Randomized cross-over study investigating the tolerability and side effects of an intra-oral air-cooling device compared to ice in healthy volunteers.

Oral cryotherapy (OC) is a common preventive treatment of oral mucositis (OM) and is recommended in international guidelines. Ice and air OC have previously been shown to result in temperature reductions of 8.1-12.9 °C, and 14.5 °C, respectively, in healthy volunteers. However, no direct comparison between these two modalities has been performed. The primary aim was to investigate the tolerability and side effects of air OC using an intra-oral air-cooling (IOAC) device compared with ice OC. The secondary aim was to evaluate the temperature reduction in the mouth for the two respective methods. Cross-over study with randomization to order of treatment, in 15 healthy volunteers. We evaluated the self-reported intensity, frequency, and discomfort for 13 pre-defined side effects used in previous studies. All participants were able to complete both OC sessions, although one participant required reduced airflow in the air OC arm. The subjects reported more discomfort from being cold, having sensitive teeth, and numbness in the ice OC group, while they reported more discomfort from swallowing when subjected to air OC. No significant difference in the median temperature reduction was detected in the two modalities, except for the dorsal posterior part of the tongue where temperature reduction was larger in the ice OC group. We found that oral cooling using a new IOAC device was tolerated and seems to be safe in healthy volunteers.

Primary evaluation of an air-cooling device to reduce oral mucositis: a pilot study in healthy volunteers.

Oral mucositis is a common side effect of chemo and radiotherapy causing painful ulcers in the oral mucosa. One of the preventive treatments recommended in international guidelines is oral cryotherapy (OC). Randomized clinical trials on OC have used ice and ice-chips to cool the mouth, but this cooling method can be difficult for the patients to tolerate. Studies have shown that OC with ice for a period of 60 min reduces the oral temperature by 12.9 °C. The aim of this pilot study was to evaluate the temperature reduction and tolerability of OC using an intra-oral air-cooling (IOAC) device in healthy volunteers. Twelve healthy volunteers, mean age 35.4 years, were included in the study. They were treated with OC using the IOAC device for 60 min. Measurements of temperature were obtained at baseline, 5 and 60 min using a FLIR® C2 camera. After the OC session, tolerability and adverse events were documented using a questionnaire. All participants were able to use the device for 60 min. The overall temperature reduction after 5 min of OC was 10.7°C (p < 0.01) and after 60 min 14.5°C (p < 0.01). The most common adverse events were bad fit of the mouthpiece (n = 6), hypersalivation (n = 6), and difficulties swallowing (n = 5). The oral device reduced the temperature of the oral mucosa as much as treatment with ice with tolerable adverse events. The mouthpiece will be remodeled to improve tolerability before further studies are conducted.

Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial.

CONTEXT: There is no established pharmacological treatment for the core symptoms of chronic fatigue syndrome (CFS). Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacological properties that might benefit patients with CFS. OBJECTIVE: To compare the efficacy and tolerability of galantamine hydrobromide in patients with CFS. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial conducted June 1997 through July 1999 at 35 outpatient centers in the United Kingdom (n = 17), United States (n = 14), the Netherlands (n = 2), Sweden (n = 1), and Belgium (n = 1) involving 434 patients with a clinical diagnosis of CFS (modified US Centers for Disease Control and Prevention criteria). INTERVENTIONS: A total of 89 patients were randomly assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 91 patients, 7.5 mg; and 86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching placebo tablets 3 times per day. MAIN OUTCOME MEASURES: The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Questionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma-free cortisol levels and cognitive performance on a computer-based battery of tests. RESULTS: After 16 weeks, there were no statistically significant differences between any of the galantamine or placebo groups in clinical condition on the Clinician Global Impression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influenced the primary or any secondary outcome measures. CONCLUSION: This trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS.

Intensive hormone monitoring in women with unexplained infertility: evidence for subtle abnormalities suggestive of diminished ovarian reserve.

OBJECTIVE: To determine hormone levels across the menstrual cycle in women with rigorously defined unexplained infertility. DESIGN: Prospective study. SETTING: National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the following rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months' duration, with no male factor, anatomic or functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); (3) ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles and normal hormonal screens, and were matched for age and BMI with patients. MAIN OUTCOME MEASURE(S): Daily gonadotropin and steroid hormone levels across the menstrual cycle. RESULT(S): Basal FSH and LH levels in the early, middle and late follicular phases were increased significantly in the group with unexplained fertility compared with the normal controls. The mean (+/-SD) early follicular FSH levels were 7.0 +/- 0.57 mIU/mL in the unexplained-infertility group and 4.7 +/- 0.37 mIU/mL (conversion factor to SI units, 1.00) in the normal controls, respectively. There was no difference between groups over the periovulatory or luteal phase. Midluteal mean (+/-SD) P levels were lower in the unexplained-infertility group than in the normal controls (13.7 +/- 1.6 versus 24.0 +/- 3.2 ng/mL [conversion factor to SI units, 3.180]). Mean E2 concentrations were elevated in the group with unexplained infertility versus normal controls in the early through the late follicular phase but reached significance only in the midfollicular phase. Mean prolactin levels were elevated consistently across the menstrual cycle in the unexplained-infertility group compared with those in normal controls but reached significance only in the early and late follicular and midluteal phases of the cycle. Cortisol concentrations were similar between the two groups. CONCLUSION(S): These data indicate that there are subtle alterations in various hormones measured across the menstrual cycle in women with unexplained infertility compared with those in normal controls, suggesting a diminished ovarian reserve.

Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50.

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.

Midcycle increase of prolactin seen in normal women is absent in subjects with unexplained infertility.

OBJECTIVE: To compare the bioactive and immunoactive PRL in normal and unexplained infertility subjects. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, Wayne State University and The University of Michigan. PATIENT(S): Twelve normal, fertile women compared with 12 patients with unexplained infertility. INTERVENTION(S): Serum samples were obtained across the menstrual cycle and for each subject, 5 pools were prepared by combining serum aliquots from the early follicular, late follicular, midcycle, and midluteal and late luteal phases of the cycle. MAIN OUTCOME MEASURE(S): Niobium lymphoma cell bioassay and an immunoradiometric assay were used to quantitate PRL. RESULT(S): A midcycle increase in PRL was seen in controls by both assays and these levels were greater compared with other cycle stages. Comparison of midcycle PRL between groups showed differences only between bioactive PRL (34.2 +/- 8.3 versus 19.2 +/- 3.4 ng/mL [conversion factor to SI unit, 1.00]). The ratios between bioactive and immunoactive PRL were comparable. Significant correlation between bioactive and immunoactive PRL was seen for both control (r = 0.616) and unexplained infertility (r = 0.660) groups. CONCLUSION(S): The midcycle elevations of bioactive and immunoactive PRL seen in normal women were absent in women with unexplained infertility. This alteration in PRL dynamics may be a part of subtle differences in the reproductive hormone profile of women with unexplained infertility compared with their fertile counterparts.

Unexplained infertility: evaluation of the luteal phase; results of the National Center for Infertility Research at Michigan.

OBJECTIVE: To evaluate the luteal phase in women with rigorously defined unexplained infertility. DESIGN: Prospective study. SETTING: National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months duration, with no male factor, anatomic-functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); [3] ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles, normal hormonal screen, and were matched for age and BMI to patients. MAIN OUTCOME MEASURE(S): Pattern of follicular growth rate and luteal phase hormonal profile. RESULT(S): Women with unexplained infertility did not differ in menstrual cycle characteristics, follicular growth rate or mean preovulatory follicle diameter, or endometrial biopsy dating. The mean levels of P tended to be lower in the unexplained infertility group throughout the luteal phase, but only the midluteal interval reached statistical significance. Luteal phase mean integrated P or urinary PDG levels of unexplained infertility women did not differ from those of fertile controls. The ratio of integrated E2:P also was significantly greater in women with unexplained infertility than in fertile controls. CONCLUSION(S): Women with rigorously defined unexplained infertility have subtle hormonal anomalies during the luteal phase when compared with fertile controls.

Seasonality prevalence and incidence of depressive disorder in a general practice sample: identifying differences in timing by caseness.

A total of 2225 consecutive consulting general practice patients attending a North London Health Centre over the course of a year were screened and interviewed for the presence of psychiatric disorder using the GHQ and SADS; 196 patients suffering from RDC depressive disorders were identified and followed up for a further 12 months. A difference in prevalence incidence and recovery time was identified between major and minor depression. Various associations between season of onset and a range of variables were observed. Logistic modelling identified interactions between some of these variables some of which have not been explored in previous studies.

Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.

Plasma concentration of estradiol following transdermal administration of Systen 50 or Menorest 50.

Circulating levels of 17 beta estradiol (E2) following the administration of fixed doses of E2, show a great variability in kinetics depending upon the product administrated, the routes of administration, and the interindividual variations in absorption and metabolism. This might have important implications both in terms of tolerance and effectiveness. Two new forms of transdermal E2 (SYSTEN Cilag and MENOREST Rhone-Poulenc Rorer) have been recently accepted in Europe for the treatment of climacteric symptoms. The present study was undertaken to compare the pharmacokinetic characteristics of plasma E2 profile under these two drugs. It was carried out in 30 healthy postmenopausal volunteers according to good clinical practice after informed consent, as a single blind, randomised, cross-over study during the classical wearing period of 4 days. Plasma E2 concentration was determined 24 hours before, 1/2 hour before and then 2, 4, 8, 12, 24, 48, 72, 84, 96 hours after the first patch administration. E2 measurement was performed using a specific direct radioimmunoassay developed in the FRH laboratories. The main criteria for this method were an intraassay coefficient of variation (CV) less than 6%, an interassay CV less than 8% in a concentration range of 15-140 pg/ml and a quantitative detection limit (LOQ) of 2.7 pg/ml with a 20% CV. The following kinetic parameters were analysed: C(max), C(mean), C96 and MRT. The bioequivalence was assessed by analysis of variance of C(max), C(mean), C96 and AuC after logarithmic transformation, complemented by Westlake test (95%). Data show that these two products are identical in terms of C(max) but C(mean), C96 and AuC are statistically greater when MENOREST 50(R) is administered; furthermore, E2 levels decrease more rapidly and more deeply with SYSTEN 50 than MENOREST 50. The differences of pharmacokinetic profiles after administration of two different forms of the same dose of 50 micrograms transdermal 17 beta estradiol might have important medical consequences.

Estrone sulfate-sulfatase and 17 beta-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence.

The evaluation of estrogens (estrone, estradiol, and their sulfates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of estrone sulfate (E1S) which is 15-25 times higher than in the plasma. Breast cancer tissue contains the enzymes necessary for local synthesis of estradiol and it was demonstrated that, despite the presence of the sulfatase and its messenger in hormone-dependent and hormone-independent breast cancer cells, this enzyme operates particularly in hormone-dependent cells. Different progestins: Nomegestrol acetate, Promegestone, progesterone, as well as Danazol, can block the conversion of E1S to E2 very strongly in hormone-dependent breast cancer cells. The last step in the formation of estradiol is the conversion of E1 to this estrogen by the action of 17 beta-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E2) in hormone-dependent cells, but oxidative (E2-->E1) in hormone-independent cells. Using intact hormone-dependent cells it was observed that Nomegestrol acetate can block the conversion of E1 to E2. It is concluded, firstly, that in addition to ER mutants other factors are involved in the transformation of hormone-dependent breast cancer to hormone-independent, this concerns the enzymatic activity in the formation of E2; it is suggested that stimulatory or repressive factor(s) involved in the enzyme activity are implicated as the cancer evolves to hormone-independence; secondly, different drugs can block the conversion of E1S to E2. Clinical trials of these "anti-enzyme" substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.

Fluid retention syndrome and fibromyalgia.

Fluid retention syndrome (FRS) or idiopathic oedema is an unusual clinical entity almost exclusively seen in women, which remains under-diagnosed and poorly understood. It can produce a variety of symptoms ranging from headaches and blurring of vision to abdominal pains and diarrhoea [1]. More commonly it presents with symptoms of bloating, fatigue and generalized weakness. We describe four cases of FRS who presented to the rheumatology clinic with signs and symptoms of fibromyalgia. We also discuss the common features of these two conditions and argue that rheumatologists need to be aware of this condition.

Reduction of hyperglycemia after oral glucose load by the new alpha 2-adrenergic receptor antagonist SL 84.0418 in healthy subjects.

OBJECTIVE: To assess the antihyperglycemic activity of a new peripherally acting alpha 2-adrenergic receptor antagonist, SL 84.0418 in healthy volunteers METHODS: This was a randomized, double-blind crossover study. The effects of 10, 50, and 100 mg SL 84.0418 on blood glucose, plasma insulin, C-peptide, glucagon, epinephrine, and norepinephrine were investigated in comparison with placebo and 5 mg glipizide before and after an oral glucose challenge (75 gm). RESULTS: Peak blood glucose and area under the blood-glucose curve were dose-dependently reduced by SL 84.0418; the extent of this reduction was similar with 100 mg SL 84.0418 and glipizide. Glipizide but not SL 84.0418 decreased nadir blood glucose. Plasma insulin and C-peptide were increased by glipizide but not by SL 84.0418. Treatments did not modify plasma glucagon. Plasma epinephrine increased during glipizide treatment and plasma norepinephrine increased during treatment with 50 and 100 mg SL 84.0418. Systolic and diastolic blood pressure were moderately enhanced by 50 and 100 mg SL 84.0418. Adverse effects reflecting alpha 2-adrenergic receptor blockade occurred more frequently with 100 mg SL 84.0418. The adverse effect profile of 50 mg SL 84.0418 was not different from that observed with glipizide. CONCLUSION: The alpha 2-adrenergic receptor antagonist SL 84.0418 dose dependently reduced the increase in blood glucose after glucose load without modification of plasma insulin. It may represent an alternative to sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus. Further studies are needed to assess its efficacy and tolerability in non-insulin-dependent patients.

A. I. F. Scott & C. P. L. Freeman's "Edinburgh Primary Care Depression Study.

"OBJECTIVE--To compare the clinical efficacy, patient satisfaction, and cost of three specialist treatments for depressive illness with routine care by general practitioners in primary care. DESIGN--Prospective, randomised allocation to amitriptyline prescribed by a psychiatrist, cognitive behaviour therapy from a clinical psychologist, counselling and case work by a social worker, or routine care by a general practitioner. SUBJECTS AND SETTING--121 patients aged between 18 and 65 years suffering depressive illness (without psychotic features) meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition for major depressive episode in 14 primary care practices in southern Edinburgh. MAIN OUTCOME MEASURES--Standard observer rating of depression at outset and after four and 16 weeks. Numbers of patients recovered at four and 16 weeks. Total length and cost of therapist contact. Structured evaluation of treatment by patients at 16 weeks. RESULTS--Marked improvement in depressive symptoms occurred in all treatment groups over 16 weeks. Any clinical advantage of specialist treatments over routine general practitioner care were small, but specialist treatment involved at least four times as much therapist contact and cost at least twice as much as routine general practitioner care. Psychological treatments, especially social work counselling, were most positively evaluated by patients. CONCLUSIONS--The additional costs associated with specialist treatments of new episodes of mild to moderate depressive illness presenting in primary care were not commensurate with their clinical superiority over routine general practitioner care. A proper cost-benefit analysis requires information about the ability of specialist treatment to prevent future episodes of depression.

[Antiovulatory action of chlormadinone acetate]. / Action anti-ovulatoire de l'acétate de chlormadinone.

Antiovulatory action of chlormadinone acetate (5 mg twice daily from day 7 to day 25) has been assessed in 6 healthy volunteers by daily determination of plasma FSH, LH, estradiol and progesterone. Hormonal profiles during the second treated cycle show that preovulatory gonadotropin surge is blunted and that no significant progesterone secretion occurs. Estradiol production is variable up to the middle of the cycle, and then homogeneously low normal. Menstrual cyclicity is respected and ovarian function is restored during the first cycle after treatment disruption.

[Antiovulatory action of chlormadinone acetate]. / Action anti-ovulatoire de l'acetate de chlormadinone.

PIP: The antiovulatory action of chlormadinone acetate was studied in six healthy volunteers who were given two daily doses of 5 mg each from the seventh to the twenty-fifth cycle day. Chlormadinone acetate is of potential interest as a contraceptive method for the small group of women with contraindications to synthetic estrogens and norsteroid progestins for whom no other methods are acceptable. The observation period included four cycles: a control cycle before treatment during which ovulation was confirmed, two treatment cycles, and an observation cycle after treatment. Antiovulatory action was assessed by daily determination of plasma FSH, LH, estradiol, and progesterone levels. The results confirmed the antiovulatory action of chlormadinone acetate and revealed no clinical signs of functional ovarian cysts or premenstrual syndrome. In all cases, the LH surge observed in the control cycle was blunted by chlormadinone acetate, while the base gonadotropin levels were not modified. Hormonal profiles in the second treatment cycle showed no preovulatory gonadotropin surge and no significant progesterone secretion. Estradiol production was variable through midcycle and then low normal in all subjects. In the last cycle week, the estradiol level was below 50 pg/ml in two cases and between 50 and 100 pg/ml in the others. In five cases out of six, the level of progesterone was 1 ng/ml or lower. In the sixth case, the data were incompatible with ovulation. Cycle tolerance was good and ovarian function returned during the first posttreatment cycle. No significant variation in weight or blood pressure was observed at the end of the second treatment cycle.^ieng

The psychological complications of therapeutic abortion.

Psychological or psychiatric disturbances occur in association with therapeutic abortions but they seem to be marked, severe, or persistent in only a minority (approximately 10%) of women. These consist mostly of caseness depression and anxiety. Psychoses are very uncommon, being reported in only 0.003% of cases - most of whom have a history of previous psychiatric illness. Certain groups are especially at risk from adverse psychological sequelae; these include those with a past psychiatric history, younger women, those with poor social support, the multiparous, and those belonging to sociocultural groups antagonistic to abortion. This is not to overlook the fact that, adopting a crisis-resolution framework, subsequent termination of an unwanted pregnancy is itself 'therapeutic'. A better understanding of the nature of the risk factors would enable clinicians to identify vulnerable women for whom some form of psychological intervention might be beneficial.