Clinical effects

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

SSRIs are widely used for treatment of depression, as well as, for example, panic disorders and obsessive—compulsive disorder. These dmgs are well recognized as clinically effective antidepressants having an improved side-effect profile as compared to the TCAs and irreversible MAO inhibitors. Indeed, these dmgs lack the anticholinergic, cardiovascular, and sedative effects characteristic of TCAs. Their main adverse effects include nervousness /anxiety, nausea, diarrhea or constipation, insomnia, tremor, dizziness, headache, and sexual dysfunction. The most commonly prescribed SSRIs for depression are fluoxetine (31), fluvoxamine (32), sertraline (52), citalopram (53), and paroxetine (54). SSRIs together represent about one-fifth of total worldwide antidepressant unit sales. 

Correlation between clinical effectiveness and receptor affinities, however, can be seen with other receptors in addition to the dopamine D2 receptor. These include other dopaminergic receptors, as well as noradrenergic and serotonergic receptors. For example, most antipsychotics also have high affinity for a -adrenoceptors and 5-HT2 receptors (225). Some antipsychotics have been shown to be selective for the adrenoceptor versus the a -adrenoceptor, for example, spiperone [749-02-0] (226) and risperidone (61) (221]... 

HT, after chronic adininistration of all clinically effective antidepressants and after electroconvulsive treatment. A detailed review of the neuropharmacology of antidepressants is available (30). 

Levopropoxyphene [2338-37-6] (42), the optical antipode of the dextrorotatory analgetic propoxyphene, is an antitussive without analgetic activity. The 2-naphthalenesulfonate salt has a less unpleasant taste than the hydrochloride salt, and is widely used. Clinical effectiveness has been demonstrated against pathological and artificially induced cough, but the potency is somewhat less than codeine. The compound is reported not to cause addiction. Levopropoxyphene can be prepared (62) by first resolving [ -dimethylamino-CX-methylpropiophenone with dibenzoyl-(+)-tartaric acid. The resolved... 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

No clinical effects but small depletions in normal white cells count and in platelets likely within 2 days. 

Hirsh, J., Dalen, J. E., Deykin, D., Poller, L., and Bnssey, H., 1995. Oral anti-coagnlants Mechanism of acdon, clinical effectiveness, and optimal dier-apentic range. Chest 108 231S-246S. 

A cinnamoylamide, cinromide (44), is a long-acting anticonvulsant similar in its clinical effects to phenacetamide but is less hepatotoxic. The synthesis involves the straightforward amidation of acid via the intermediate acid chloride (SOCl 2) It appears that the drug is mainly deethylated in... 

Hirsh J, Dalen JE, Anderson DR et al (2001) Oral anticoagulants mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119 (Suppl.) 8S-21S... 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Several groups of CNS active drugs exert all or some of their clinical effects by their action on the GABAergic system. 

There are multiple mechanisms known to underlie the neuronal cell damage associated with injury or disease that at least theoretically could be targeted for pharmaceutical intervention. Currently however, there is no clinically available therapeutic agent that can reliably protect the brain from progressive neurodegenerative processes for sustained periods. Due to the extensive amount of preclinical research that has been conducted in recent years, there is a basis for optimism, however, it appears likely that some of these approaches will result in clinically effective therapeutic modalities in the near future. A short overview of some of the investigational approaches to combat neurodegeneration appears below. 

The main indication for certain psychostimulants is ADHD in children and adults [4]. Recent research shows that the clinical effect and benefit are dramatic even in adults. About 60% of adult patients receiving stimulant medication showed moderate-to-marked improvement, as compared with 10% of those receiving placebo. The core symptoms of hyperactivity,... 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Calcium is contraindicated in patients with hypercalcemia or ventricular fibrillation and in patients taking digitalis. Calcium is used cautiously in patients with cardiac disease. Hypercalcemia may occur when calcium is administered with the thiazide diuretics. When calcium is administered with atenolol there is a decrease in Hie effect of atenolol, possibly resulting in decreased beta blockade. There is an increased risk of digitalis toxicity when digitalis preparations are administered with calcium. The clinical effect of verapamil may be decreased when the drug is administered with calcium. Concurrent ingestion of spinach or cereal may decrease file absorption of calcium supplements. 

---