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Phototoxicity mechanisms: chlorpromazine photosensitized damage to DNA and cell membranes.

Photosensitized damage to biological molecules is the initial process in phototoxic responses. It is now recognized that many phototoxic compounds can photosensitize damage to more than one type of biological substrate. The in vitro light-initiated reactions of phototoxic compounds with DNA, soluble proteins and membrane components can be classified by their molecular mechanisms: (1) those in which an excited state of the phototoxic compound (or an unstable species derived from it) reacts directly with the biological substrate and (2) those in which a molecule derived from the phototoxic compound (a photoproduct or an activated oxygen species) reacts with the biological substrate. This paper describes the mechanisms by which chlorpromazine photosensitizes damage to membranes, protein and DNA and compares them to the mechanisms of photosensitization by psoralens, porphyrins, dyes, and other molecules.

Acridines↗

Potent block of potassium currents in rat isolated sympathetic neurones by the uncharged form of amitriptyline and related tricyclic compounds.

1. The block of K+ currents by amitriptyline and the related tricyclic compounds cyproheptadine and dizocilpine was studied in dissociated rat sympathetic neurones by whole-cell voltage-clamp recording. 2. Cyproheptadine (30 microM) inhibited the delayed-rectifier current (Kv) by 92% and the transient current (KA) by 43%. For inhibition of Kv, cyproheptaidine had a KD of 2.2 microM. Dizocilpine (30 microM) inhibited Kv by 26% and KA by 22%. The stereoisomers of dizocilpine were equally potent at blocking Kv and KA. 3. Amitriptyline, a weak base, was significantly more effective in blocking Kv at pH 9.4 (KD = 0.46 microM) where the ratio of charged to uncharged drug was 50:50 compared with pH 7.4 (KD = 11.9 microM) where the ratio was 99:1. 4. N-methylamitriptyline (10 microM), the permanently charged analogue of amitriptyline, inhibited Kv by only 2% whereas in the same cells amitriptyline (10 microM) inhibited Kv by 36%. 5. Neither amitriptyline nor N-methylamitriptyline had a detectable effect on Kv when added to the intracellular solution. 6. It is concluded that the uncharged form of amitriptyline is approximately one hundred times more potent in blocking Kv than the charged form. However, this does not seem to be due to uncharged amitriptyline having better access to an intracellular binding site.

Amitriptyline↗

Pathophysiology and treatment of sleep apnea.

The sleep apnea syndromes have attracted the interest of physicians and scientists in many different disciplines because the disorders involve the physiology of sleep, the control of respiration, the function of the upper airway, and the clinical sequelae upon cardiac, pulmonary, and psychological function. Over the eight years since this subject was last reviewed here (1), the pathophysiology of obstructive sleep apnea has become better understood. A variety of new treatments are now available. However, our clinical knowledge of the syndrome and its natural history have changed little. The high prevalence of these syndromes and related disorders such as snoring is only beginning to be apparent. This chapter reviews current understanding of these syndromes, with particular emphasis on recent advances, and highlights questions for future investigation. First, we consider normal upper airway function and the control of breathing during sleep. Then, we apply this information to a consideration of the pathophysiology, clinical features, and treatment of sleep apnea syndromes.

Airway Resistance↗

Preliminary clinical experience with imipramine HCl in the treatment of sleep apnea syndrome.

In the last 2 years we have systematically treated 31 sleep apnea patients with 25-50 mg imipramine HCl given 30 min before bedtime. Imipramine treatment was attempted for nonoverweight patients with negative ear, nose and throat (ENT) findings and for patients who had not responded to weight reduction or ENT surgery (in all patients the apneas were not considered life threatening). Thirteen of the 31 (41.9%) patients, of whom 9 had central apnea, reported subjective improvement in diurnal and nocturnal symptoms within 10-15 days from the initiation of treatment. Sleep laboratory recordings conducted 1-5 months after the beginning of treatment revealed a significant decrease in the total number of apneas from 242 +/- 156 to 142.8 +/- 120.1 (p less than 0.01) in these patients. We concluded that treatment with imipramine may benefit selected sleep apnea patients particularly of the central type.

Adult↗

Uptake of 3H-norepinephrine in different segments of the human non-pregnant and pregnant uterus.

Tissue specimens from uterine cervix and corpus of non-pregnant and pregnant women were incubated in vitro in the presence of 3H-norepinephrine. The uptake in the cervix exceeded those of the lower and upper segments of the corpus, and this difference was most pronounced at term pregnancy. The neuronal uptake in the cervix constituted approximately 80% of the total uptake and was higher than in isthmus and fundus (50 and 20%, respectively). The results favour the notion that cervical nerves remain functionally intact throughout pregnancy and support previous histochemical studies demonstrating a segmental difference in uterine innervation and a partial denervation of the myometrium at term.

Cervix Uteri↗

The relationship between hiatus hernia and tricyclic antidepressants: a report of five cases.

Of five patients who were receiving tricyclic antidepressants, two experienced an aggravation of preexisting hiatus hernia, and three with previously normal gastrointestinal X rays developed hiatal herination. The author suggests that this group of drugs may exert an anticholinergic effect on the esophageal sphincter and reduce the tone of the esophagogastric sphincter, thus aggravating existing hiatus hernia or causing its development.

Adult↗

Hypomania and mania after withdrawal of tricyclic antidepressants.

Seven patients who had been maintained on tricyclic antidepressants developed signs of hypomania or mania shortly (two-seven days) after drug withdrawal. Three patients responded promptly to treatment with neuroleptics. One patient receiving lithium and three others who received no further drug treatment experienced more gradual resolution of symptoms. Tricyclic withdrawal is accompanied by changes in the turnover rate of individual neurotransmitters as well as by shifts in the equilibrium between various transmitter systems. These events may be accompanied by alterations in mood. Although relapse to depression is more common, hypomania or mania may also occur.

Adult↗

Nonsurgical treatment of snoring and obstructive sleep apnea.

Self-help remedies, such as exercise, weight loss, sleep positioning, avoidance of sedatives, and use of anti-snore devices may be helpful in mild snorers, but are of limited use in patients with obstructive sleep apnea. Drug therapy with stimulants is also for mild cases and side effects are limiting factors. CPAP is highly effective in patients whose apnea is severe enough to enforce compliance. In all these nonsurgical treatments, the prospect of a lifetime of drug therapy or mechanical ventilation is quite disheartening; when given a reasonable hope for a more permanent cure, most patients will opt for surgical management.

Humans↗

Effect of tricyclic antidepressant drugs on lymphocyte membrane structure.

Tricyclic antidepressant-induced perturbations of murine splenic lymphocyte membranes and cell surface concanavalin A receptor mobility have been investigated using the fluorescent probes diphenylhexatriene and fluorescein-conjugated concanavalin A. Results of these studies illustrate the possible relationship between tricyclic antidepressant-induced membrane perturbations and tricyclic antidepressant-induced suppression of the normal murine lymphocyte mitogen response. Tricyclic antidepressant effects on murine splenic lymphocyte membranes are dose-, time- and temperature- dependent. Murine lymphocyte concanavalin A cell surface receptor mobility is not apparently altered by the tricyclic antidepressants.

Animals↗