piperidines and Diabetic-Neuropathies

There have been several long term studies (greater than 4 weeks) of cisapride in a variety of gastroparetic conditions. All of these studies have used cisapride 10 mg t.i.d. or q.i.d. Chronic idiopathic dyspepsia Cisapride has been shown to be effective in both improving symptoms and also delayed gastric emptying in a six week study. In another placebo controlled study of two weeks, gastric emptying was improved but symptoms did not improve significantly. Diabetic gastroparesis In a four week study, cisapride has been shown to be effective in improving symptoms and solid phase gastric emptying. A six weeks study demonstrated both improvement of solid and liquid gastric emptying and symptoms. Progressive systemic sclerosis Cisapride was effective in improving symptoms over a four week period. Myotonic dystrophy Cisapride was effective in improving solid phase gastric emptying and symptoms over a four week period. Combined studies In two combined studies, cisapride has been shown to be effective in a variety of gastroparetic conditions. One year studies In three open long term studies, cisapride appears to be the first prokinetic agent to demonstrate long term efficacy for up to one year.

Topics: Cisapride; Clinical Trials as Topic; Diabetic Neuropathies; Domperidone; Gastric Emptying; Humans; Metoclopramide; Piperidines; Serotonin Antagonists

To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN).. In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18 to 75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period. The primary efficacy endpoint was time to efficacy failure among "primary responders" (≥30% decrease in evening pain intensity during the run-in). Secondary endpoints were time to efficacy failure among "all responders" (≥20% decrease in evening pain intensity during the run-in) and mean change from baseline in evening pain intensity throughout last 3 days of the double-blind period.. Of the 182 patients treated during the run-in, 170 were randomized in the double-blind period, including 65 primary responders and 88 responders. There was no significant difference in proportion of patients with efficacy failure during the double-blind period with filorexant versus placebo among primary (24.3% vs. 32.1% [P=0.411]) or all (34.0% vs. 43.9% [nominal P=0.302]) responders or in mean change from baseline in evening pain intensity scores (estimated treatment difference: -0.587 [P=0.269], primary; -0.687 [P=0.108], all). Adverse events were reported by 24.7% of patients during the run-in. A higher proportion of patients treated with filorexant versus placebo reported adverse events during the double-blind period (23.9% vs. 13.4%).. These data do not provide evidence for the efficacy of nightly filorexant for the treatment of PDN.

Topics: Adolescent; Adult; Aged; Circadian Rhythm; Diabetic Neuropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neurologic Examination; Orexin Receptor Antagonists; Pain Measurement; Piperidines; Pyrimidines; Single-Blind Method; Treatment Outcome; United States; Young Adult

To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.. Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.. Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).. Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

Topics: Adult; Aged; Autonomic Nervous System; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurologic Examination; Peripheral Nerves; Piperidines; Thiazoles

To investigate the role of motilin in diabetic gastroparesis, we evaluated gastric emptying and plasma concentrations of motilin in diabetic patients. Gastric emptying of radiopaque marker was significantly delayed in the diabetics with autonomic neuropathy (n = 14) compared with the healthy controls (n = 6) (p < 0.01). Mean plasma motilin concentrations were significantly higher in the diabetics with autonomic neuropathy compared with the healthy controls (p < 0.01). A positive correlation was observed between gastric emptying and plasma motilin concentrations in the healthy controls (r = 0.955, p < 0.01), whereas these values were inversely correlated in the diabetics (r = 0.620, p < 0.01). Oral administration of cisapride (15 mg/day.14 day) significantly accelerated gastric emptying without an effect on plasma motilin concentration (p = 0.03). These observations suggest that gastric emptying in the diabetics with autonomic neuropathy is delayed despite elevated levels of motilin, and that cisapride accelerates gastric emptying, independent of the plasma motilin concentration.

Topics: Autonomic Nervous System Diseases; Cisapride; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Female; Gastric Emptying; Humans; Male; Middle Aged; Motilin; Piperidines; Serotonin Antagonists; Stomach Diseases

Two groups of patients suffering from polyneuropathy were treated by sabeluzol. The first group--a double blind placebo controlled study consisting of 30 diabetics of type II did not prove either significant differences of their subjective complaints or changes of their objective findings (the dose of sabeluzole being 2 x 10 mg/d). The second group--open study--consisting of 26 patients suffering from polyneuropathy of various origin, treated by sabeluzole 3 x 10 mg/d. The therapeutic effect was significantly higher in comparison to the above mentioned lower doses of the medicament (manifesting statistical significance of 5 and 10%); the authors make a point of sabeluzol's therapeutic efficacy, especially in cases with acute polyneuropathy onset and point out the necessity of several months lasting treatment. Positive effect upon the pseudoneurasthenic syndrome in many patients indicates its usefulness also in other disorders than are these of polyneuropathy.

Topics: Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Nervous System Diseases; Piperidines; Thiazoles

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Electromyography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Degeneration; Neurologic Examination; Peripheral Nerves; Piperidines; Sensory Thresholds; Synaptic Transmission; Thiazoles

To determine the possible role of endogenous opioid peptides in the action of imipramine and paroxetine in painful diabetic neuropathy, beta-endorphin concentrations in plasma were measured in 20 patients during a double-blind, placebo-controlled randomized three-way crossover trial. Despite a significant reduction in neuropathy symptoms during both imipramine and paroxetine treatment, the beta-endorphin level was unaltered throughout the study. The plasma concentration of beta-endorphin was not related to plasma drug concentrations. Thus, this study does not provide evidence of a role of endogenous opioid peptides in the mechanism of action of imipramine and paroxetine in painful diabetic neuropathy.

Topics: Adult; Aged; Antidepressive Agents; beta-Endorphin; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Imipramine; Male; Middle Aged; Paroxetine; Piperidines

The aim of the study was to use a novel combination of two methods for the simultaneous evaluation of two effects of oral cisapride in 10 diabetic patients with autonomic neuropathy; gastric empyting time was measured by following radio-opaque markers and orocaecal transit time by the sulphasalazine-sulphapridine method. The study was of double-blind, randomized, placebo-controlled, cross-over design. It was possible to evaluate the effect of a prokinetic drug on gastric emptying and orocaecal transit times using these two noninvasive techniques at the same time. Cisapride significantly reduced both the gastric empyting (1.2 h versus 2.1 h) and orocaecal tansit (5.9 h versus 7.7 h) times.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cisapride; Diabetic Neuropathies; Double-Blind Method; Female; Gastric Emptying; Gastrointestinal Transit; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists; Time Factors

Radionuclide gastric solid-phase emptying was studied in 10 subjects with diabetic gastroparesis comparing the acute intravenous administration of cisapride (2.5, 5, 10 mg), placebo, and metoclopramide (10 mg). No hemodynamic or electrocardiographic changes were noted. While both cisapride and metoclopramide normalized impaired solid emptying, cisapride at its highest dosage (10 mg) resulted in significantly faster gastric emptying (P = 0.003) than metoclopramide. The effects of cisapride were dose related and correlated well (r = 0.48, P less than 0.01) with the plasma drug levels. Clinical studies of chronic oral usage must take into account the dose-related response and factors affecting blood levels.

Topics: Adult; Autonomic Nervous System Diseases; Cisapride; Diabetic Neuropathies; Dose-Response Relationship, Drug; Female; Gastric Emptying; Humans; Male; Metoclopramide; Piperidines; Radionuclide Imaging; Serotonin Antagonists; Stomach; Stomach Diseases

Antroduodenal manometry was used to assess motility in 10 healthy volunteers and 15 diabetics with cardiac autonomic neuropathy whilst they received 20 mg cisapride orally or an apparently identical placebo. Interdigestive motility was recorded after an overnight fast and for 2 hours following a 500 kcal liquid meal. Active treatment did not influence the number or duration of interdigestive motility cycles in either group although antroduodenal co-ordination in both the fasting and the fed state was enhanced by cisapride (P less than 0.05). In diabetics the postprandial antral motility index was increased by cisapride, whereas in healthy subjects antral and duodenal motility indices were increased both fasting and in the fed state (P less than 0.05). These results suggest that impaired antroduodenal co-ordination is of importance in delaying gastric emptying by diabetic subjects.

Topics: Adult; Autonomic Nervous System Diseases; Cisapride; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Double-Blind Method; Duodenum; Eating; Fasting; Female; Gastric Emptying; Gastrointestinal Motility; Humans; Male; Manometry; Middle Aged; Motor Activity; Piperidines; Pyloric Antrum; Serotonin Antagonists

The effect of the selective serotonin reuptake inhibitor paroxetine on diabetic neuropathy symptoms was examined in comparison to imipramine and placebo in a randomised, double-blind, cross-over study. Paroxetine was given as a fixed dose of 40 mg/day, while the dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 400-600 nM. Paroxetine significantly reduced the symptoms of neuropathy as measured by both observer- and self-rating, but was somewhat less effective than imipramine. However, patients showing a weaker response to paroxetine than to imipramine had lower plasma concentrations of paroxetine than patients with similar response to the 2 drugs. On imipramine 5 patients dropped out because of intolerable side effects and 4 of 19 patients completing the study reported withdrawal symptoms after discontinuing imipramine. On paroxetine no patients dropped out due to side effects and no withdrawal symptoms were reported. Self-rating showed no depressive symptoms at baseline, and no changes during the study. Neither paroxetine nor imipramine caused changes in objective measures of peripheral nerve function. In conclusion, 40 mg paroxetine/day significantly reduced the symptoms in peripheral diabetic neuropathy, and it was suggested that by dose adjustment on the basis of drug level monitoring, paroxetine may become as effective as imipramine. Paroxetine was devoid of the often disturbing autonomic side effects limiting the use of imipramine in several patients.

Topics: Depression; Desipramine; Diabetic Neuropathies; Humans; Imipramine; Nervous System; Osmolar Concentration; Paroxetine; Piperidines; Serotonin Antagonists; Time Factors

Nineteen diabetic patients with autonomic neuropathy were enrolled in a double-blind crossover study of cisapride, metoclopramide and placebo. Symptoms were evaluated from diary cards and from assessments undertaken at the end of each eight week treatment period. Measurements of oesophageal transit, gastric emptying and whole gut transit were made before treatment began and at the end of each treatment period. Three patients dropped out early in the study, and the results from 16 patients were analysed. The severity of autonomic neuropathy, judged from cardiovascular reflex tests, correlated with delayed oesophageal transit and prolonged gastric emptying, but abnormal oesophageal transit and gastric emptying were often unrelated to the presence of upper gastrointestinal symptoms. Neither cisapride nor metoclopramide had a statistically significant effect on oesophageal transit, gastric emptying or whole-gut transit, nor was any significant effect on symptoms identified, although a trend towards reduced nausea and vomiting with metoclopramide and reduced epigastric fullness and diarrhoea with cisapride was suggested. Upper gastrointestinal symptoms correlate poorly with objective abnormalities of gastrointestinal motor function in diabetes. In consequence, the symptomatic benefit to be expected from correction of these motor abnormalities remains uncertain.

Topics: Adult; Autonomic Nervous System Diseases; Blood Glucose; Cisapride; Diabetic Neuropathies; Double-Blind Method; Electrocardiography; Esophagus; Female; Gastric Emptying; Gastrointestinal Transit; Glycated Hemoglobin; Humans; Male; Metoclopramide; Middle Aged; Patient Compliance; Piperidines; Serotonin Antagonists

There have been several long term studies (greater than 4 weeks) of cisapride in a variety of gastroparetic conditions. All of these studies have used cisapride 10 mg t.i.d. or q.i.d. Chronic idiopathic dyspepsia Cisapride has been shown to be effective in both improving symptoms and also delayed gastric emptying in a six week study. In another placebo controlled study of two weeks, gastric emptying was improved but symptoms did not improve significantly. Diabetic gastroparesis In a four week study, cisapride has been shown to be effective in improving symptoms and solid phase gastric emptying. A six weeks study demonstrated both improvement of solid and liquid gastric emptying and symptoms. Progressive systemic sclerosis Cisapride was effective in improving symptoms over a four week period. Myotonic dystrophy Cisapride was effective in improving solid phase gastric emptying and symptoms over a four week period. Combined studies In two combined studies, cisapride has been shown to be effective in a variety of gastroparetic conditions. One year studies In three open long term studies, cisapride appears to be the first prokinetic agent to demonstrate long term efficacy for up to one year.

Topics: Cisapride; Clinical Trials as Topic; Diabetic Neuropathies; Domperidone; Gastric Emptying; Humans; Metoclopramide; Piperidines; Serotonin Antagonists

The pharmacological inhibition of glial activation is one of the new approaches for combating neuropathic pain in which the role of glia in the modulation of neuropathic pain has attracted significant interest and attention. Neuron-glial crosstalk is achieved with N-methyl-D-aspartate-2B receptor (NMDAR-2B) activation. This study aims to determine the effect of ifenprodil, a potent noncompetitive NMDAR-2B antagonist, on activated microglia, brain-derived neurotrophic factors (BDNF) and downstream regulatory element antagonist modulator (DREAM) protein expression in the spinal cord of streptozotocin-induced painful diabetic neuropathy (PDN) rats following formalin injection. In this experimentation, 48 Sprague-Dawley male rats were randomly selected and divided into four groups: (n = 12): control, PDN, and ifenprodil-treated PDN rats at 0.5 μg or 1.0 μg for 7 days. Type I diabetes mellitus was then induced by injecting streptozotocin (60 mg/kg, i.p.) into the rats which were then over a 2-week period allowed to progress into the early phase of PDN. Ifenprodil was administered in PDN rats while saline was administered intrathecally in the control group. A formalin test was conducted during the fourth week to induce inflammatory nerve injury, in which the rats were sacrificed at 72 h post-formalin injection. The lumbar enlargement region (L4-L5) of the spinal cord was dissected for immunohistochemistry and western blot analyses. The results demonstrated a significant increase in formalin-induced flinching and licking behavior with an increased spinal expression of activated microglia, BDNF and DREAM proteins. It was also shown that the ifenprodil-treated rats following both doses reduced the extent of their flinching and duration of licking in PDN in a dose-dependent manner. As such, ifenprodil successfully demonstrated inhibition against microglia activation and suppressed the expression of BDNF and DREAM proteins in the spinal cord of PDN rats. In conclusion, ifenprodil may alleviate PDN by suppressing spinal microglia activation, BDNF and DREAM proteins.

Topics: Animals; Brain-Derived Neurotrophic Factor; Diabetic Neuropathies; Formaldehyde; Kv Channel-Interacting Proteins; Male; Microglia; Nerve Tissue Proteins; Neuralgia; Piperidines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Repressor Proteins; Spinal Cord

Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.

Topics: Analgesics; Animals; Chronic Pain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Tolerance; Enzyme Inhibitors; Epoxide Hydrolases; Gait Analysis; Male; Morphine; Phenylurea Compounds; Piperidines; Pregabalin; Rats; Rats, Sprague-Dawley; Streptozocin

This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli.. DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B.. We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

Topics: Analgesics; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Hyperalgesia; Male; Nociceptive Pain; Nociceptors; Pain Measurement; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Streptozocin

NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the treatment of l-DOPA-induced dyskinesia. It is a highly selective serotonin 5-HT. The activity of NLX-112 was tested in mouse models of acute pain (hot plate), tonic pain (intraplantar formalin test), in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin (STZ)-induced model of painful diabetic neuropathy.. NLX-112 may have significant potential for treatment of tonic pain but may be less promising as a candidate for treatment of chemotherapy-induced or diabetic neuropathic pain.

Topics: Analgesics; Animals; Antineoplastic Agents; Cyclohexanes; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Hyperalgesia; Male; Mice; Motor Activity; Neuralgia; Nociceptive Pain; Organoplatinum Compounds; Oxaliplatin; Piperazines; Piperidines; Pyridines; Random Allocation; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Streptozocin; Touch

Diabetic neuropathy is a common complication of diabetes. This study evaluated the role of Fyn kinase and N-methyl-d-aspartate receptors (NMDARs) in the spinal cord in diabetic neuropathy using an animal model of high-fat diet-induced prediabetes. We found that prediabetic wild-type mice exhibited tactile allodynia and thermal hypoalgesia after a 16-wk high-fat diet, relative to normal diet-fed wild-type mice. Furthermore, prediabetic wild-type mice exhibited increased tactile allodynia and thermal hypoalgesia at 24 wk relative to 16 wk. Such phenomena were correlated with increased expression and activation of NR2B subunit of NMDARs, as well as Fyn-NR2B interaction in the spinal cord. Fyn(-/-) mice developed prediabetes after 16-wk high-fat diet treatment and exhibited thermal hypoalgesia, without showing tactile allodynia or altered expression and activation of NR2B subunit, relative to normal diet-fed Fyn(-/-) mice. Finally, intrathecal administrations of Ro 25-6981 (selective NR2B subunit-containing NMDAR antagonist) dose-dependently alleviated tactile allodynia, but not thermal hypoalgesia, at 16 and 24 wk in prediabetic wild-type mice. Our results suggested that Fyn-mediated NR2B signaling plays a critical role in regulation of prediabetic neuropathy and that the increased expression/function of NR2B subunit-containing NMDARs may contribute to the progression of neuropathy in type 2 diabetes.

Topics: Animals; Blood Pressure; Body Weight; Diabetic Neuropathies; Diet, High-Fat; Disease Models, Animal; Eating; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain Threshold; Phenols; Piperidines; Prediabetic State; Proto-Oncogene Proteins c-fyn; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spinal Cord

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.

Topics: Animals; Diabetic Neuropathies; Half-Life; Humans; Ligands; Male; Microsomes, Liver; Pain; Pipecolic Acids; Piperidines; Protein Binding; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Solubility; Structure-Activity Relationship; Thiazines

Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1-71.4nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1±15.4% maximal possible effect (MPE) at the dose of 23.8nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8-257.8nmol/animal in a similar efficacy range with a maximal efficacy of 76.0±12.1% MPE at the dose of 257.8nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.

Topics: Analgesics; Animals; Benzimidazoles; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Hyperalgesia; Imidazoles; Male; Morphine; Naloxone; Nociceptin Receptor; Pain Threshold; Piperidines; Rats; Receptors, Opioid; Receptors, Opioid, mu; Spiro Compounds

We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators--fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively--which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.

Topics: Amidohydrolases; Analgesics; Animals; Cannabinoids; Carrageenan; Diabetic Neuropathies; Drug Synergism; Enzyme Inhibitors; Epoxide Hydrolases; Hyperalgesia; Male; Mice; Pain Measurement; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley; Small Molecule Libraries; Streptozocin

Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, nonchannel, nonneurotransmitter therapeutic target for pain is the enzyme soluble epoxide hydrolase (sEH). The sEH degrades natural analgesic lipid mediators, epoxy fatty acids (EpFAs), therefore its inhibition stabilizes these bioactive mediators. Here we demonstrate the effects of EpFAs on diabetes induced neuropathic pain and define a previously unknown mechanism of pain, regulated by endoplasmic reticulum (ER) stress. The activation of ER stress is first quantified in the peripheral nervous system of type I diabetic rats. We demonstrate that both pain and markers of ER stress are reversed by a chemical chaperone. Next, we identify the EpFAs as upstream modulators of ER stress pathways. Chemical inducers of ER stress invariably lead to pain behavior that is reversed by a chemical chaperone and an inhibitor of sEH. The rapid occurrence of pain behavior with inducers, equally rapid reversal by blockers and natural incidence of ER stress in diabetic peripheral nervous system (PNS) argue for a major role of the ER stress pathways in regulating the excitability of the nociceptive system. Understanding the role of ER stress in generation and maintenance of pain opens routes to exploit this system for therapeutic purposes.

Topics: Animals; Apoptosis; Autophagy; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Epoxide Hydrolases; Male; Neuralgia; Peripheral Nervous System; Phenylbutyrates; Phenylurea Compounds; Piperidines; Rats, Sprague-Dawley; RNA, Messenger; Skin; Streptozocin; Tunicamycin

In this study, we investigated the effects of locally (intraplantar) applied remifentanil, a μ opioid receptor agonist, to the paws and tested whether locally N-methyl d-aspartate (NMDA) receptors agonist or antagonist can modify remifentanil-induced effects in diabetic rats.. Effects of locally (intraplantar) remifentanil, NMDA and MK801 or their combinations were investigated by measuring the latencies, thresholds and two biochemical parameters (malondialdehyde (MDA) and nitric oxide (NO)), in streptozotocin induced diabetic rats.. Diabetic rats exhibited hyperalgesia and allodynia and remifentanil treatment aggravated the hyperalgesia and allodynia. The hyperalgesic and allodynic effects of remifentanil decreased in diabetic rats as compared to healthy rats. MK801 suppressed the hyperalgesic and allodynic actions of remifentanil in diabetic rats. However, hyperalgesic and allodynic actions of NMDA increased in diabetic rats. In contrast to age matched group, the combination of NMDA and remifentanil did not produce synergistic actions in diabetic rats. The levels of MDA and NO in the paw tissues of the diabetic rats significantly increased. MK801 significantly decreased NO levels, but not MDA, in diabetic rats.. The hyperalgesic and allodynic actions of locally treated remifentanil may decrease in diabetic conditions. Increases in NMDA receptors activation, reactive oxygen species production and NO release may modify the sensitivity to remifentanil in diabetes induced neuropathic pain states.

Topics: Analgesics, Opioid; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Malondialdehyde; N-Methylaspartate; Nitric Oxide; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Remifentanil; Streptozocin

We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Male; Motor Neurons; Neural Conduction; Oxidative Stress; Pain Measurement; Pain Threshold; Piperidines; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Time Factors; Uracil; Vasodilation; Weight Gain

To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient.. A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale).. This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia.. This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

Topics: Aged; Anti-Infective Agents, Urinary; Blood Glucose; Carbamates; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Drug Interactions; Energy Intake; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Diabetes is one of the leading causes of painful neuropathy and to date, besides a tight glycemic control, a viable treatment for this complication is not available. Rimonabant is a selective cannabinoid CB(1) receptor antagonist that produces a significant increase in insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of rimonabant in relieving diabetes-induced neuropathic pain. The repeated treatment with rimonabant evoked a significant attenuation of mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of diabetic neuropathy. Metabolic changes induced by hyperglycemia lead to oxidative stress, deregulation of cytokine control and reduced production and transport of nerve growth factor (NGF), and all these factors contribute to neuropathic pain. Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the reduced glutathione (GSH) depletion. The same repeated treatment inhibited tumor necrosis factor (TNFalpha) overproduction in the spinal cord and increased the NGF support. This rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for painful diabetic neuropathy other than treating the diabetic condition per se.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Hindlimb; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Oxidative Stress; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sciatic Nerve; Time Factors

The aim of this study is to investigate the effect of rimonabant, which has antiatherosclerotic and antiinflammatory properties, on peripheral neuropathy in a diabetic rat. Diabetic rat models were induced by treatment with streptozotocin and then either normal or diabetic rats were treated with an oral dose of 10mg/kg/day rimonabant or placebo for 24 weeks. We quantified the densities of intraepidermal (PGP9.5+) nerve fiber and total skin (RECA-1+) capillary length. We also measured the current perception threshold, as defined by the intensity of sine-wave stimulus, skin blood flow after treadmill running and TNF-alpha level in spinal cord tissue or plasma. After 24 weeks, rimonabant reduced the body weight and food intake in both diabetic and normal rats, but it had no effect on blood sugar levels. In addition, rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density (5.53+/-0.12 vs. 4.36+/-0.27/mm, P<0.05) and alleviated the increased current perception threshold in rimonabant-treated versus control diabetic rats. These responses were closely associated with the attenuation of skin capillary loss (1.98+/-0.07 vs. 1.67+/-0.10 mm/mm(2), P<0.05), increase in skin blood flow (14.93+/-1.08 vs. 12.07+/-0.87 TPU, P<0.05) and reduction in TNF-alpha level in tissue (70.10+/-4.99 vs. 91.18+/-3.34 pg/mg, P<0.05) in rimonabant-treated diabetic rats compared with placebo. These findings suggest that rimonabant can be beneficial for treatment of diabetic peripheral neuropathy, possibly due to its potential role in micro- and macrovessel protection and its anti-inflammatory properties.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Glucose Tolerance Test; Immunohistochemistry; Inflammation; Male; Neurons; Peripheral Nerves; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Skin; Streptozocin; Time Factors; Tumor Necrosis Factor-alpha

Cannabinoid CB(1) receptors mediate, in part, the neuroprotectant properties of endocannabinoids, and altered signalling via the CB(1) receptor may contribute to the pathogenesis of diabetic neuropathy. We investigated CB(1) receptor function in PC12 cells differentiated into a neuronal phenotype with nerve growth factor (NGF, 50 ng/ml) in 5.5 and 50 mM concentrations of glucose. High glucose was associated with impaired NGF-induced neurite outgrowth (P < 0.01; n = 185-218) and reduced expression of CB(1) receptor mRNA (P < 0.01; n = 6) on day 6 of culture. Whilst treatment of hyperglycemic cells with HU210 (0.03-3 microM) increased neurite length in a concentration-dependent manner (P < 0.01; n = 136-218), CB(1) receptor expression was not significantly altered by chronic agonist stimulation (P = 0.32; n = 6 per group). Application of the CB(1) agonist HU210 (1 microM) inhibited capsaicin-induced calcium transients to a similar degree in cells cultured in high glucose (40%) versus normal (43%) (P < 0.05; n = 33-50). HU210-mediated rescue of neurite outgrowth and inhibition of calcium influx was blocked by the selective CB(1) antagonist AM251 (1 microM), but not by the selective CB(2) antagonist AM630 (1 microM), confirming the role of CB(1) receptors. High glucose treatment did not significantly elevate endocannabinoid levels. These results suggest that high glucose concentrations are associated with decreased expression, but preserved function of CB(1) receptors in nerve cells.

Topics: Animals; Calcium; Capsaicin; Diabetic Neuropathies; Dose-Response Relationship, Drug; Dronabinol; Glucose; Hyperglycemia; Indoles; Nerve Growth Factor; Neurites; Neurogenesis; Neurons; Neuroprotective Agents; PC12 Cells; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Sensory System Agents

Sensory neural dysfunction is common in patients with peripheral neuropathy, a major complication of diabetes mellitus. In animal models of inflammatory and neuropathic pain cannabinoids potently attenuate pain behaviour, cannabinoid (CB) receptors located on nociceptive primary afferent neurones being important in their anti-hyperalgesic actions. A key measure of sensory neurone function is stimulus-evoked neuropeptide release. We investigated the effect of cannabinoid on capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from the rat paw skin in vitro, comparing non-diabetic and streptozotocin-induced diabetic animals. Diabetes caused a greater than two-fold increase in basal and capsaicin-evoked CGRP release. The synthetic CB(1)/CB(2) receptor agonist, CP55940 (100 nM), inhibited capsaicin-evoked CGRP release in both non-diabetic (30.92+/-7.69%, P<0.05) and diabetic animals (37.82+/-9.85%, P<0.05). The CB(1) receptor antagonist SR141716A (100 nM), but not the CB(2) receptor antagonist SR144528 (100 nM), significantly attenuated the inhibitory action of CP55940. The endogenous cannabinoid, anandamide (100 nM) inhibited capsaicin-evoked CGRP release in non-diabetic animals (28.88+/-7.12%, P<0.05) but neither the CB(1) nor the CB(2) receptor antagonist attenuated this action of anandamide. Anandamide (100 nM) did not significantly inhibit capsaicin-evoked CGRP release from the paw skin of diabetic animals, but it did produce a small stimulation of CGRP release at high concentrations (10 microM). These data suggest that peripheral CB(1) receptors mediate inhibition of capsaicin-evoked neuropeptide release from the paw skin of both non-diabetic and diabetic animals. However, pathological changes in the diabetic animals appear to preclude the non-CB(1) receptor mediated inhibitory action of the endogenous cannabinoid, anandamide.

Topics: Animals; Calcitonin Gene-Related Peptide; Cannabinoids; Capsaicin; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Hindlimb; In Vitro Techniques; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Reference Values; Rimonabant; Skin

Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151 003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na(+),K(+)-ATPase, and glutathione deficits in diabetic rats.. Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na(+),K(+)-ATPase activity were measured in extracts from homogenised sciatic nerves.. After 8 weeks of diabetes, sciatic blood flow was 50 % reduced. Two weeks of WAY151 003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20 % diabetic motor conduction deficit, however, at high doses ( > 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na(+),K(+)-ATPase activity, 42 % reduced by diabetes, was partially corrected by low but not high dose WAY151 003. In contrast, only a very high dose of chelerythrine partially restored Na(+),K(+)-ATPase activity. A 30 % diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151 003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment.. Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na(+),K(+)-ATPase defects.

Topics: Alkaloids; Animals; Benzophenanthridines; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Male; Neural Conduction; Phenanthridines; Piperidines; Protein Kinase C; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase

Assessment of gastric emptying time by ultrasonography is increasingly used to evaluate gastroparesis. At first normal values have to be defined. In 20 healthy volunteers the upper value of half emptying time after a semisolid meal was 50 min. A good correlation of gastric emptying time evaluated by scintigraphy was found. Diabetics with autonomous neuropathy had a remarkable delay in gastric emptying, not seen in patients with functional dyspepsia. In dyspeptic patients pathologic width of the antrum (measured by planimetry after overnight fasting) decreased during therapy with cisapride in correlation to the improvement of symptoms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cisapride; Diabetic Neuropathies; Dyspepsia; Female; Gastric Emptying; Gastroparesis; Humans; Male; Middle Aged; Piperidines; Reference Values; Sympathomimetics; Ultrasonography

Author trie to prove a possible positive effect of sabeluzole in patients with diabetic polyneuropathy. All patients were examined by EMG stimulating method for n. tibialis sin., n. peroneus sin. and n. medianus dx. The distal motor latency, motor conduction velocity and sensory conduction velocity with areas of motor evoked responses were evaluated. The realised test had lower sensitivity than the originally planned one and the expected positive effect of sabeluzole was not proved by this method.

Topics: Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electromyography; Humans; Piperidines; Thiazoles

Gut transit using radiopaque markers was assessed in 5 healthy subjects and 24 diabetic patients. In the diabetics, various parameters including duration of the disease and diabetic complications, such as neuropathy, retinopathy and nephropathy, were determined, and the relationships between gut transit times and these complications were evaluated. The effect of cisapride on gut transit was studied in 10 diabetic patients. Large intestinal, descending colon, distal colon, and whole gut transit times were delayed in diabetics with autonomic neuropathy compared to controls and to diabetics without autonomic neuropathy (P less than 0.01). There was no difference in proximal colon transit times among them. An inverse correlation was observed between CVRR and the transit times for descending colon, distal colon, large intestine and whole gut. Large intestinal and whole-gut transit times were delayed in diabetics with retinopathy or with nephropathy compared to diabetics without those complications (P less than 0.01). In the diabetics, oral administration of 7.5 mg/day of cisapride for 2 weeks significantly accelerated descending colon transit (P less than 0.05) and partially accelerated distal colon, large intestinal and whole-gut transit. It is concluded that diabetics with autonomic neuropathy have delayed transits for the whole gut and that this finding is apparent to some extent in the distal colon but not in the proximal colon. Chronic oral administration of cisapride, a gastrointestinal prokinetic drug, was effective to improve these gastrointestinal motility disorders in diabetics with autonomic neuropathy.

Topics: Administration, Oral; Adult; Cisapride; Colon; Contrast Media; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Gastrointestinal Motility; Humans; Intestine, Small; Male; Middle Aged; Piperidines; Serotonin Antagonists

Steady-state plasma concentrations of paroxetine were studied at five or more paroxetine dose levels (10 to 70 mg/day) in each of 13 extensive metabolizers of sparteine and at three or four dose levels (10 to 40 mg/day) in each of three poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. On a dose of 30 mg/day there was a 25-fold variation in steady-state concentrations (25 to 670 nmol/L). The upper extreme of this variation was made up by the poor metabolizers of sparteine and the lower extreme by some fast extensive metabolizers. Further, within the extensive metabolizer group, steady-state levels showed a significant, positive correlation with sparteine metabolic ratio at all dose levels. On increasing doses, a disproportionate increase in plasma drug levels was observed in the majority of patients. In nearly all extensive metabolizers the concentration-dose data were best described by a pharmacokinetic model assuming elimination by at least two kinetically distinct processes, one a high-affinity saturable process and one a low-affinity linear process. Estimates of clearance at low drug levels of the high-affinity process showed a significant negative correlation with the sparteine metabolic ratio. Clearance of the low-affinity process was not related to the metabolic ratio and was of the same magnitude in extensive and poor metabolizers. The data thus confirmed that the metabolism of paroxetine and sparteine cosegregates and indicated that the enzyme responsible for a high-affinity saturable paroxetine elimination process is identical with CYP2D6, the source of the sparteine oxidation polymorphism.

Topics: Adult; Aged; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Oxidation-Reduction; Paroxetine; Phenotype; Piperidines; Polymorphism, Genetic; Serotonin Antagonists; Sparteine

A single-blind dose-escalation study with the selective serotonin reuptake inhibitor paroxetine was conducted in 19 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by self-rating using visual analog scales. After an initial placebo period, paroxetine doses were increased from 10 mg/day in 10 mg steps, until the dose was 30-70 mg/day. In all except four patients, there was a marked relief of symptoms. Plasma concentrations of paroxetine above 300-400 nM were required to insure maximal relief in the majority of patients responding on paroxetine, but a considerable interindividual variation was observed (10-800 nM, median of 195 nM). The therapeutic effect appeared to increase gradually as the plasma concentration increased. The great interindividual variation in the pharmacokinetics of paroxetine was confirmed, but as the effect is maximal within approximately 1 week, and the drug is nontoxic, it may be clinically feasible simply to titrate the dose from 20 mg/day until the maximal effect is achieved. However, it is advised that titration to an effect, in diabetic neuropathy using doses above 50 mg/day, be undertaken with care as there is limited experience with doses above this level in any population. The beneficial effect of paroxetine appeared to be maintained unaltered during an additional 1 month open-label treatment on optimal paroxetine doses.

Topics: Adult; Aged; Diabetic Neuropathies; Dosage Forms; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Pain Measurement; Paroxetine; Piperidines; Serotonin Antagonists

Ultrasound examination of ten insulin-dependent diabetics with neuropathic gastroparesis demonstrated that gastric motility can be increased by intravenous injection of both cisapride and metoclopramide (Paspertin) (P less than 0.05 to less than 0.0005). During a one-hour period of observation stimulation lasted longer after cisapride than metoclopramide, but there were no qualitative differences between them. Compared with healthy subjects the frequency of antral contractions was increased after both drugs (P less than 0.05 and less than 0.025, respectively). Intensity and speed of contraction was less in patients than in the control subjects, but this effect was significant only for speed of contraction 20 min after injection of the drugs (P less than 0.05). The results indicate that ultrasonography makes it possible to monitor drug treatment of abnormal gastric emptying in diabetics by measurement of both frequency and degree of antral contraction.

Topics: Adult; Cisapride; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Gastric Emptying; Gastrointestinal Motility; Humans; Male; Metoclopramide; Middle Aged; Muscle Contraction; Paralysis; Piperidines; Pyloric Antrum; Stomach Diseases; Ultrasonography

Topics: Autonomic Nervous System; Diabetic Neuropathies; Humans; Male; Middle Aged; Nervous System Diseases; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Biomedical Research; Colchicine; Colectomy; Colitis; Colitis, Ulcerative; Colonic Diseases; Colonic Diseases, Functional; Crohn Disease; Diabetic Neuropathies; Diarrhea; Diphenoxylate; Diverticulitis; Diverticulitis, Colonic; Drug Therapy; Dysentery; Dysentery, Amebic; Enteritis; Gastroenteritis; Humans; Piperidines; Postgastrectomy Syndromes; Postoperative Complications; Toxicology; Virus Diseases