[Experimental analysis of some cardiovascular effects of Verapamil]. / Analisi sperimentale di alcuni effetti cardiovascolari del Verapamil

In vivo and in vitro experiments showed that Verapamil dilates the coronaries, prevents coronary spasm, produces Ca++-antagonism, offers protection against myocardial necrosis, prevents arrhythmia, reduces pressure, increases the purinergic reactivity and produces inhibition of platelet aggregation. It was devoid of competitive-adrenolytic activity in the heart and vessels. A methoxy derivative of the drug (D-600) had a negative inotropic and chronotropic action and was more hypotensive than Verapamil.

Pregnancy in lung transplant recipients.

Eight female lung transplant recipients, all of whom became pregnant after transplant, were reported to the National Transplantation Pregnancy Registry from US transplant centers. Outcomes of the 8 pregnancies were 4 live births, 3 therapeutic abortions, and 1 spontaneous abortion. Three of the 4 newborns were premature, with low birth weight (< 2500 grams). Rejection during pregnancy occurred in 3 pregnancies (38%). All 8 transplant recipients reported at least 1 complication during pregnancy, including shortness of breath, rejection, and infection. Two of the 4 deliveries were by cesarean section. At follow-up, all children were developing well with no residual problems. Female lung transplant recipients may face higher risks during pregnancy than other solid organ transplant recipients.

New tricyclic enamine derivatives with CNS depressant properties.

63 tricyclic enamine derivatives were synthetized and pharmacologically tested. Many of the screened compounds showed remarkable CNS depressant chlorpromazine-like activities. The compounds no. 9 (substituents CH3, Cl, H), 18 (substituents CH3, F, H) and 27 substituents CH3, OCH3, H) resulted the most interesting and were studied in comparison with chlorpromazine and chlordiazepoxide. They were submitted to further studies in view of trials in humans.

Pharmacological properties of new neuroleptic compounds.

RMI 61 140, RMI 61 144 and RMI 61 280 are newly synthetized N-[8-R-dibenzo(b,f)oxepin-10-yl]-N'-methyl-piperazine-maleates which show interesting psychopharmacologic effects. This work contains the results of a study performed with these three compounds, in order to demonstrate their neuropsycholeptic activity in comparison with chloropromazine (CPZ) and chlordiazepoxide (CPD). The inhibition of motility observed in mice shows that the compounds reduce the normal spontaneous motility as well as the muscle tone. The central-depressant activity is evidenced by increased barbiturate-induced sleep and a remarkable eyelid ptosis can also be observed. Our compounds do not show any activity on electroshock just as do CPZ and CPD. As to the antipsychotic outline, our compounds show strong reduction of lethality due to amphetamine in grouped mice and a strong antiapomorphine activity. They show also an antiaggressive effect and an inhibitory activity on avoidance behaviour much stronger than CPZ. We have also found extrapyramidal effects, as catalepsy, common to many tranquillizers of the kind of the standards used by us. As for vegetative phenomena, the compounds show hypotensive dose related action ranging from moderate to strong, probably due to an a-receptor inhibition. Adrenolytic activity against lethal doses of adrenaline, antiserotonin and antihistaminic effects, as well as other actions (hypothermia, analgesia, etc.) confirm that RMI 61 140, RMI 61 144 and RMI 61 280 are endowed with pharmacologic properties similar and more potent than those of CPZ. Studies on the metabolism of brain catecholamines show that they are similar to CPZ, although with less effect on dopamine level.

Multivariate analysis in the pharmacological evaluation of a saluretic compound.

The pharmacological evaluation of the diuretic activity of a compound -- performed measuring the urinary volume and determining its electrolyte content -- may be usefully integrated by a multivariate analysis, in order to: express a general evaluation for each animal in terms of positive or negative response; evaluate the false positive responses of the control group animals and the negative responses in the treated animals on the basis of the general response. An example of application relating to a well-known saluretic, 4-chloro-N-(2-furfuryl)-5-sulfamoyl-anthranilic acid (furosemide), is reported.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Safety of pregnancy in the female transplant recipient population must include consideration of 3 outcomes--mother, baby and transplanted graft. In the majority of female recipients studied, pregnancy does not appear to cause excessive or irreversible problems with graft function, if the function of the transplant organ is stable prior to pregnancy. However, a small percentage of recipients identified within each organ system may develop rejection, graft dysfunction and/or graft loss that may be related to the pregnancy and may occur unpredictably. Outcomes are not entirely similar among all organ systems, and one must consider risks on an individual organ basis. It appears reasonable to advise female recipients to wait one or 2 years after transplantation before attempting pregnancy to insure that function of the transplanted organ is adequate and stable and also to allow for stabilization of immunosuppressive medications. Favorable outcomes, however, have occurred when recipients have become pregnant less than one year from transplant, so cases must be analyzed individually. Immunosuppressive medications may have to be adjusted during pregnancy, and in some cases, rejections occur requiring additional immunosuppressive regimens (steroids and in several cases OKT3). Whether increasing immunosuppressive doses during pregnancy to adjust for falling levels lessens the rejection risk has never been studied prospectively. There is concern based on animal reproductive studies that the risk of birth defects and/or spontaneous miscarriage is increased in women exposed to MMF during pregnancy. Of the 9 pregnancies reported to the registry to date, there have been no birth defects noted among 5 liveborn of female recipients exposed to MMF. Data remain limited. For female recipients, a high incidence of low birth-weight and prematurity compared to the general population has been a consistent outcome, however, there has been no specific pattern of malformation in their newborn or any apparent increase in the incidence of small-for-gestational-age newborn. Long-term follow-up of children to date by the NTPR has been encouraging. A recent report in the literature has suggested impairment of immune function in newborn of CsA-treated mothers. Further study is needed. Some mothers have chosen to breastfeed. The potential risk to the newborn of ingested immunosuppressives compared with the potential benefits of breastfeeding is unknown and options must be discussed with the recipient. From earlier registry reports, recipients with deteriorating graft function, such as liver recipients with recurrent hepatitis C and/or other recipients with deteriorating graft function, appear to be at risk for worsened graft function with pregnancy. Outcomes of male recipient fathered pregnancies have been favorable and appear to be similar to the general population, but this group has not been as well studied as female recipients. No structural problems have been noted in the 38 offspring of males on MMF at the time of conception. Within each organ group, some female recipients have reported more than one pregnancy, sometimes on differing immunosuppressive regimens. If there is stable graft function, additional successful pregnancies are possible. Continued entries to the registry, especially in light of newer immunosuppressives and combinations of agents, are needed to continue to provide guidelines for management. The NTPR acknowledges the cooperation of transplant recipients and over 200 centers nationwide who have contributed their time and information to the registry. The NTPR is supported by grants from Novartis Pharmaceuticals Corp., Fujisawa Healthcare, Inc., Roche Laboratories Inc. and Wyeth-Ayerst Pharmaceuticals, Inc.

Visuospatial orientation in Parkinson's disease.

Visuospatial functioning in patients with Parkinson's disease was investigated using neuropsychological measures of basic visual perception, complex perceptual discrimination, and spatial orientation. Three subgroups of patients were described: (a) those with broadly impaired visuospatial abilities, (b) those with generally intact abilities, and (c) those whose performance on a task of spatial orientation was lower than their performance on a task of complex perceptual discrimination. These subgroup differences were also concordant with three other variables: age, duration of disease, and degree of dementia. It is suggested that decreases in spatial orientation functioning in Parkinson's disease may reflect the speed of progression of this disease.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Specific data on pregnancies following transplantation continue to accrue in the National Transplantation Pregnancy Registry (NTPR) in each type of organ recipient, with the following conclusions: 1. While the majority of kidney recipients appear to tolerate pregnancy well, a small percentage develops rejection, graft dysfunction and/or graft deterioration. Overall, there is a slight increase in the mean postpartum creatinine level when compared with the prepregnancy level, which has been noted in previous investigations by the NTPR. One neonatal death attributed to thrombotic cardiomyopathy was noted in a set of twins of a tacrolimus-based kidney recipient, but no other death has been noted in any of the additional reports among the recipients given newer immunosuppression regimens. Follow-up of offspring of these recipients is ongoing. 2. No structural malformations have been noted among offspring exposed to mycophenolate mofetil, but exposures are limited. (5 mothers, 29 fathers). 3. Female liver recipients with biopsy-proven acute rejection during pregnancy appear to be at greater risk for both poorer newborn outcomes and recurrent rejection episodes. In the setting of acute rejection diagnosed during pregnancy, close attention is warranted, anticipating that birthweight may be lower and that a substantial percentage of these female recipients may have recurrent rejection episodes. 4. Pancreas-kidney grafts can maintain normoglycemia throughout pregnancy. A high incidence of maternal hypertension, prematurity and low birthweight have been noted, so, as in other recipient groups, these are high-risk pregnancies. Maternal pancreas and kidney function must be closely monitored. 5. No specific prepregnancy predictors of adverse outcomes have yet been identified among heart or lung recipients although none of the deaths among heart recipients in the NTPR database occurred within 2 years of delivery. When compared with other solid organ recipients, female lung recipients may face higher risks, particularly related to rejection. Whether prepregnancy factors can help to predict either heart or lung recipients at risk requires continued study. 6. No structural malformations or significant learning disabilities have been noted in follow-up of the offspring of CsA-treated females, the largest group of offspring followed to date with a mean age of 4-5 years. Continued surveillance of children will be essential to determine if effects become apparent as age-related developmental delays or other problems in immune function or fertility later in life. 7. Newer regimens as well as new combinations of agents will continue to be studied. It is essential that non-viable as well as viable pregnancy outcomes be reported to the registry (i.e., recipients with pregnancies that result in spontaneous abortion or termination should be included for study). True estimates of non-viable outcomes have been difficult to assess. Additionally, inclusion of reports of pathologic evaluations at delivery hospitals will be helpful to determine whether spontaneous abortions are a result of lethal malformations related to immunosuppressive or other medication exposure. Safety of pregnancy for parent and child remain the primary goals of the NTPR.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Female solid organ recipients with good graft function generally tolerate pregnancy well. However, the combination of mother, fetus, transplanted organ, and immunosuppressive and other medications increases the complexity of management and raises the specter of adverse outcomes. For the mother, considerations include the nature of the original disease (i.e. genetic risk of transmission), co-morbid conditions which increase pregnancy risk (i.e. hypertension, diabetes, renal insufficiency), and long-term maternal prognosis. For the fetus, questions include the adequacy of maternal physiology (cardiac, renal, glycernic control, etc.), exposure to medications, and exposure to infectious agents. The transplanted organ must accommodate the increased workload of pregnancy and the needs of the fetus. The delicate balance between immunosuppression and rejection may be altered by the pregnancy. The impact of pregnancy on recurrent disease can also be an issue. Medication issues include changes in drug pharmacokinetics and the potential for adverse effects on the fetus. These effects could include chromosomal aberrations, structural malformations, organ-specific toxicity, intrauterine growth retardation, and immune system development. For female kidney recipients there are sufficient data to demonstrate a direct relationship between creatinine levels before and during pregnancy and risk of graft loss in the postpartum period. Pregnancy itself does not appear to adversely affect stable graft function. Among liver recipients, those with recurrent viral hepatitis may have deterioration of graft function with subsequent pregnancies. These recipients should be apprised accordingly, as maternal deaths have occurred in this setting. Postpartum depression and potential for medication noncompliance require vigilance. The safety of pregnancy from the NTPR analysis to date has been largely derived from the experience with CsA-based regimens. For recipients on CsA there have been good maternal outcomes without any specific or predominant malformation patterns in the offspring. For the general population, malformations occur in approximately 3% of live births. To date, there is no indication that this incidence has increased despite the complex medical regimens of transplant recipients. Data are accruing with tacrolimus and Neoral. Continuing data entry and continued follow-up of off-spring will allow for further recommendations, especially in light of the new medications and combinations. Recipients should be advised to wait one to 2 years after transplant before considering pregnancy. Those with stable graft function, and with no rejection, graft dysfunction, or deterioration should still be apprised of the high risk of prematurity and low birthweight, although maternal risks appear low. These are high-risk pregnancies, requiring close communication and cooperation between the high-risk obstetrician and the transplant team. The use of the FDA pregnancy categories should not be the sole reason for choosing a particular immunosuppressive drug. Agents such as Neoral and tacrolimus would appear to offer some advantage as blood levels can be measured. At present, no safety guidelines can be given for mycophenolate mofetil, OKT3, or ATG. Identification of prepregnancy factors predictive of higher risks and appropriate counseling and management guidelines are major NTPR goals, and depend on the continued assistance and cooperation of the transplant community.

Report from the national transplantation pregnancy registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR continues to analyze the safety of pregnancy in female transplant recipients as well as outcomes of pregnancies fathered by male transplant recipients. With regard to female recipients, pregnancy does not appear to adversely affect graft function, when the function of the transplanted graft is stable prior to pregnancy. A small percentage of recipients with each transplanted organ develops rejection, graft dysfunction or graft loss. These events may occur in recipients with pre-pregnancy graft dysfunction or on occasion, occur unpredictably. Female cyclosporine-treated kidney recipients with both shorter and longer intervals from transplant to conception have been analyzed, with favorable outcomes noted. It appears sensible to continue to advise recipients to wait one to 2 years after transplant to allow for stable graft function as well as stabilization of immunosuppressive medications. However, given that favorable outcomes can occur with either shorter or longer intervals, these recipients need to be counseled and followed on a case-by-case basis. Newer agents and more potent regimens are under continued surveillance. Two cases with structural malformations have been noted in female recipient offspring with exposure to MMF during pregnancy. Data remain limited and are insufficient to determine a specific malformation incidence. The risk of graft rejection as well as graft dysfunction must be weighed against the risk of potential teratogenicity when maintaining female recipients on MMF during pregnancy. For male recipients maintained on MMF, there have been no patterns of problems noted in their offspring. The structural malformation incidence in newborn of cyclosporine-treated recipients is in the range expected for the general population without any specific predominance of malformations. It remains to be seen whether or not any specific pattern of problems will become apparent in the newborn with newer regimens. Controversy surrounding breastfeeding continues, although it has become an option that some recipients choose to consider. Data have accrued in liver, heart, pancreas-kidney and lung recipients. Among lung recipients, there appears to be poorer maternal survival postpartum, which may be related to pregnancy or may be inherent in this population. Continued entries to the registry, especially in light of newer combinations of immunosuppressive agents, should help to provide the guidelines for management. All centers are encouraged to participate.

The auditory P 300 correlates with specific cognitive deficits in Parkinson's disease.

An abnormally prolonged latency of the P 300 event-related potential has been reported in several types of dementing illnesses, including Parkinson's disease (PD). While some PD patients have dementia, a significant number of PD patients have less severe cognitive impairments. We examined the relationship between the auditory P 300 and a neuropsychological battery of 11 tasks in 43 PD patients. The quantitative relationship between the individual neuropsychological measures and the P 300 was examined using partial correlation and analysis of covariance techniques which controlled for age, education, and illness duration. The strongest correlations were between P 300 and both short-term memory and visual perception. Global cognitive deficits do not appear to relate to the abnormal P 300 responses in PD: instead, specific aspects of cognitive decline accounted for the electrophysiological abnormalities. An abnormally long or absent P 300 correlated with deficits on select cognitive tasks: those involving memory, visual perception, and abstract reasoning. The interactions between anatomical and neurochemical abnormalities in PD are discussed in light of the pattern of deficits seen in this study.