Biomedical subjects

Fabrizio De Ponti

Publications and source records attributed to Fabrizio De Ponti.

At least 19 recordsLinked to original sources

PubMed2006

Adherence to chronic cardiovascular therapies: persistence over the years and dose coverage.

AIM: To evaluate adherence to chronic cardiovascular drug treatments, in terms of long-term persistence and dose coverage. METHODS: General practice prescription data of antihypertensives, lipid-lowering agents, oral hypoglycaemic agents and nitrates were collected over a 5-year period (1998-2002) in a Northern Italian district (Ravenna, 350,000 inhabitants). We selected subjects (>40 years) receiving at least one prescription of the above drugs in December 1999. For each patient, we documented the regimen at the time of selection and evaluated adherence to treatment during the following 3 years in terms of persistence (at least one prescription per year) and daily coverage (recipients of an amount of medication consistent with daily treatment). RESULTS: Fewer than 10% of the 32 068 selected subjects were naive to treatment. Antihypertensives were the most represented therapeutic category. Among patients already on treatment in December 1999, persistence was virtually complete, whereas >40% of naive patients withdrew within 1 year, except for nitrates. The rates of coverage were always much lower than the corresponding values of persistence. Coverage was significantly higher in older patients (chi(2) for trend 69.41; P < 0.001), males (odds ratio 1.30; 95% confidence interval 1.25, 1.36) and users receiving more than one therapeutic category. CONCLUSIONS: Lack of adherence to chronic cardiovascular treatments represents an important matter of concern: although most people continued treatment over the years, less than 50% received an amount of drugs consistent with daily treatment, thus jeopardizing the proved beneficial effects of available medications.

Adult↗

PubMed2006

An update on the first decade of the European centralized procedure: how many innovative drugs?

AIMS: In a previous paper, we proposed an algorithm to assess the degree of therapeutic innovation of the agents approved by the European centralized procedure, which must be followed by biotechnological products and is optional for drugs claimed as innovative. A low overall degree of therapeutic innovation (about 30%) was found. This figure may be an underestimate of the actual level of innovation, because common biotechnological products, such as recombinant human insulins, must follow this procedure. To test the hypothesis that therapeutic innovation prevails among nonbiotechnological products, we evaluated separately the degree of therapeutic innovation of biotechnological vs. nonbiotechnological agents in the first decade of European Medicines Agency activity, also studying a possible time trend. METHODS: We assessed, for each drug: (i) the seriousness of the target disease, (ii) the availability of previous treatments, and (iii) the extent of therapeutic effect according to the previously proposed algorithm. RESULTS: Our analysis considered 251 medicinal products corresponding to 198 active substances, classified according to four main areas as therapeutic agents (88.9%), diagnostics (5.5%), vaccines (5.1%) and life-style drugs (0.5%). Among all therapeutic agents, 49 out of 176 agents (28%) were classified as having an important degree of therapeutic innovation. Fifteen out of 60 biotechnological therapeutic agents were considered important therapeutic innovations (25%), whereas this figure was 29% for nonbiotechnological agents. CONCLUSIONS: Among active substances claimed as innovative by the manufacturers, only a minority deserve this definition according to our algorithm.

Drug Approval↗

PubMed2006

Enteric neuroplasticity evoked by inflammation.

Neuroplastic changes in the enteric nervous system (ENS) may be observed in physiological states, such as development and aging, or occur as a consequence of different pathological conditions, ranging from enteric neuropathies (e.g., Hirschsprung's disease) to intestinal (e.g., inflammatory bowel disease) or extra-intestinal diseases (e.g., Parkinson's disease). Studying ENS plasticity may help to elucidate the pathophysiology of several diseases and have a bearing on the development of new pharmacological interventions. In the present review, we would like to focus on neuronal plasticity evoked by gastrointestinal inflammation occurring in inflammatory bowel disease and in a subset of patients with severe derangement of gut motility due to an enteric neuropathy characterized by an inflammatory infiltrate of the enteric plexuses. Major features of neuroplasticity within the enteric microenvironment encompass structural abnormalities ranging from nerve re-arrangement (e.g., hypertrophy and hyperplasia) to degeneration and loss of enteric ganglion cells; altered synthesis, content and release of neurotransmitters as well as up- or down-regulation of receptor systems; gastrointestinal dysfunction characterized by sensory-motor and secretory impairment of the gut. Interestingly, neuronal changes may also occur in segments of the gastrointestinal tract remote from the site of the original inflammation, e.g. the ileum may show neuroplastic changes during colitis. Sometimes, the inflamed site may even be outside the gut. Among potential mechanisms underlying ENS plasticity, neurotrophins and enteric glia deserve special attention. A better comprehension of ENS plasticity during inflammation could be instrumental to develop new therapeutic options for patients with IBD and inflammatory enteric neuropathies.

Animals↗

PubMed2006

Differential role of cyclooxygenase 1 and 2 isoforms in the modulation of colonic neuromuscular function in experimental inflammation.

This study examines the role played by cyclooxygenase (COX) isoforms (COX-1 and -2) in the regulation of colonic neuromuscular function in normal rats and after induction of colitis by 2,4-dinitrobenzenesulfonic acid (DNBS). The expression of COX-1 and COX-2 in the colonic neuromuscular layer was assessed by reverse transcription-polymerase chain reaction and immunohistochemistry. The effects of COX inhibitors on in vitro motility were evaluated by studying electrically induced and carbachol-induced contractions of the longitudinal muscle. Both COX isoforms were constitutively expressed in normal colon; COX-2 was up-regulated in the presence of colitis. In normal and inflamed colon, both COX isoforms were mainly localized in neurons of myenteric ganglia. In the normal colon, indomethacin (COX-1/COX-2 inhibitor), SC-560 [5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor), or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) enhanced atropine-sensitive electrically evoked contractions. The most prominent effects were observed with indomethacin or SC-560 plus DFU. In the inflamed colon, SC-560 lost its effect, whereas indomethacin and DFU maintained their enhancing actions. These results were more evident after blockade of noncholinergic pathways. In rats with colitis, in vivo treatment with superoxide dismutase or S-methylisothiourea (inhibitor of inducible nitric-oxide synthase) restored the enhancing motor effect of SC-560. COX inhibitors had no effect on carbachol-induced contractions in normal or DNBS-treated rats. In conclusion, in the normal colon, both COX isoforms act at the neuronal level to modulate the contractile activity driven by excitatory cholinergic pathways. In the presence of inflammation, COX-1 activity is hampered by oxidative stress, and COX-2 seems to play a predominant role in maintaining an inhibitory control of colonic neuromuscular function.

Animals↗

PubMed2006

Gastro-intestinal problems and concomitant medication in NSAID users: additional findings from a questionnaire-based survey in Italy.

BACKGROUND: In a previous questionnaire-based survey, we found extensive use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects with risk factors for serious gastrointestinal complications. AIM: This study focused on the use of NSAIDs in subjects who reported either (a) pre-existing disorders which would have required caution in using NSAIDs (e.g. dyspepsia/heartburn or peptic ulcer) or (b) co-medication with drugs having a high risk of interacting with NSAIDs. METHODS: Between March and September 2002, 65 general practitioners (GPs) submitted a validated self-administered questionnaire on health status and drug use to 3,250 subjects (age >or=18 years, stratified by sex and age). The questionnaire was divided into three parts: (1) sociodemographic information, (2) symptoms/illnesses (in the previous 6 months) and (3) drugs taken during the previous week. RESULTS: Of the 2,738 subjects who filled in the questionnaire (84% of responders), 633 (23%) used NSAIDs and, among them, 114 (18%) were chronic users. Among the subjects reporting dyspepsia/heartburn or ulcer (n=909 of 2,738), 24% were occasional NSAID users and 6% chronic users. Of the chronic NSAID users reporting gastrointestinal symptoms, 35% also used a drug for acid-related disorders, but only 14% used daily a proton pump inhibitor (PPI). One hundred six subjects used concomitantly more than one NSAID. Eighteen percent of the subjects using corticosteroids also reported NSAID use; similar proportions were seen in subjects using selective serotonin reuptake inhibitor (SSRI) antidepressants or calcium channel blockers, whereas 6% of the subjects with oral anticoagulants used NSAIDs. CONCLUSIONS: Our study shows that NSAIDs are frequently used in patients with upper gastrointestinal complaints or in combination with potentially interacting medications. Adverse effects and untoward drug interactions should be monitored in patients treated with NSAIDs in order to minimise their occurrence.

Adult↗

PubMed2005

Initial treatment of hypertension and adherence to therapy in general practice in Italy.

BACKGROUND: Antihypertensive agents are among the most used therapeutic classes. The approach to the pharmacological treatment of hypertension is guided by international recommendations and adherence to treatment is known to result in effective prevention of cardiovascular risk. AIM: The aim of this study was to evaluate the pattern of use of antihypertensive agents in general practice in terms of drug choice for the initial treatment of hypertension and adherence to treatments among newly recruited patients. METHODS: We collected the data of all antihypertensive drugs prescribed by general practitioners (GPs) and reimbursed between January 1998 and December 2002 by a Local Health Authority of Emilia Romagna (Ravenna district, 350,000 inhabitants). We selected subjects aged 40 years and older, permanently living in the area during the whole period of the study, who received their first prescription of antihypertensives between January and December 1999, with no prescription of antihypertensive agents in the previous year. For each patient, we documented the starting regimen and evaluated adherence to treatment in terms of persistence during the years (patients were defined persistent if they received at least one prescription per year) and in terms of daily coverage (patients were defined covered if they received an amount of drugs consistent with a daily treatment). Finally, switches or addition of other therapeutic classes during the 3-year period were identified. RESULTS: A cohort of 6,043 subjects receiving their first antihypertensive treatment in 1999 was obtained. Regarding the starting regimen, monotherapies with angiotensin converting enzyme inhibitors (n = 1,597; 26%) or calcium channel blockers (n = 1126; 19%) were the most frequently prescribed. Of the patients, 21% started with a drug combination regimen. Regarding adherence to treatment, 18% of the cohort received only one prescription throughout the 3 years, 13% received more than one prescription but stopped the therapy during the first year, 69% were persistent during the second year and 60% also during the third year. Only 34% were covered during the first year and 24% also during the second year, whereas only 20% of the patients resulted covered throughout the 3 years. Among persistent patients, 41% maintained the same antihypertensive regimen throughout the 3 years, 25% added other drugs to the initial treatment and 34% switched to completely different regimens. CONCLUSIONS: Our findings reflect the lack of convergence among guidelines on the drug class(es) to be considered as first choice in the initial treatment of hypertension. Although an intervention in this field may have important implications in terms of cost savings, the ongoing debate does not allow us to draw definite conclusions on whether measures should be taken by the National Health Authority. However, the lack of adherence to antihypertensive treatment is undoubtedly a matter of concern for public health and should be addressed with appropriate interventions.

Adult↗

PubMed2005

QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development.

Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.

Animals↗

PubMed2005

Idiopathic Dyspepsia.

Idiopathic dyspepsia refers to pain and/or discomfort perceived in the epigastrium that is not secondary to organic, systemic, or metabolic diseases. Symptoms may overlap with those of gastroesophageal reflux disease and irritable bowel syndrome. Gastrointestinal motor disorders, hypersensitivity to mechanical or chemical stimuli, and psychosocial factors can act individually or in concert to induce the symptoms of dyspepsia. Accordingly, there is no single therapy, and treatment must be individualized. Eradication of Helicobacter pylori infection rarely achieves symptom improvement. Treatment of idiopathic dyspepsia should begin by reassuring the patient about the benign nature of the syndrome and educating them on the knowledge that has been achieved in recent years regarding potential causes of the syndrome. Both prokinetic and antisecretory drugs have been reported to improve dyspeptic symptoms, but results are not completely convincing. Although well-designed studies demonstrate superiority of proton pump inhibitors over placebo, it should be noted that patients with nonerosive gastroesophageal reflux disease were invariably included; when these patients are excluded, the benefit of antisecretory medications is questionable. We suggest that patients with idiopathic dyspepsia be initially treated according to the predominant symptom. Those with epigastric pain/burning should receive a trial with standard doses of proton pump inhibitors for 4 to 8 weeks, whereas prokinetic patients should be prescribed at recommended doses for similar periods of time to patients with nonpainful dyspeptic symptoms such as posprandial fullness, early satiety, nausea, or vomiting. Nonresponders may benefit from combination therapies or short trials with higher doses of drugs. Visceral analgesics and antidepressants can also be prescribed alone or in combinations with other therapeutic strategies. Recent studies demonstrate utility for psychologic therapy and hypnotherapy, although truly controlled studies are difficult in this area. Herbal medicines deserve further evaluation.

Journal Article↗

PubMed2005

Effect of muscarinic receptor blockade on canine gastric tone and compliance in vivo.

Muscarinic pathways are involved in maintaining gastric tone during fasting and atropine is known to decrease gastric tone via blockade of a tonic vagal cholinergic input. Our aim was to assess the role of different muscarinic receptors in modulating canine gastric tone and compliance in vivo by using "selective" muscarinic receptor antagonists (telenzepine, AF-DX 116 and 4-DAMP for M1, M2, and M3 receptors, respectively) and the non-selective muscarinic receptor antagonist atropine. In four fasting, conscious dogs, we characterized the pressure-volume relationship in the proximal stomach by using a barostat. Drug effects were investigated by studying pressure-volume relationships before and 15 min after intravenous administration telenzepine, AF-DX 116, 4-DAMP or atropine. Pressure-volume curves were fitted by non-linear regression analysis. Before drug administration, the curve that best fitted the pressure-volume relationship was exponential. Atropine (100 microg kg-1) immediately decreased baseline gastric tone, i.e. relaxed the stomach (Deltavolume at 2 mmHg=236+/-15 ml; P<0.05), and significantly (P<0.01) shifted the pressure-volume curve to the left. Telenzepine, at the lowest dose (3 microg kg-1), shifted the pressure-volume curve to the right (P<0.01). AF-DX 116 at the lower dose (422 microg kg-1) had no effect on baseline gastric tone or the gastric pressure-volume curve, whereas the higher dose (2532 microg kg-1) significantly shifted the pressure-volume curve to the left (P<0.01), but did not increase baseline gastric volume. Finally, 4-DAMP (13.5, 45, 135 microg kg-1) immediately decreased baseline gastric tone (Deltavolume at 2 mmHg=97+/-29 ml, 110+/-35 ml and 155+/-21 ml, respectively) and significantly shifted the pressure-volume curve to the left (P<0.01). We conclude that muscarinic pathways are involved in modulating canine gastric tone and compliance during fasting: M3 receptors seem to play a key role in excitatory pathways, whereas the shift of pressure-volume curve to the right observed with the lowest dose of telenzepine is consistent with the existence of M1 receptors on inhibitory pathways.

Animals↗

PubMed2005

5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum.

BACKGROUND & AIMS: The 5-hydroxytryptamine 7 (5-HT7) receptors mediate intestinal smooth muscle relaxation. In this study, we evaluated the expression of 5-HT7 receptors in the guinea pig ileum and their role in peristalsis and accommodation of the circular muscle. METHODS: We used immunohistochemistry and confocal microscopy with whole tissue and cultured myenteric neurons. Peristalsis was induced by delivering a solution into the oral end of an isolated ileal segment. The effect of the selective 5-HT7 receptor antagonist SB-269970 (100 nmol/L) on peristaltic activity was evaluated at 30, 60, and 90 minutes and compared with control. RESULTS: 5-HT7 receptor immunoreactivity was localized to numerous myenteric neurons, a few submucosal neurons, and a few smooth muscle cells of the ileum. In enteric cultured neurons, 5-HT7 receptor immunoreactivity was observed in subpopulations of after hyperpolarizing neurons and descending neurons as identified by neuron-specific nuclear protein or calbindin and neuronal nitric oxide synthase or vasoactive intestinal peptide antibodies, respectively. SB-269970 significantly increased the threshold pressure by 33.3% +/- 2.2% (P < .001) and by 27.2% +/- 1.6% (P < .05) at 60 and 90 minutes, respectively, without modifying the threshold volume. The accommodation significantly decreased by 27.5% both at 60 and 90 minutes (P < .05). CONCLUSIONS: Our results indicate that endogenous 5-HT is involved in the modulation of circular muscle accommodation during the preparatory phase of peristalsis via the activation of 5-HT7 receptors expressed by neurons in addition to smooth muscle cells. Overstimulation of these receptors leading to an exaggerated accommodation of circular muscle might contribute to abdominal symptoms in functional bowel disorders.

Animals↗

PubMed2005

Therapeutic innovation in the European Union: analysis of the drugs approved by the EMEA between 1995 and 2003.

Since January 1995, all European Union applications for marketing approval for medicinal products derived from biotechnology and other drugs considered potentially innovative follow the EMEA centralized procedure. In order to assess the overall degree of therapeutic innovation of these drugs, we considered, for each approved agent, its target, the availability of previous treatments and the extent of its therapeutic effect. The following scores for therapeutic innovation were assigned through a consensus process: 'A' (important), 'B' (moderate) and 'C' (modest). The overall degree of important/moderate therapeutic innovation was 47% of all therapeutic agents (32% important; 15% moderate). Most (80%) of the EMEA-approved therapeutic agents were for serious diseases. The remaining ones were for risk factors (7%) or nonserious diseases (13%).

Drug Approval↗

PubMed2004

Pattern of NSAID use in the Italian general population: a questionnaire-based survey.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medicines in the developed countries. The most important adverse reactions involve the upper gastrointestinal tract and can be life threatening. A detailed knowledge of the pattern of use of NSAIDs may help doctors in advising their patients about appropriateness and safety of use. AIM: The aim of the present survey was to evaluate the prevalence and pattern of NSAID use in the general population, as well as the main characteristics of NSAID users. METHODS: Between March and September 2002, a self-administered questionnaire was submitted to a random sample, stratified by gender and age, representative of the Italian adult population (n=3,250). The questionnaire was divided into three parts regarding: (1) sociodemographic information, (2) symptoms/illnesses and (3) any drug taken during the previous week and the corresponding purpose. A statistical analysis (logistic regression) was performed. RESULTS: Of the 2,738 subjects who filled in the questionnaire, 65% took at least one drug in the previous week and, among them, 35% used NSAIDs (top drug class; n=633). Of the NSAID users, 20% were >/=65 years of age and 18% were chronic users (daily or frequent use for more than 6 months). NSAID use was significantly higher in women, both for overall and chronic use. The older age groups showed an increasing risk of chronic NSAID use. Among NSAIDs, nimesulide was the most used compound (35%) followed by acetylsalicylic acid (14%) and ibuprofen (11%). The main reasons for NSAID use, as reported by subjects, were: headache (25%), osteoarticular pain (19%), unspecified pain (15%) and osteoarthrosis (9%). More than 50% of all the NSAIDs were prescribed by physicians (general practitioner, specialist, hospital physician), whereas about 44% were taken as self-treatment or following the advice of a pharmacist, relative/friend, etc. CONCLUSIONS: Our study confirms that NSAIDs are widely used in the Italian general population and that, in most cases, they are used in accordance with their approved indications. However, their large and often chronic use in the elderly, as well as the high frequency of self-treatment, recommends a higher awareness by all physicians.

Adult↗

PubMed2004

Delayed Gastric Emptying in Functional Dyspepsia.

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.

Journal Article↗

PubMed2004

Antibacterial macrolides: a drug class with a complex pharmacological profile.

Macrolides are widely used antibacterial agents. Although generally well tolerated, they have a number of important additional pharmacological effects, which can sometimes result in significant adverse reactions. This review focuses on three of these side effects: the prokinetic action associated with stimulation of motilin receptors, the proarrhythmic effect due to prolongation of the QT interval of the electrocardiogram and the potential for drug interactions due to inhibition of drug metabolising enzymes. For macrolides that have obtained marketing authorisation in Italy, United Kingdom or United States of America, we also considered whether these actions are properly reported in the approved summaries of the product characteristics and tried to provide strategies to identify patients at risk of significant side effects when macrolides are administered.

Animals↗

PubMed2004

Inflammatory neuropathies of the enteric nervous system.

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Enteric Nervous System↗

PubMed2004

Progress with novel pharmacological strategies for gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis. In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.

Animals↗

PubMed2004

Prokinetics in the treatment of acute intestinal pseudo-obstruction.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) is characterized by an acute obstruction of the large bowel that is unrelated to mechanical causes. The evidence that cholinesterase inhibitors are effective in relieving acute colonic pseudo-obstruction raised interest in the pharmacological management of this condition. This review analyzes the pharmacological treatment of patients with Ogilvie's syndrome. Intravenous neostigmine is the best pharmacological treatment, leading to rapid colonic decompression. New colokinetic agents, including 5-HT(4) receptor agonists and motilides, may represent other useful therapeutic options for Ogilvie's syndrome.

Animals↗

PubMed2003

Prescriptions of antidepressants in primary care in Italy: pattern of use after admission of selective serotonin reuptake inhibitors for reimbursement.

BACKGROUND: Italy is reported to have a relatively low consumption of antidepressants. This is probably due to the fact that until 2000 antidepressants were reimbursed with some restrictions. AIM: To describe the pattern of use of antidepressants in primary care in Italy, after admission of selective serotonin reuptake inhibitors (SSRIs) for reimbursement without restrictions. METHODS: We collected prescription data of antidepressants (ATC code: N06) reimbursed between January 1999 and March 2002 from three local health authorities in Emilia Romagna. Then, we calculated the prevalence of use for the different therapeutic classes of antidepressants, by age and gender. Moreover, after selecting a cohort of incident adult patients to follow for 6 months after the first prescription, we analysed the continuity, the average daily doses and the average duration of treatment. RESULTS: Out of 1000 subjects, 78 received at least one prescription of antidepressants in 1 year. The prevalence of use increased with age from 43 to 136/1000. Women used antidepressants more frequently than men, with a ratio varying from 1.6 to 2, depending on age. SSRIs were the most used drugs (63%), and their prevalence of use diminished with age; on the contrary, use of mianserine and trazodone increased with age, and that of the other antidepressants did not vary. About 60% of the subjects received occasional prescriptions. Continuous treatment was more frequent with SSRIs and in subjects older than 34 years. Daily doses were higher in patients receiving newer drugs (0.9-1 DDD per day), and lower in patients receiving the older agents (0.3-0.4 DDD per day). The average daily doses were usually lower than those recommended for the treatment of the major depression, especially for tricyclics, trazodone and reboxetine. Overall, doses were within the recommended range in about 75% of recipients of newer antidepressants (i.e., SSRIs, venlafaxine, mirtazapine and reboxetine), and in less than 30% of recipients of older drugs (i.e., tricyclics, trazodone and mianserine). In 59% of subjects receiving continuous treatment, the duration of the therapeutic course was at least 6 months. CONCLUSIONS: We found a high prevalence of use of antidepressants in primary care with a frequency of occasional use higher than in other countries. Only rarely were doses and duration of treatment consistent with recommendations for treatment of depression. Recipients of newer drugs received doses consistent with a use for major depression more frequently than others; however, rates of 6 month duration did not differ among drug classes.

Adult↗