Observation of side effects

Another very prominent example of the development of dmgs for new indications, from the fortuitous observation of side effects, is that of the sulfonamides. Several sulfonamides of the first generation had, in addition to their antibacterial effect, either diuretic or hypoglycemic activities. Correspondingly, specific diuretics, antiglaucomics, antihypertensives, and antidiabetics could be developed in this group of compounds [11,14,16]. 

Development of new drugs can happen in many ways. Drugs have been developed following observation of side effects when being used for other purposes. It is now known... 

Drug Discovery from the Observation of Side Effects... 

Many drugs in the past resulted from experimental or clinical observation of side effects. 

Lithium. In the lithium carbonate treatment of certain psychotic states, a low incidence (3.6%) of hypothyroidism and goiter production have been observed as side effects (6,36) (see Psychopharmacologicalagents). It has been proposed that the mechanism of this action is the inhibition of adenyl cyclase. Lithium salts have not found general acceptance in the treatment of hyperthyroidism (see Lithiumand lithium compounds). 

The time to perforation may be influenced considerably by the random occurrence of pits that happen to meet after starting from opposite sides of a sheet. This chance meeting of pits may be determined only to a slight extent by the composition of the material and, therefore, will interfere with observations of the effects of composition. 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Indomethacin treatment is associated with a high incidence (30%) of side effects typical for those seen with other NSAIDs (see above). Gastrointestinal side effects, in particular, are more frequently observed after indomethacin than after administration of other NSAIDs. The market share of indomethacin ( 5%) is therefore low compared to that for other non-steroidal anti-rheumatic agents. 

The indications for these agents are in principle identical to those of the non-selective NSAIDs although the substances have not yet received approval for the whole spectrum of indications of the conventional NSAIDs. Because they lack COX-1-inhibiting properties, COX-2-selective inhibitors show fewer side effects than conventional NSAIDs. However, they are not free of side effects because COX-2 has physiological functions that are blocked by the COX-2 inhibitors. The most frequently observed side effects are infections of the upper respiratory tract, diarrhoea, dyspepsia, abdominal discomfort and headache. Peripheral oedema is as frequent as with conventional NSAIDs. The frequency of gastrointestinal complications is approximately half that observed with conventional NSAIDs. 

In the early clinical trials of Pravadoline (248), the Sterling-Winthrop Research group observed CNS side effects. In an effort to circumvent these issues, indenes were explored as an alternative core [197]. The rationale behind this approach came from the observation that sulindac (308), an indene analogue of indomethacin (309), had anti-inflammatory properties comparable to (309) but without the CNS-associated side effects. 

The data on the adverse reactions of the fluoroquinolones which have received the most extensive clinical evaluation (ciprofloxacin, ofloxacin, pefloxacin, norfloxacin and enoxacin), involving about 30,000 patients, have been the subject of a review [54a], An important point noted in this review involves the difficulty in detecting an important severe adverse reaction if it is of relatively low frequency, until there has been a very large patient exposure (some examples are provided in which at least 150,000-300,000 exposures would be required to observe the importance of side-effects, resulting in an alert, which have been discovered with specific drugs). However, the majority of side-effects observed thus far with the fluoroquinolones have been minor,... 

Antipsychotics in a few small studies have been shown to be helpful. To date this research is limited to typical antipsychotics. Nevertheless, the excellent track record of atypical antipsychotics in treating schizophrenia and the lower burden of side effects lead us to recommend atypical antipsychotics as a first-line treatment for STPD as well. Low doses of risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole are all reasonable options. If no therapeutic effect is observed, doses should be increased. 

Structure is also essential in complex biological molecules. A lot of medicines used for psychiatric illnesses such as depression rely on their ability to interact with certain proteins in the brain. For instance, a class of antidepressants—medications that alleviate the symptoms of depression—act on proteins involved with the collection (reuptake) of the chemical serotonin, and they are known as selective serotonin reuptake inhibitors (SSRIs). This class of antidepressants includes Prozac and Zoloft. Earlier medications were also effective and are still sometimes used though they produce a number of side effects, such as dietary problems. Although an SSRI can also generate potentially dangerous side effects, psychiatrists tend to observe these effects less often. (Brain chemistry is the subject of chapter 3.)... 

According to Kuhn s observations, the effect of imipramine became apparent in some cases after a few days in other cases several weeks passed before any therapeutic effect could be seen. He estimated his failure rate at 20 25%, but regarded his sample as too small for any reliable estimate to be made. If the medicament was discontinued too soon, there was said to be a danger of relapse. It was also not possible to ascertain from his observations whether imipramine shortened the natural duration of the depressive phase. The best therapeutic successes were recorded in endogenous depression and in cases of depression which first appeared at the menopause, in cases where vital symptoms were clearly in the foreground". Kuhn also provided a comprehensive list of side effects of imipramine. which nevertheless in his view did not appreciably restrict use of the medicament. (None of the claims regarding the clinical pattern of action of imipramine made by Kuhn on the basis of open... 

Since point mutations of the ras proto-oncogene are often found in cancer, a vaccine was made with mutated ras peptides mixed with Detox. In a phase I study, CD4+ proliferation and CD8+ cytotoxicity specific to the mutated peptide, were observed. The side effects were minimal and one patient showed a stabilisation of the disease [213],... 

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