Cardiac metabolism: A technical spectrum of modalities including positron emission tomography,single-photon emission computed tomography,and magnetic resonance spectroscopy

Noninvasive techniques for the assessment of cardiac metabolism are important for the detection of potentially salvageable tissue in jeopardized areas of the myocardium. The correct identification of hibernating and stunned myocardium in patients with severely depressed cardiac function can have vital therapeutic consequences for the patient. Changes in myocardial fatty acid and glucose metabolism during acute and prolonged ischemia can be traced by positron-emitting or gamma-emitting radiopharmaceuticals. Alternatively,³¹P-labeled magnetic resonance spectroscopy can be used for the assessment of high-energy phosphate metabolism. It is not yet clear which modality will emerge as the most useful in the clinical setting. Positron emission tomography (PET) that uses combinations of flow tracers and metabolic tracers offers unique opportunities for quantification and high-resolution static and rapid dynamic studies. Currently, assessment of glucose metabolism with¹⁸F-fluorodeoxyglucose is regarded as the gold standard for myocardial viability and prediction of improvement of impaired contractile function after revascularization. However, preserved oxidative metabolism may be required for potential functional improvement, and therefore assessment of residual oxidative metabolism by¹¹C-labeled acetate PET may prove to be more accurate than¹⁸F-fluorodeoxyglucose PET, which reflects both anaerobic and oxidative metabolism. Moreover, because fatty acids are metabolized only aerobically, they are excellent candidates for the clinical assessment of myocardial viability and prediction of functional improvement after revascularization. Especially derivatives of fatty acids that are not metabolized but accumulate in the myocyte are attractive for myocardial imaging. Examples are¹²³I-beta-methyl-p-iodophenyl pentadecanoic acid and 15-(o-¹²³I-phenyl)-pentadecanoic acid. These tracers can be detected by planar scintigraphy and single-photon emission computed tomography, which are more economical and widely available than PET. In addition, 511 keV collimators have been developed recently, making the detection of positron emitters by planar scintigraphy and single-photon emission computed tomography feasible. The experience with³¹P-labeled magnetic resonance spectroscopy in humans is still limited. With current magnetic resonance spectroscopic techniques, insufficient spatial resolution is achieved for clinical purposes, but the possibility of serial measurements to monitor rapid changes of phosphate-containing molecules in time makes magnetic resonance spectroscopy very valuable for the research of myocardial metabolism.     

EndocrinologyHormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix)

A third-generation gonadotrophin-releasing hormone antagonist(Cetrorelix) was used during ovarian stimulation in 32 patientsundergoing assisted reproduction, in order to prevent the prematureluteinizing hormone (LH) surge. In all patients, ovarian stimulationwas carried out with two or three ampoules of human menopausalgonadotrophin (HMG), starting on day 2 of the menstrual cycle.In addition, 0.5 mg of Cetrorelix was administered daily fromday 6 of HMG treatment until the day of ovulation inductionby human chorionic gonadotrophin (HCG). A significant drop inplasma LH concentration was observed within a few hours of thefirst administration of Cetrorelix (P<0.005). Moreover, noLH surge was detected at any point in the treatment period inany of the 32 patients. A mean oestradiol concentration of 2122±935ng/1 was observed on the day of the HCG administration, indicatingnormal folliculogenesis. Like LH, progesterone concentrationalso dropped within a few hours of the first administrationof Cetrorelix (P< 0.005). A 0.5 mg daily dose of Cetrorelixprevented a premature LH surge in all the 32 patients treated.     

Timing ovulation for intrauterine insemination with a GnRH antagonist

BACKGROUND: We aimed to assess the efficacy of a GnRH antagonist in intrauterine insemination (IUI) cycles to increase number of mature ovulatory follicles and pregnancy rates. METHODS: Prospective randomized study. Women (18-38 years old) with primary/secondary infertility were included. Eighty-two patients were randomly assigned to controlled ovarian stimulation (COS) consisting of rFSH + GnRH antagonist or rFSH alone. RESULTS: A non-significant increase in the total amount of rFSH was seen in the GnRH antagonist group (707+/-240 IU) with respect to the control group (657+/-194 IU). The number of mature follicles (> or =16 mm) was significantly higher in the GnRH antagonist group than in the control group (2.4+/-1.4 versus 1.7+/-1.2, P<0.05). Pregnancy rates were significantly increased in the group of patients receiving the GnRH antagonist (38%) compared to the control group (14%). The only non-single pregnancy (triplets) occurred in the antagonist group. CONCLUSIONS: In this preliminary study, adding the GnRH antagonist to the COS protocol for IUI cycles significantly increased pregnancy rates. Nevertheless, these results may not be associated directly with the antagonist itself but with the fact that more mature ovulatory follicles are present by the day of the hCG. Finally, the risk for multiple gestations needs to be carefully evaluated.     

Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.     

A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists

BACKGROUND: Eliciting an endogenous LH surge by GnRH-agonist for the induction of final oocyte maturation may be more physiological compared with the administration of HCG. However, the efficacy of this intervention in patients treated for IVF with GnRH antagonists remains to be assessed. METHODS: 106 patients were randomized to receive either 10 000 IU urinary HCG or 0.2 mg Triptorelin for triggering final oocyte maturation. Ovarian stimulation for IVF was performed with a fixed dose of 200 IU recombinant FSH and GnRH antagonist was started on stimulation day 6. Luteal phase was supported with micronized vaginal progesterone and oral estradiol. The study was monitored continuously for safety and stopping rules were established. RESULTS: No significant differences were present in the number of cumulus-oocyte complexes retrieved, in the proportion of metaphase II oocytes, in fertilization rates or in the number and quality of the embryos transferred between the two groups. However, a significantly lower probability of ongoing pregnancy in the GnRH agonist arm prompted discontinuation of the trial, according to the stopping rules established (odds ratio 0.11; 95% confidence interval 0.02-0.52). CONCLUSIONS: Lower probability of ongoing pregnancy can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing ovarian stimulation for IVF with GnRH antagonists.     

Potent depressant effects of adenosine analogs on hippocampal slow-wave activity in the unanesthetized rat

Summary Adenosine and its analogs have previously been shown to exert a depressant effect on several measures of hippocampal excitability in the hippocampal slice and intact anesthetized preparation. In the present report, we examined the effects of intraventricular injections of adenosine analogs on hippocampal slow-wave activity in the freely moving rat. Each of three adenosine analogs— 5-N-ethylcarboxamidoadenosine (NECA) and N⁶-(phenylisopropyl) adenosine (L- and D-PIA) — were found to strongly suppress hippocampal electroencephalographic (EEG) activity. For instance, low doses of NECA (0.5 g) produced an 80–90% decrease in the amplitude of the hippocampal EEG. NECA was approximately 20-fold more potent than L-PIA, and L-PIA was twice the potency of D-PIA. In separate experiments in the anesthetized rat, NECA and L-PIA were found to block completely the activation of the hippocampal theta rhythm elicited with brainstem stimulation. The effects of adenosine analogs on both the hippocampal EEG and theta rhythm were very effectively reversed with methylxanthine, 8-para-sulphophenyl-theophylline (8-PSPT). The present findings demonstrate that adenosine analogs exert a powerful depressant effect on the hippocampal EEG in the natural unanesthetized state, and suggest that changes in the levels of endogenous adenosine may play a significant role in modulating the normal activity and function of the hippocampus.This work was supported in part by National Science Foundation grant BNS-8403544 to RPV     

Ovarian stimulation by clomiphene citrate and hMG in combination with cetrorelix acetate for ICSI cycles

BACKGROUND: The introduction of GnRH antagonists such as cetrorelix acetate has made possible the simplification of ovarian stimulation. However, the most effective protocol for their administration has not yet been clearly defined. METHODS: Forty women with male-factor infertility undergoing 40 ICSI cycles were included in the study. Clomiphene citrate at 100 mg a day was given from cycle day 3 through day 7. hMG at 150 IU was given on cycle days 4, 6 and 8, and was adjusted from day 9 according to the follicular and hormone responses. Cetrorelix acetate at 2.5 mg was administered when the leading follicle reached 14 mm. The remaining 0.5 mg was divided into two 0.25 mg injections for possible later use. Serum FSH, LH, estradiol and progesterone levels were measured daily from the day of cetrorelix acetate injection until hCG was given. RESULTS: Serum LH level was suppressed effectively for 4 days. Four patients (10%) needed one or two additional injections of 0.25 mg cetrorelix acetate. No premature LH surge was detected in any of the women treated. Sixteen women became pregnant (40%), of which 14 pregnancies (35%) were ongoing at the time of writing. CONCLUSIONS: This study demonstrates that this new protocol is feasible for couples with male-factor infertility undergoing ICSI.     

Induction of ovulation after gnRH antagonists

The gonadotrophin-releasing hormone (GnRH) antagonist binds competitively to the receptors and thereby prevents endogenous GnRH from exerting its stimulatory effect on the pituitary cells. This causes suppression of gonadotrophin secretion which occurs immediately after administration of the antagonist. When using GnRH antagonist in controlled ovarian stimulation, ovulation or maturation of the oocyte can, therefore, be induced by a variety of drugs, e.g. native GnRH, recombinant LH or short-acting GnRH agonists. Short-acting GnRH agonists were recommended for triggering ovulation in cases with a high risk of developing ovarian hyperstimulation syndrome (OHSS). Since it is evident that GnRH is required to initiate the LH surge and the oestradiol rise, a single administration of GnRH antagonist during the late follicular phase delays the LH surge. Studies showed that a single s.c. administration of 3 or 5 mg of Cetrorelix in the late follicular stage was sufficient to prevent the LH surge for 617 days. This phenomenon can be used in high responder patients who are prone to OHSS. The question whether this delay has any effect on oocyte quality and maturation still remains unanswered. Overall, there are four uses for GnRH antagonist: (i) using short-acting GnRH agonists for triggering ovulation in cases in which the GnRH antagonist is part of the protocol for ovarian stimulation. Recombinant LH and native LHRH could also be used as triggers of LH surge; (ii) delaying the LH surge in cases prone to OHSS by treatment with GnRH antagonist; (iii) to administer GnRH antagonist during the luteal phase to decrease the activity of corpora lutea; (iv) in polycystic ovarian disease with elevated LH the LH/FSH ratio can be corrected with the injection of GnRH antagonist prior to and during ovarian stimulation.     

Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization

In 1673 treatment cycles stimulated with buserelin and HMG, for IVF, GIFT or ZIFT, the severe ovarian hyperstimulation syndrome (OHSS) occurred in 10 cycles (0.6%). Eight patients were hyperandrogenic and showed an increased ovarian response to HMG. After replacement of a maximum of three embryos or zygotes, seven women became pregnant. Three women had a multiple gestation. All patients recovered uneventfully with conservative treatment. Support with progesterone or continuation of the agonist during the luteal phase did not prevent OHSS, confirming that the ovulatory HCG dose is the most important factor in inducing this severe complication. Luteal supplementation with HCG and/or HCG production during implantation could exacerbate OHSS.     

The LHRH antagonist cetrorelix: a review

In those clinical situations in which an immediate and profound suppression of gonadotrophins is desired, LHRH agonists have the disadvantage of producing an initial stimulatory effect on hormone secretion. Therefore, the use of GnRH antagonists which cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the receptors is much more advantageous. One of the most advanced antagonist produced to date is Cetrorelix, a decapeptide which has been shown to be safe and effective in inhibiting LH and sex-steroid secretion in a variety of animal species and in clinical studies as well. Clinical trials in patients suffering from advanced carcinoma of the prostate, benign prostate hyperplasia, and ovarian cancer are currently in progress and have already shown the usefulness of this new treatment modality. In particular, the concept that a complete suppression of sex-steroids may not be necessary in indications such as uterine fibroma, endometriosis and benign prostatic hyperplasia represents a promising novel perspective for treatment of these diseases. Following completion of phase III trials in controlled ovarian stimulation for IVF regimens, Cetrorelix was given marketing approval and, thus, became the first LHRH antagonist available clinically.