Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM.

We have previously suggested that quinine and cinchonine could be good candidates for clinical circumvention of multidrug resistance (MDR) in hematological malignancies because of their tolerance and their retained efficacy in serum. In the present study, we have used the well-characterized multidrug resistant human leukemic cell line K562/ADM to compare the effect in vitro of quinine and cinchonine on doxorubicin, mitoxantrone, and vincristine uptake and cytotoxicity. In serum-free medium, quinine induced a dose-dependent increase of doxorubicin uptake reaching about 200% at 40 microM, while it had a slight and no effect on mitoxantrone and vincristine uptake respectively. In the same conditions, cinchonine induced a rapid and significant increase in the accumulation of the three drugs, reaching a plateau phase between 5 and 10 microM. Quinine and cinchonine induced both potentiation of doxorubicin, vincristine and mitoxantrone cytotoxicity in K562/ADM cells. However, quinine reached a plateau phase at 10 microM, while cinchonine had a maximal effect at 5 microM and was significantly more potent at low concentrations. When diluted in plasma, cinchonine was less bound to proteins than quinine. The free fraction of alkaloids was 37-55% for cinchonine and 20-30% for quinine. Cinchonine-induced enhancement of vincristine cellular accumulation was little modified by plasma proteins. When incubated in whole blood, the fraction of cinchonine trapped in red blood cells was rapidly and completely exchangeable with plasma. We conclude that cinchonine is a stronger inhibitor of MDR than quinine.

Helpless behavior (escape deficits) in streptozotocin-diabetic rats: resistance to antidepressant drugs.

Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.

Are antidepressant-like effects of triiodothyronine (T3) in rodents related to an hyperthyroid state?

1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg/kg/day were active in the yohimbine test. 7. L-5-HTP-induced head twitches were potentiated by a dose of .25 mg/kg/day and in the learned-helpless paradigm, the lowest effective dose was .06 mg/kg/day. 8. Plasma T3 values obtained in the same conditions were not significantly different from control at doses less than .5 mg/kg/day, and increased dramatically with higher doses, suggesting an accumulation of the hormone in plasma. 9. The doses inducing an hyper-triiodothyroninemia coincided with physiological signs of hyperthyroidism in the animals (i.e. loss of weight and slight hyperthermia). Thus, the active dose range of T3 was below the lowest dose required to produce a significant hyperthyroid state. 10. This results suggest that a clinical benefit could be obtained with low doses of T3 that do not significantly induce an hyperthyroidism.

Effects of glipizide on beta-endorphin secretions in response to hyperglycaemia in obese cafeteria rats.

Regulation of blood glucose involves the integration of the central nervous system with both hormonal and neural mechanisms. Considerable evidence suggests that beta-endorphin is involved in the regulation of feeding in experimental animals and man. Previous studies have shown that beta-endorphin plays an important role during hyperglycaemia. Glipizide has been shown to increase glucose metabolism by both pancreatic and extrapancreatic actions. This study indicates that glipizide may exert its pharmacological action in obese cafeteria rats through a modification of beta-endorphin secretions via central and peripheral mechanisms.

Effects of glipizide on beta-endorphin concentration in the brain of genetically diabetic (db/db) mice.

Sulphonylurea drugs have been shown to augment glucose metabolism by both pancreatic and extrapancreatic actions. The regulation of glucose involves a modification of beta-endorphin secretions via central and peripheral mechanisms. beta-Endorphin participates in the regulation of feeding and is implicated both in obesity and diabetes mellitus. This study shows that glipizide could exert its pharmacological action in genetically diabetic (db/db) mice via beta-endorphin secretions by a central mechanism.

[The prescription in dispensary practice]. / La prescription en pratique officinale.

Although the medical prescription is a well-established process, prescribing in the pharmacy does not follow a well-defined set of rules as, in official terms, there is no such thing as a pharmaceutical prescription. Despite this fact, daily pharmacy practice involves giving professional advice and dispensing drugs not only in fulfillment of a medical practitioner's prescription but also by selling drugs the pharmacist personally advises use of. In this particular case, the pharmacist must assess the patients desire for a specific treatment and determine whether it is well founded. The pharmacist has to decide whether he/she can deal with the presenting symptom or whether the person should be referred to a practising physician. For example, often-recurring mouth disease such as mouth-ulcers and gingivitis can be handled within the pharmacy. The pharmacist may think of implementing a suitable treatment involving dietary and hygienic counselling and dispense carefully selected drugs. The situation is similar in many other clinical conditions. As the pharmacist has had professional training in drugs at the university and teaching hospital, he/she is the expert in drugs and can rightly claim entitled to prescribing drugs within reasonable limits.

[Testing of an ultraviolet Halothane Meter]. / Mise à l'essai d'un "Halothane Meter" à ultraviolets.

The object of Halothane Meter (HM) study is to estimate its reliability (accuracy and stability) and its possible effect on the degradation of the molecule by the action of the UV (254 nm). The zero instability of the apparatus, clinically evident, is due to the constructor who undertakes to modify it. The molecule analysis, treated in vivo (4 hours of anesthesia) and in vitro by irradiation respectively by the HM (cathodeon 254 nm) and a source of some wavelength UV is realised by UV spectrophotometry, IR spectrophotometry, RMN spectrometry. The results of all analysis allow to exclude the molecule degradation which could impede the recirculation of treated gas in a closed circle.

[Filter circuits and pollution]. / Circuits filtres et pollution.

The contamination of air of a 50 m3 operating room has been analyzed after three and half hours of halothane enaesthesia with a closed circle system and an opened system. The analysis has been made by gaz chromatography. Concentrations of Halothane found during the use of an opened system are 100 to 120 times the allowable norms in U.S.A. After using the closed circle system, the analysis of air does not reveale any trace of Halothane.

[Role of community pharmacist in the management of patients in ophthalmology]. / Place du pharmacien de ville dans la prise en charge des patients en ophtalmologie.

OBJECTIVES: To assess the role of community pharmacists in ophthalmology, to evaluate the frequency of giving patients advice, and to report their difficulties in daily practice. MATERIAL AND METHODS: An anonymous questionnaire consisting of 13 questions was sent to 620 community pharmacists of Burgundy (France). Pharmacists were asked about their ophthalmic products, their ophthalmic activity in giving patients advice on ocular symptoms, and patients' expectations. For analysis, community pharmacies were separated into three groups: pharmacies in rural areas (under 2000 inhabitants), pharmacies in an urban zone with fewer than 10,000 inhabitants, and pharmacies in an urban zone with more than 10,000 inhabitants. RESULTS: The response rate was 46.9%. Ophthalmic products were mainly glasses for presbyopia (84.5%), eye care hygiene products (76.0%), and contact lens solutions (55.3%). Ophthalmic vitamin supplements were sold by 36.8% of pharmacists, mainly in urban areas. On average, the pharmacist was consulted for ocular problems seven times a week. Acute benign symptoms were most frequent. Advice on prescriptions came next. Then, information on contact lenses and chronic ocular disease were given (cataract, glaucoma, visual acuity loss, age-related maculopathy). Finally, the pharmacist either sold the patient an ocular treatment or oriented the patient to an ophthalmologist when needed. DISCUSSION: The pharmacist and his staff are active players in providing advice on ocular diseases and taking care of patients. Moreover, pharmacists have to manage ocular therapeutics, urgent symptoms, and chronic diseases. However, in our study, 46.0% of pharmacists felt confident with their knowledge on ophthalmology, 36.4% did not give their opinion, and 7.0% were uncomfortable with some questions. Most community pharmacists mentioned a lack of continuing education from pharmaceutical companies and postgraduate education on ocular diseases and treatment, mainly for age-related maculopathy.

Thyroid function and reversal by antidepressant drugs of depressive-like behavior (escape deficits) in rats.

Several investigations have suggested that a special relationship exists between thyroid function and affective disorders and/or therapeutic response to antidepressants. The present study shows that the reversal by clomipramine, desipramine, imipramine and nialamide of depressive-like behavior in rats (escape deficits produced by previous exposure to uncontrollable stress) was markedly attenuated in hypothyroid rats (propylthiouracil, 0.05% in the drinking water). Conversely, the effect of these same antidepressants was significantly hastened in euthyroid rats given daily triiodothyronine. This supports the notion of intricate thyroid/CNS interactions in the mechanisms of action of antidepressant drugs.

Prenatal diagnosis of atypical Tay-Sachs disease by chorionic villi sampling.

We studied a family at risk for atypical TSD in which the index case showed, clinically, a late onset and a gradual psychomotor deterioration and biochemically, a residual hex. A activity in leucocytes. Two prenatal diagnoses of affected fetuses were made in this family. The first one on amniotic cells, the second one on trophoblast biopsy samples. Both of them were confirmed after abortion on cultured cells. Prenatal diagnosis of TSD, even of some atypical forms is possible using trophoblast biopsy, but formal confirmation should be obtained on cultured trophoblasts.

[Platelet antioxidant enzyme activities in arteriopathy]. / Activités des enzymes antioxydantes plaquettaires au cours de l'artériopathie.

Some publications have pointed out that oxygen free radicals can induce injury of vessel wall and increase platelet aggregation and clotting, which can suppose a dependent relationship with arteriosclerotic process. We therefore studied the hypothesis of a possible abnormal platelet antioxidant enzymatic equipment in arteriopathic patients. A control group of 20 healthy subjects and an other one of 40 non diabetic patients with peripheral arterial disease were investigated, and the following tests were performed: measure of transcutaneous oxygen tension (PTCO2), determination of activity of platelet superoxide dismutase (SOD), glutathione-peroxidase (G-Px) and catalase (CAT). A significant decrease of SOD and G-Px is observed in platelets of arteriopathic patients. This decrease seems to be correlated with the severity of ischemia. The pathological reduction of platelet antioxidant equipment can be one factor enhancing thrombotic complications in chronic arterial disease.

High frequency of beta-hexosaminidase deficiency in lymphoblastoid cell lines.

The activity of seven lysosomal enzymes was determined in 25 lymphoblastoid cell lines. These lines included normal controls transformed with Epstein-Barr virus, Burkitt's lymphomas and other lymphomas with or without EBV genome. Four lines were deficient in total beta-hexosaminidase activity. The deficiency was as severe as that of the variant O (Sandhoff's disease) of clinical beta-hexosaminidase deficiency. The electrophoretic pattern was also similar to that observed in Sandhoff's disease. The possible mechanisms explaining the high frequency of beta-hexosaminidase deficiency in lymphoblastoid cell lines are discussed.