comparison with the high serum levels. The serum drug concentration-time profile fitted a two-compartment pharmacokinetic model. Further studies are warranted as epidurally administered MNTX may have the potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.

Economics of preoperative evaluation clinics.

Studies continue to support that a process for screening patients prior to their planned anesthesia and surgery can optimize both the status of the patient, decreasing delays and cancellations, and optimize the use of resources, ensuring that needed testing is completed and unneeded testing is avoided.

A review of the potential role of methylnaltrexone in opioid bowel dysfunction.

Opioids are widely used analgesics in patients with advanced cancer. However, their effectiveness for pain relief is often limited by the most frequently occurring side effect, opioid bowel dysfunction (OBD). Because conventional laxation measures are often ineffective in treating OBD, alternative approaches need to be investigated. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal (GI) tract rather than by those in the central nervous system (CNS). Opioid antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse analgesia or cause opioid withdrawal symptoms. Methylnaltrexone (MNTX) is a novel quaternary derivative of naltrexone that does not cross the blood-brain barrier and acts as a selective peripheral opioid receptor antagonist. In normal volunteers, intravenous or oral MNTX reverses opioid-induced reduction in bowel motility without affecting analgesia. Bioavailability of MNTX is low after oral administration, and plasma levels do not correlate with its actions in the gut, suggesting a predominantly local luminal action of MNTX on the gut. In patients receiving long-term opioid therapy, MNTX administered intravenously or orally was effective in reducing the delay in oral-cecal transit and eliciting laxation responses in all subjects without causing withdrawal symptoms. MNTX is a peripherally selective opioid antagonist that may have clinical utility in managing OBD with minimal adverse effects.

Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.

BACKGROUND: Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. METHODS: This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time. RESULTS: In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. CONCLUSION: Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.

CONTEXT: Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient. OBJECTIVE: To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation. DESIGN: Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998. SETTING: Clinical research center of a university hospital. PARTICIPANTS: Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation. MAIN OUTCOME MEASURES: Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups. RESULTS: The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study. CONCLUSIONS: Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

Gastric effects of methylnaltrexone on mu, kappa, and delta opioid agonists induced brainstem unitary responses.

In this study, we evaluated the gastric effects of methylnaltrexone, an opioid receptor antagonist that does not cross the blood-brain barrier in vivo, on mu, kappa and delta opioid agonists induced brainstem unitary responses in an in vitro neonatal rat brainstem-gastric preparation. Single units in the medial subnucleus of the nucleus tractus solitarius (NTS), responding to electrical stimulation of subdiaphragmatic vagal fibers, were recorded. Selective opioid receptor agonists and antagonists were applied only to the gastric compartment of the bath chamber and thus, the brainstem functions of the preparation were not affected by the drugs. The peripheral gastric effects of a mu opioid receptor agonist, DAMGO, and a kappa opioid receptor agonist, U-50,488H, were evaluated on 58 tonic units that received the subdiaphragmatic vagal inputs. For approximately 78% of the units observed, DAMGO (1.0 microM) and U-50,488H (1.0 microM) induced a concentration-dependent inhibition of 62.1+/-9.3% (mean +/- SE) and 49.2+/-6.5% of the control level of the NTS neuronal activity, respectively. Methylnaltrexone competitively antagonized the DAMGO-induced brainstem neuronal effects. Methylnaltrexone at an 18.8-fold higher concentration also reversed U-50,488H-induced NTS neuronal responses. Naloxone, a non-selective opioid receptor antagonist, reversed the inhibitory effects of DAMGO and U-50,488H at much lower concentrations (3.8% and 0.5%, respectively) compared to methylnaltrexone. Only 18% of the NTS neurons evaluated showed inhibitory responses to a delta receptor agonist, DPDPE, (19.7+/-5.0% at 10 microM), and this inhibition could not be reversed by methylnaltrexone in the concentration range we tested. In addition, when methylnaltrexone (1.0 microM) alone was applied to the gastric compartment, there was an activation (8.5+/-2.1%) of the NTS neurons receiving subdiaphragmatic vagal inputs, suggesting an endogenous gastric opioid action in the modulation of brainstem neuronal activities.

Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine.

Opioid compounds are commonly used analgesics. After opioid administration, troublesome subjective effects, such as dysphoria, dizziness, nausea, and pruritus, have been reported. While some if not all of these are believed to occur due to central nervous system effects of opioids, the anecdotal reports heard from volunteers in our other studies suggest that a peripheral opioid antagonist reduced some of these effects. In this double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone, a selective peripheral opioid receptor antagonist, to decrease subjective effects after administering morphine to normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on 'nauseous', 'skin itch', 'stimulated', and 'flushing'. Oral methylnaltrexone 19.2 mg/kg significantly decreased these four ratings. Plasma methylnaltrexone concentrations at two different oral doses were also measured to correlate between pharmacological effects of the compound and its plasma levels. Our results suggested that methylnaltrexone has a potential therapeutic value in decreasing some undesirable subjective effects associated with opioid medications.

Effects of low-dose morphine on gastric emptying in healthy volunteers.

Appropriate preoperative pain therapy for patients undergoing surgery may be withheld due to the fear that opioids will inhibit gastric emptying and increase the risk of aspiration. Previously, doses of 5 to 10 mg of morphine have been shown to delay gastric emptying time. However, the effect of lower doses of morphine on gastric emptying in humans has not been reported. In this study, the effects of intravenous morphine 0.05 mg/kg-3.5 mg for 70-kg body weight, a dose that can cause analgesia--on gastric emptying were evaluated in a double-blind, randomized, placebo-controlled study in 15 healthy human volunteers using the acetaminophen test. Our data indicated that this low dose of morphine significantly prolonged the gastric emptying time. Thus, even small doses of morphine inhibit gastric emptying. This effect may be important in patients undergoing surgery, in patients receiving other oral medications after surgery in ambulatory settings, and in instances of patient-controlled analgesia.

Gut motility and transit changes in patients receiving long-term methadone maintenance.

This study was conducted to survey gut motility and transit in 19 volunteers receiving methadone maintenance who were opioid-dependent, and to measure the oral-cecal transit time in these individuals using the lactulose hydrogen breath test. None of these patients reported constipation problems before use of illicit drugs. During current long-term methadone therapy, 58% of patients experienced some degree of constipation, and two of these 19 patients reported that constipation was a very serious problem. Mean +/- standard deviation (SD) oral-cecal transit time in these individuals was 159+/-49.2 minutes, which is significantly longer than the transit time recorded in two previous studies of healthy volunteers (P < 0.01). These results indicate that tolerance to opioids does not appear to extend to gastrointestinal motility and transit. It seems that patients receiving long-term methadone therapy are a good model for use in evaluating gastrointestinal effects of opioid antagonists.

Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine.

PURPOSE: Morphine can have either an emetic or an antiemetic effect. The emetic effect of morphine can be blocked by methylnaltrexone (MNTX), a quaternary opioid antagonist with peripheral action. In this study, we tested the hypothesis that administering MNTX to block the peripheral emetic effect of morphine would unmask the central antiemetic effect of the morphine. The net result, we hypothesized, would be a reduction in apomorphine- or cisplatin-induced emesis. METHODS: MNTX 0.25 mg/kg and morphine 1 mg/kg were administered to conscious dogs which were then challenged with the potent emetic agents apomorphine or cisplatin. Emesis was assessed by the presence of characteristic retching motions accompanied by the regurgitation of gastric contents. RESULTS: We observed that apomorphine challenges of 0.1 mg/kg and of 0.03 mg/kg produced 100% emesis in control animals. After pretreatment with MNTX and morphine, the frequency of emesis with the larger dose of apomorphine was reduced to 50% and with the smaller dose to 22%. MNTX alone did not block apomorphine-induced emesis. In animals challenged with cisplatin 3 mg/kg, the emetic response was 100%. Emesis did not occur in animals pretreated with MNTX 0.25 mg/kg and morphine 1 mg/kg before cisplatin. CONCLUSIONS: Our results demonstrate that MNTX combined with morphine reduces apomorphine-induced emesis and blocks cisplatin-induced emesis. These results support the hypothesis that the emetic effect of morphine is peripheral and its antiemetic action is central. In combination, MNTX and morphine may have a clinical role in the treatment of chemotherapy-induced emesis.

Dose-related effects of oral acetaminophen on cold-induced pain: a double-blind, randomized, placebo-controlled trial.

The cold-pressor test is a widely used pain-induction model in humans. This method has been shown to be a sensitive measure for detecting opioid analgesia. However, nonsteroidal anti-inflammatory drugs have not produced consistent analgesic effects with use of this model. The analgesic effect of acetaminophen (INN, paracetamol) on cold pressor-induced pain has not been reported by other investigators. In this study, a double-blind, randomized, placebo-controlled design was used to evaluate the dose-related effects of oral acetaminophen on cold pressor-induced pain in 18 normal healthy human subjects. We observed dose-related analgesic activity of oral acetaminophen using the cold pressor-induced pain model in these subjects. There were statistically significant main effects of both dose and time (pain and bothersomeness ratings decreased with increasing drug dose and increased over time). In pairwise comparisons only the contrast between the highest dose of acetaminophen (1000 mg) and placebo reached statistical significance. Results from our study suggest that the cold-pressor method may have clinical value in evaluating nonopioid analgesic agents.

The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastrointestinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single-blind oral placebo and intravenous placebo, followed by randomized, double-blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral-cecal transit time from 114.6 +/- 37.0 minutes (mean +/- SD) to 158.6 +/- 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine-induced increase in oral-cecal transit time (110.4 +/- 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single-blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine-induced delay in oral-cecal transit time (p < 0.005 compared with morphine alone), and a dose-dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long-term opioid use.

Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study.

N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine-induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold-pressor test. Morphine significantly increased oral-cecal transit time from 104.6 +/- 31.1 minutes (mean +/- SD) to 163.3 +/- 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine-induced increase in oral-cecal transit time (106.3 +/- 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine-induced delay in oral-cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid-induced constipation.