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S Garattini

Publications and source records attributed to S Garattini.

At least 37 records · Page 2Linked to original sources
PubMed2000

Does placebo help establish equivalence in trials of new antidepressants?

Clinical trials of new antidepressants usually compare a new drug to a reference antidepressant and to a placebo. The placebo is intended to validate the trial in the case of a no-difference outcome, i.e., it helps in assessing equivalence. The aim of the present paper is to test whether placebo has indeed helped establish equivalence of effect in comparative trials of new antidepressants. We carried out an example of sample size determination first in a trial to show a difference between the new and control drug, and second in a trial to assess equivalence between two competing drugs. Finally, we retrospectively calculated the maximum difference accepted as equivalence of effect in published trials of new antidepressants. Assuming a response rate to antidepressants of 70%, 294 subjects for each treatment group are needed to show a 10% difference between two antidepressant drugs and more than 1,300 to assess equivalence at a 5% level of delta, the maximum difference acceptable as equivalence of effect. The level of delta in published trials of new antidepressants ranges between 12 and 43%, suggesting they cannot claim to demonstrate equivalence of effect. Therefore, the presence of a placebo arm for comparison didn't help establish whether both drugs really worked the same way. Comparative trials of new antidepressants should adopt a two-arm design, a suitable number of patients and a high standard in the experimental design in order to minimise possible control-event rate variation.

Antidepressive Agents↗
PubMed2000

Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus.

Limbic status epilepticus was induced in rats by unilateral 60-min electrical stimulation of the CA3 region of the ventral hippocampus. As assessed by RT-PCR followed by Southern blot analysis, transcripts of interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist and inducible nitric oxide synthase were significantly increased 2 h after status epilepticus in the stimulated hippocampus. Induction was maximal at 6 h for interleukin-1beta (445%), interleukin-6 (405%) and tumour necrosis factor-alpha (264%) and at 24 h for interleukin-1 receptor antagonist (494%) and inducible nitric oxide synthase (432%). In rats with spontaneous seizures (60 days after status epilepticus), interleukin-1beta mRNA was still higher than controls (241%). Immunocytochemical staining of interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha was enhanced in glia with a time-course similar to that of the respective transcripts. Sixty days after status epilepticus, interleukin-1beta immunoreactivity was increased exclusively in neurons in one third of the animals. Multiple intracerebroventricular injections of interleukin-1 receptor antagonist (0.5 microg/3 microL) significantly decreased the severity of behavioural convulsions during electrical stimulation and selectively reduced tumour necrosis factor-alpha content in the hippocampus measured 18 h after status epilepticus. Thus, the induction of spontaneously recurring seizures in rats involves the activation of inflammatory cytokines and related pro- and anti-inflammatory genes in the hippocampus. These changes may play an active role in hyperexcitability of the epileptic tissue.

Animals↗
PubMed2000

Glutamic acid, twenty years later.

This review examines progress in understanding the physiologic functions of glutamic acid in the body since the first symposium on glutamic acid physiology and biochemistry was held at the Mario Negri Institute in Milan in 1978. The topics reviewed, although not exhaustive, include the metabolism of glutamic acid, umami taste, the role of glutamic acid as a neurotransmitter, glutamate safety and the development of new drugs resulting from the knowledge of the neurodegeneration induced by high doses of glutamic acid.

Animals↗
PubMed1999

Antidepressant drug use in Italy since the introduction of SSRIs: national trends, regional differences and impact on suicide rates.

Little is known about the use of antidepressant drugs in Italy since the introduction of selective serotonin reuptake inhibitors (SSRIs). To fill this gap, we examined antidepressant drug sales data from 1988 to 1996 for the whole country, and for the years 1995 and 1996 on the regional level. National suicide trends from 1988 to 1994 were also examined to assess whether the increasing use of SSRI antidepressants was associated with changes in suicide rates. From 1988 to 1996 an increase of antidepressant sales of 53% was recorded. This increase reflected increasing use of SSRIs, which in 1996 accounted for more than 30% of total antidepressants sold. The analysis of regional differences demonstrated heterogeneity between north, center, and south. In the south prescriptions of antidepressants and use of SSRIs were lower than in the rest of the country. In the 7-year period over which SSRI use increased, male suicide rates increased from 9.8 to 10.2 per 100,000 inhabitants, and female suicide rates declined from 3.9 to 3.2 per 100,000. These data suggest that SSRIs gave a new impetus to antidepressant sales. However, possible public health benefits related to the shift from old to new antidepressants have yet to be demonstrated.

Antidepressive Agents↗
PubMed1999

Clinical trials of new antipsychotics: a critical appraisal.

In recent years the efficacy of new antipsychotics has been investigated through a number of randomized controlled trials. This paper considers some methodological flaws that affect these studies and proposes possible solutions. The final goal is the implementation of a new generation of trials with the aim of demonstrating superiority of effect of the new antipsychotic over the reference one.

Antipsychotic Agents↗
PubMed1998

Antidepressant agents: from tricyclics to serotonin uptake inhibitors.

BACKGROUND: The number of antidepressant drugs available in the market has grown rapidly in the last few years. The present paper underlines some of the pre-clinical and clinical problems that call close attention from the regulatory authorities when approving new drugs. METHODS: We present here a review of the literature. RESULTS: A wide heterogeneity in the action of the various antidepressants precludes any single theory about the pathogenesis and therapy of depression. Antidepressant activity, in fact, may be achieved by acting on a number of different monoaminergic mechanisms. The variety in the neurochemical effects of antidepressants is not reflected in clinical trials, which tend to stereotypy. In many cases clinical trials aim at demonstrating equivalence rather than differences in efficacy. Regulatory authorities should, therefore, pay attention in accepting the equivalence of effects of a new drug in relation to a reference one: most clinical trials of new antidepressant drugs do not have the power to detect clinically relevant differences. CONCLUSIONS: Unconventional new pre-clinical tests are needed to generate antidepressants with a different mechanism of action. Clinical studies are needed to promote objective comparative evaluation of the cost, benefits and toxic effects of new antidepressants.

Antidepressive Agents↗
PubMed1998

The drug market in four European countries.

Prescription drugs should be therapeutically validated products which are selected for the treatment of accurately diagnosed diseases according to the principles of evidence-based medicine. However, industrial promotion of pharmaceuticals has meant that drug prescription patterns are not always concordant with these ideals. For example, consideration of the most sold drugs in 4 European countries--Italy, France, Germany and the United Kingdom--in 1992 and 1996 shows that marked variations in the utilisation of therapeutic classes, single active principles, and even routes of administration of the same active principles exist in these countries. To some extent, these differences reflect the influence of promotion by national pharmaceutical companies, but they also arise from other factors, such as the lack of adequate pharmacological training of physicians, the paucity of reliable comparative clinical data to allow clinicians to distinguish between large numbers of more expensive 'me-too' drugs and their prototypes, and the idiosyncrasies of national drug approval and registration systems. In addition, differences in prices across countries as well as the length of time a drug has been on the market may be contributing factors. It is hoped that the creation in 1995 of the European Medicines Evaluation Agency (EMEA), which is working towards centralisation of drug marketing approval in the European Union (EU), will usher in the establishment of a common pharmaceutical culture that will combat some of the variations and inconsistencies in drug prescribing patterns evident in European countries. Adoption of such evidence-based and more rational prescribing patterns should not only reduce the number of unnecessary and perhaps undesirable prescriptions written for patients but also relieve the financial burden on national health services in EU countries.

Drug Industry↗