Lithium and the Treatment of Alcoholism: A Critical Review

Lithium has been tried in many psychiatric conditions but its efficacy has been firmly established only in the case of certain affective disorders. Many alcoholics are also clinically depressed and it therefore seems possible that lithium could be of benefit in treating alcoholics who have concurrent affective disturbances; this suggestion is supported by the results of studies so far reported. For the moment however, evidence from long-term investigations on alcoholics indicate that therapeutic effects of lithium are not simply caused by an alleviation of associated affective disorders, and the role of the mood disturbance in treatment response is not clear. Observations in acute studies suggest a possible mechanism of action, as lithium can attenuate the mood-elevating effects of alcohol in subjects who abuse drugs or are depressed. Unfortunately many of these clinical reports are uncontrolled and can be criticized on other methodological grounds, and further double-blind studies which include comparisons with other drug treatments are required. Studies on rodents show that alcohol drinking is often reduced by lithium, but these results must be interpreted cautiously because lithium may produce conditioned aversion to alcohol and such a mechanism of action is unlikely in long-term studies on man.     

Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.

1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peribursal fat plane of the shoulder: anatomic study and clinical experience

A comprehensive anatomic and radiographic analysis of the peribursal fat plane in 12 cadavers confirmed that the fat plane seen on radiographs represents extrasynovial fat lining the subacromial bursa and documented the anatomic relations of the bursa. A three-part retrospective clinical evaluation of rotator cuff tears, calcific tendinitis, and rheumatoid arthritis was performed. Two osteoradiologists blindly graded the appearance of the peribursal fat plane with the shoulder in external versus internal rotation in 21 patients with arthrographically intact rotator cuffs and 21 patients with disrupted rotator cuffs. The peribursal fat plane was seen better with disrupted rotator cuffs. The peribursal fat plane was seen better with the shoulder in internal rotation and was seen in 60% of control subjects but only 21% of patients with rotator cuff tears. Partial or complete obliteration of this fat plane is a sensitive (79%) but less specific (60%) indicator of rotator cuff tears. Obliteration of the peribursal fat plane by inflammatory processes in adjacent tissues, including calcific tendinitis and rheumatoid arthritis, occurred with a high frequency.     

Effects of cocaine and ethylcocaine on schedule-controlled responding in rats.

The effects of cocaine and benzoylecognine ethyl ester (ethylcocaine), its metabolite found only in simultaneous users of cocaine and ethanol, were studied in rats responding for food under a multiple fixed-ratio fixed-interval schedule of food presentation. Both cocaine and ethylcocaine increased rates of responding under the fixed-interval component and decreased the quarter life. Both drugs only decreased rates of responding under the fixed-ratio component. Cocaine was approximately equipotent to ethylcocaine. Ethylcocaine may contribute to interactions between cocaine and ethanol by exerting cocaine-like effects not seen with other cocaine metabolites.     

Non-invasive stimulation of the P6 (Neiguan) antiemetic acupuncture point in cancer chemotherapy.

The beneficial effects of transcutaneous electrical stimulation of the P6 antiemetic point (Neiguan) as an adjuvant to standard antiemetics was studied in over 100 patients in whom chemotherapy-induced sickness was not adequately controlled by antiemetics alone. Although the results were not quite as good as with invasive acupuncture, more than 75% patients achieved considerable benefit from what was a non-toxic procedure. The use of large diffuse low impedence electrodes simplifies the technique. The 2 hourly application of Sea Bands prolongs the antiemetic action. Best results were obtained from the 2 hourly self-administration of 5 min of transcutaneous electrical stimulation of P6 using a simple battery-operated TENS machine (15 Hz) to activate a large, easy-to-place surface electrode and increasing current until Qi is elicited.     

Dendrosome-based delivery of siRNA against E6 and E7 oncogenes in cervical cancer

Although small interfering RNA (siRNA) treatment holds great promise for the treatment of cancers, the field has been held back by the availability of suitable delivery vehicles. For cervical cancer the E6 and E7 oncogenes are ideal siRNA targets for treatment. The purpose of the present study was to explore the potential of dendrosomes for the delivery of siRNA targeting E6 and E7 proteins of cervical cancer cells in vitro. Optimization of dendrimer generation and nitrogen-to-phosphate (N/P) ratio was carried out using dendrimer–fluorescein isothiocyanate oligo complexes. The optimized N/P ratios were used in formulating complexes between dendrimers and siRNA targeting green fluorescence protein (siGFP). Although formulation 4D100 (dendrimer-siRNA complex) displayed the highest GFP knockdown, it was also found to be highly toxic to cells. In the final formulation 4D100 was encapsulated into dendrosomes so as to mask these toxic effects. The optimized dendrosomal formulation (DF), DF3 was found to possess a siGFP-entrapment efficiency of 49.76% ± 1.62%, vesicle size of 154 ± 1.73 nm, and zeta potential of +3.21 ± 0.07 mV. The GFP knockdown efficiency of DF3 (dendrosome) was found to be almost identical to that of 4D100, but the former was completely nontoxic to the cells. DF3 containing siRNA against E6 and E7 was found to knock down the target genes considerably, as compared with the other formulations tested. Our results imply that dendrosomes hold potential for the delivery of siRNA and that a suitable targeting strategy could be useful for applications in vivo.From the Clinical EditorsiRNA treatment holds great promise for the treatment of cancers, but overall, the availability of suitable delivery vehicles remains a major issue. The purpose of this study was to explore the potential of dendrosomes for the delivery of siRNA targeting specific proteins in cervical cancer cells in vitro. The results suggest that dendrosomes hold potential for the delivery of siRNA and a suitable targeting strategy could be useful for applications in vivo.     

Rehospitalization for respiratory illness in infants of less than 32 weeks' gestation

All 133 surviving infants of gestational age less than or equal to 32 weeks born July 1, 1985, to June 30, 1986, as well as a socioeconomically matched full-term control group were observed prospectively for 2 years to determine the incidence of rehospitalization for respiratory illness. Perinatal and seasonal factors associated with increased risk for such hospitalizations were also examined. Forty-seven (36%) preterm infants were rehospitalized compared with 3 (2.5%) of 121 term infants (P less than .001). Preterm infants with and without rehospitalization were similar for mean birth weight (1104 +/- 329 g and 1188 +/- 360 g, respectively) and gestational age (28 +/- 2 weeks for both groups); however, infants who were subsequently rehospitalized had required more days of mechanical ventilation, supplemental oxygen therapy, and neonatal intensive care. While a history of bronchopulmonary dysplasia was a risk factor for rehospitalization (45% compared with 25% of those without bronchopulmonary dysplasia, P less than .05), preterm infants with no history of bronchopulmonary dysplasia still showed a 10-fold increase compared with control infants. Among the 43 infants who required no mechanical ventilation beyond the day of birth, 10 (23%) required rehospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)