A pharmacokinetic and clinical evaluation of thio-TEPA in combination with cisplatin as first-line chemotherapy for advanced epithelial ovarian carcinoma

The purpose of the study was to explore the combination of thio-TEPA with cisplatin in first-line chemotherapy of epithelial ovarian cancer with special reference to pharmacokinetic and pharmacodynamic relationships. Ten women with advanced disease were included. Pharmacokinetics of thio-TEPA were similar to those in previous studies of single drug therapy with rapid first order elimination of the parent drug and substantial intra- and interindividual variation of the area under the concentration–time curve (AUC). No effects of the drug sequence or repeated treatments were seen on the pharmacokinetics of thio-TEPA, indicating no significant influence from the coadministration of cisplatin on the distribution, metabolism or excretion of thio-TEPA. Pharmacokinetic--pharmacodynamic relationships were less pronounced compared to previous studies, probably due to the influence from cisplatin. Prolongation of treatment intervals, dosage reduction, and withholding of thio-TEPA were required due to myelosuppression, which was the dominating toxicity. Non-hematological toxicity was moderate and easily manageable, cisplatin-related toxicity did not seem to be aggravated. Response rate based on CA 125 fluctuations was 80%, overall median survival was 18 months. In conclusion, the pharmacokinetics of thio-TEPA does not seem to be significantly influenced by concomitant administration of cisplatin in female patients. Manageable toxicity, largely restricted to myelosuppression, and high response rate justify further evaluation of the current regimen.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

Accelerated Junctional Rhythm and Nonalternans Repolarization Lability Precede Ventricular Tachycardia in Casq2−/− Mice

Repolarization Lability in Casq2?/? Mice . Background: Calsequestrin‐2 (CASQ2) is a Ca²⁺ buffering protein of myocardial sarcoplasmic reticulum. CASQ2 mutations underlie a form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The CPVT phenotype is recapitulated in Casq2 ?/? mice. Repolarization lability (RL)—beat‐to‐beat variability in the T wave morphology—has been reported in long‐QT syndrome, but has not been evaluated in CPVT. Methods and Results: ECG from Casq2 ?/? mice was evaluated with respect to heart rate (HR) and RL changes prior to onset of ventricular tachycardia (VT) to gain insight into arrhythmogenesis in CPVT. Telemetry from unrestrained mice (3‐month‐old males, 5 animals of each genotype) and ECG before and after isoproterenol administration in anesthetized mice was analyzed. Average HR in sinus rhythm (SR), occurrence of nonsinus rhythm and RL were quantified. HR was slower in Casq2 ?/? animals. Accelerated junctional rhythm (JR) occurred more frequently in Casq2 ?/? mice and often preceded VT. In Casq2 ?/? mice, HR increased prior to VT onset, prior to onset of JR and on transition from JR to VT. RL increased during progression from SR to VT and after isoproterenol administration in Casq2 ?/?, but not in Casq2+/+ animals. Isoproterenol did not increase repolarization alternans in either genotype. Conclusions: Accelerated JR, likely caused by triggered activity in His/Purkinje system, occurs frequently in Casq2 ?/? mice. The absence of CASQ2 results in increased RL. The increase in HR and in RL precede onset of arrhythmias in this CPVT model. Nonalternans RL precedes ventricular arrhythmia in wider range of conditions than previously appreciated. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1355‐1363, December 2012)     

PROLACTIN, TSH, LH AND FSH RESPONSES TO A COMBINED LHRH/TRH TEST AT DIFFERENT STAGES OF THE MENSTRUAL CYCLE

A combined test with LHRH and TRH was investigated in the normal female subject during the menstrual cycle. LH and FSH responses were not affected by raised prolactin or TSH levels after TRH.
No correlation was seen between either basal levels or responses of prolactin and TSH after TRH, and no difference in responses on days 4 or 24 were observed. The increments in prolactin and TSH were significantly greater in female than in male subjects.
Although FSH responses to LHRH+TRH were not significantly different, LH responses on day 24 were greater than on day 4. A significant linear correlation between FSH and LH responses to LHRH was seen.
The results indicate that prolactin and TSH responses to TRH are greater in female than male subjects and that changes in LH and FSH after LHRH do affect these responses. Normal ranges for hormone responses after LHRH and TRH are defined.     

SERUM SEX HORMONE CONCENTRATIONS IN INSULIN DEPENDENT DIABETIC WOMEN WITH AND WITHOUT AMENORRHOEA

Abnormal steroid secretion may contribute to anovulation in insulin dependent diabetic patients with amenorrhoea. We have measured serum sex hormone-binding globulin (SHBG) and free and bound oestrogen and androgen levels in 17 such patients. As controls we included 17 patients with insulin dependent diabetes mellitus and normal menstrual cycles, 21 regularly menstruating normal women (both sampled during early follicular phase), and 23 non-diabetic patients with amenorrhoea. The diabetic patients with normal cycles had significantly higher serum concentrations of delta 4-androstenedione and testosterone than the normal women (P less than 0.01). The amenorrhoeic diabetics in contrast had significantly lower serum concentrations of SHBG, 5 alpha-dihydrotestosterone and free and total oestradiol-17 beta than either group of menstruating women (P less than 0.05), and significantly lower concentrations of delta 4-androstenedione (P less than 0.01), dehydroepiandrosterone sulphate (P less than 0.01), testosterone (P less than 0.01), and oestrone (P less than 0.05), than the cycling diabetics. The two amenorrhoeic groups had similar free and bound sex hormone concentrations except that delta 4-androstenedione levels were significantly lower in the diabetics (P less than 0.01). We conclude that the low sex hormone levels in diabetic women with amenorrhea may be due to suppression of the hypothalamic-pituitary axis in view of the impaired LH secretion found in these patients and that excess androgen secretion seems not to be of aetiological importance in amenorrhea related to diabetes mellitus. The decreased steroid levels in amenorrheic diabetics is due to their suppressed ovarian function while the increased androgen levels in diabetics with regular cycles are probably of ovarian origin.     

Anaesthetic management in patients with epidermolysis bullosa dystrophica

Successful anaesthetic management of two patients with severe epidermolysis bullosa dystrophica was accomplished with the use of ketamine-diazepam dissociative anaesthesia in one and brachial plexus block in the other. The classification and pathology of epidermolysis bullosa is considered, and the problems associated with anaesthesia in patients with this disease are discussed.