Catastrophic intrauterine spinal cord injury caused by an arteriovenous malformation.

We report a baby born with flaccid quadraparesis that was considered possibly attributable to birth injury. Postmortem examination identified an injury that occurred well before delivery caused by hemorrhage from an arteriovenous malformation of the brainstem and spinal cord. We discuss imaging modalities to diagnose neonatal cord injuries, possible treatments, prognosis and end of life decision making for these unfortunate patients. We also emphasize the importance of the autopsy in cases of suspected birth injury.

Chemotherapy of L1210 leukemia with 5-azacytidine in combination with vincristine, adriamycin, or beta-cytosine arabinoside.

The cytotoxicity of vincristine (VCR), beta-cytosine arabinoside (Ara-C), or adriamycin (ADRIA) in combination with 5-azacytidine (Aza-CR) to L1210 leukemia in vivo was measured to determine if schedule-dependent synergistic or antagonistic drug interaction occurred. Two dose levels of Aza-CR were studied (0.1 and 0.5 mg/mouse), and cytotoxicity was measured by the spleen colony assay. For the combination of Aza-CR plus VCR, cytotoxicity was essentially additive or antagonistic when VCR preceded Aza-CR and additive or synergistic when VCR followed Aza-CR. When Aza-CR was combined simultaneously with either Ara-C or ADRIA, cytotoxicity was markedly antagonistic but was additive if drugs were given sequentially. When Ara-C was given as a 24-hour infusion before Aza-CR, the resultant cell kill was antagonistic (although slightly greater than that obtained for Ara-C alone). However, antagonism was even more marked when Aza-CR was given before the 24-hour infusion of Ara-C; cell kill was less than that observed with Ara-CR alone. Synergistic cytotoxicity was observed only with VCR administered after a low dose of of Aza-CR. Therefore, scheduling of drugs in combination with Aza-CR may be critical in the determination of the antileukemic cytotoxic effects.

Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors.

Small unilamellar vesicles (SUVs), consisting of highly purified distearoyl phosphatidylcholine and cholesterol (2:1 mol ratio) selectively increased the delivery of entrapped daunorubicin to solid tumors in vivo. When measured against free drug, SUV-entrapped daunorubicin produced a nearly 10-fold increase in tumor uptake and efficacy when used to treat a murine lymphosarcoma model (P-1798). In a second murine solid tumor model, MA16C mammary adenocarcinoma, the median survival time for daunorubicin SUV treatment at 2 mg/kg (72 days) was equivalent to the median survival time for the free drug optimal dose, 20 mg/kg (70 days), again indicating a 10-fold increased therapeutic efficacy. When compared at maximum efficacious doses in the MA16C model, the proportion of long-term survivors was greater with daunorubicin SUVs: 10 long-term survivors of 10 mice treated with daunorubicin SUVs at 25 mg/kg versus 4 long-term survivors of 10 mice treated with free drug at 20 mg/kg. The lowest toxic doses for MA16C tumor-bearing animals (treatment median survival times less than controls) were 25 mg/kg for free drug and 40 mg/kg for daunorubicin SUVs. The demonstration of enhanced antineoplastic activity and an increased tolerance for daunorubicin suggests that this specific SUV composition may be an effective delivery system for a wide range of chemotherapeutic agents in the treatment of solid tumors.

Fluoxetine and extrapyramidal side effects.

OBJECTIVE: The authors' goal was to determine whether fluoxetine is associated with extrapyramidal side effects. METHOD: They assessed the notifications of extrapyramidal manifestations in patients given fluoxetine in the New Zealand Intensive Medicines Monitoring Programme, a national system that monitored adverse reactions associated with fluoxetine over a 4-year period, and determined whether these adverse reactions were causally related to fluoxetine. RESULTS: In reports of adverse reactions in 5,555 patients given fluoxetine throughout New Zealand, there were 15 notifications of extrapyramidal events probably or possibly caused by fluoxetine. Fluoxetine was the only psychotropic agent used for seven of the 15 patients; two patients were also taking lithium, four were taking neuroleptics, two were taking tricyclic antidepressants, and one was taking metoclopramide. CONCLUSIONS: The authors conclude that fluoxetine may be associated with extrapyramidal reactions. These may occur with fluoxetine alone or fluoxetine may facilitate the reaction in patients receiving psychotropic medication or dopamine receptor blocking drugs.

Intraventricular hemorrhage in the premature rabbit pup. Limitations of this animal model.

The authors used the premature rabbit model to examine the pathophysiology of intraventricular hemorrhage (IVH). They studied the brains of 167 control animals, of 45 animals after a hypertensive insult, of three animals after a bolus infusion of normal saline, and of 10 animals after both insults. In none of the brains was IVH identified. Limited reproducibility may restrict the use of this animal model.

Sequence specific molecular recognition and binding of a monocationic bis-imidazole lexitropsin to the decadeoxyribonucleotide d-[(GATCCGTATG).(CATACGGATC)]: structural and dynamic aspects of intermolecular exchange studied by 1H-NMR.

The non-exchangeable and imino proton NMR resonances of the non self-complementary decadeoxyribonucleotide d-[(GATCCGTATG).(GATACGGATC)] as well as those of the 1:1 complex of the monocatonic bis-imidazole lexitropsin 1 to this sequence have been assigned by using a combination of NOE difference, COSY and NOESY techniques. Confirmation of complete annealing of the two non self-complementary decamer strands to give the duplex decadeoxyribonucleotide is obtained by the detection of ten imino protons. It is established that the sugar-base orientations of all the bases in the duplex decamer are anti. From NOE studies, it is concluded that the duplex oligomer is right-handed and adopts a conformation in solution that belongs to the B family. A population analysis reveals that the sugar moieties exist predominantly in the S-form (2'-endo-3'-exo). Addition of 1 to the DNA solution leads to doubling of the resonances for CH6(4,5), GH8(6), TH6(7) and T-CH3(7). The base, anomeric H1' and imino proton signals for the base sequence 5'-CCGT undergo the most marked drug-induced chemical shift changes. These results provide evidence that the lexitropsin is bound to the sequence 5'-CCGT in the minor groove of the DNA. NOE measurements between the amide protons (NH1 and NH4) and the imino proton (IV and V) signals confirmed the location and orientation of 1 in the 1:1 complex, with the imino terminus oriented to C(4). The specific binding of 1 to the sequence 5'-CCGT-3' deduced in this study is in agreement with the footprinting data obtained using the Hind III/Nci fragment from pBR322 DNA [Kissinger et al. 1987 (13)]. Intramolecular NOEs observed between H4 and H9 of the lexitropsin suggest that the molecule is not planar, but subjected to propeller twisting, in both the free and bound forms. Furthermore, NOE measurements permit assignment of the DNA duplex in the 1:1 complex to the B-form, which is similar to that of the free DNA. The [(T7A8T9).(A12T13A14)] segment of the DNA shows better stacking, by propeller twisting, compared to the rest of the molecule in the free as well as the complex forms. The intermolecular rate of exchange of 1 between the equivalent 5'-CCGT sites, at a concentration of 12 mM, is estimated to be approximately 88s-1 at 308 degrees K with delta G not equal to of 63 +/- 5 KJ mol-1.

The New Zealand intensive medicines monitoring programme in pro-active safety surveillance.

Purpose-The purpose of this paper is to demonstrate the pro-active nature of the New Zealand Intensive Medicines Monitoring Programme (IMMP) and make an assessment of its effectiveness in postmarketing drug safety evaluation.Methods-The IMMP undertakes prospective observational cohort studies of selected new drugs. Patient cohorts are established from prescription data received from dispensing pharmacists nationwide. Adverse events are reported by doctors on prescription follow-up questionnaires or as spontaneous reports. The method of signal generation is reviewed with particular emphasis on the review of individual event reports and their relationship to the medicine. Signals reported over the last 10 years are assessed for timeliness in advising the regulatory authority.Results-Mean cohort size is 10,964 patients and the mean study period for each drug was 58 months. A total of 153 signals were recorded from 11 drugs with 132 (86%) being notified to the regulatory authority prior to any publication in the literature. The use of 'incidents' in controlling for reporting bias is illustrated and examples are given of data on safety in pregnancy and lactation, the assessment of deaths, reassurance with drug scares, risk comparison and signal validation studies.Conclusion-PEM type methodology is effective and cost-efficient in pro-active safety surveillance even with limited resources. Copyright (c) 2000 John Wiley & Sons, Ltd.

Application of the Gosset icterometer to screen for clinically significant hyperbilirubinemia in premature infants.

To evaluate the ability of the Gosset icterometer to identify the need for serum bilirubin measurement in premature infants we compared 269 icterometer readings with simultaneous serum bilirubin determinations in 90 premature infants of < 37 completed weeks of gestation. The relationship between serum bilirubin and icterometer values was different from that described in term infants. Mean serum bilirubin concentrations were lower at each icterometer level in premature infants than those reported in term babies. Neither interobserver variability nor the color balance of ambient light affected icterometry. Bilirubin estimates by first-time users were slightly less accurate than those made by experienced users. The icterometer provides reliable, cost-effective screening for clinically important hyperbilirubinemia in premature babies if a calibration curve specific for those infants is used. This simple device performs as well as electronic bilirubin meters when it is used in this manner.

Does surfactant therapy prolong dying? Age at in-hospital death of extremely premature babies.

We reviewed medical records of inborn babies of < 30 gestational weeks who died before hospital discharge to identify the cause of death and age at death. We compared all surfactant-treated babies born during the first 19 months of our experience in a phase III trial of exogenous surfactant prophylaxis of respiratory distress syndrome with all untreated babies born during the 19 months immediately preceding the surfactant trial. The two groups were virtually identical in birth weight and gestational age. Mortality in all gestational age groups declined by half after the initiation of surfactant treatment. The mean age at death did not change significantly. Cases of early or late mortality did not change between the two periods. Exogenous surfactant prophylaxis does not significantly prolong the lives of extremely premature babies who are destined to die before hospital discharge.

Trial of slow release diltiazem for essential hypertension in general practice.

In New Zealand diltiazem has been approved since 1984 for the treatment of angina pectoris and was available only as short acting tablets. This study was a trial of a slow release formulation in the treatment of hypertension. A single blind placebo controlled study was undertaken on 24 patients in general practice using a once daily dose with a maximum of 360 mg. The mean fall in resting supine diastolic blood pressure was 17.3 mmHg, 95% CI 14.4 to 20.2; t = 12.2, df = 23, p = 0.0001. Twelve patients (50%) achieved a fall in diastolic pressure to 90 mmHg or less with the minimum dose (120 mg) while 19 patients (79%) achieved this level with up to 360 mg daily and 22 patients (92%) had a fall of diastolic pressure of 10 mmHg or more. One patient was withdrawn because of a rash. Other adverse reactions were mild and usually tolerable.

Study of reasons for cessation of therapy with perhexiline maleate, sodium valproate and labetalol in the intensified adverse reaction reporting scheme.

A questionnaire was distributed to doctors requesting reasons for cessation of therapy in patients on three drugs being intensively monitored. Adverse events were given as the reason in 20 percent of patients stopping treatment with perhexiline, 15 percent with sodium valproate and 43 percent with labetalol. These adverse events are listed and compared with those reported spontaneously to the medical assessor for the same period. Deaths reported do not appear to be drug related. Enquiry concerning reasons for cessation of therapy would appear to be a useful adjunct to spontaneous reporting of adverse events for drugs being monitored intensively. The number of additional adverse events derived from the questionnaires approximately equalled those from spontaneous reporting.

Short term safety assessment of cilazapril.

AIMS: To undertake an event monitoring study of cilazapril in general practice during the early marketing period, to provide some comparisons with other angiotensin converting enzyme inhibitors and to assess the monitoring method. METHODS: The monitoring was undertaken in the Intensive Medicines Monitoring Programme. Cilazapril was prescribed for mild to moderate hypertension in 996 patients at a recommended dose of 2.5-5.0 mg daily. The monitoring period was six months and practitioners were asked to report all adverse events. A reaction profile was prepared and compared with profiles for lisinopril, enalapril and captopril. The chi-square test was applied to differences in proportions. RESULTS: There were 84 (8.4%) reports describing 133 adverse events; 124 (93%) were assessed as reactions. Withdrawals totalled 53 (5.3%). The most common reactions were cough (2.9%), nausea and vomiting (1.3%) and lethargy (1.1%). Cilazapril had a higher proportion of neurological reactions (p < 0.001) (mainly headache) but a lower proportion of skin reactions (p = 0.001) than the other ACE inhibitors. It also had relatively less diarrhoea and there were differences in the patterns of psychiatric reactions. CONCLUSIONS: Cilazapril has a similar reaction profile to other ACE inhibitors but this paper shows differences, some not previously reported, that may assist selection when prescribing. Although there was a high rate of reporting of known adverse reactions, other events were reported at a very low rate and spontaneous reporting is thus confirmed as an unreliable method of monitoring for unexpected adverse reactions.

Fluoxetine and hyponatraemia--a potential hazard in the elderly.

AIMS: To review reports of the association between fluoxetine and hyponatraemia. METHODS: Reports of hyponatraemia associated with fluoxetine received over a four-year period in the New Zealand Intensive Medicines Monitoring Programme have been examined and these and other case reports in the literature, discussed. RESULTS: Seven patients, all women aged 68-88 years on fluoxetine 20 mg daily, developed hyponatraemia (serum sodium 114-128 mmol/L, five within 19 days of commencement of fluoxetine. The reported rate for women over 65 years was 8.5 per thousand. Withdrawal of fluoxetine was associated with recovery in all cases. CONCLUSIONS: Fluoxetine is associated with a significant incidence of hyponatraemia in the elderly, especially during the first weeks of therapy. It is advisable to monitor electrolytes in older patients during this period.

Survey of neurological problems with amiodarone in the New Zealand Intensive Medicines Monitoring Programme.

Early in the monitoring of amiodarone it was evident that neurological events were unexpectedly frequent. A survey was then undertaken to measure the frequency of such events and to gain some impression of their clinical importance. The method of survey was the completion of questionnaires by doctors when patients were being reviewed. There was a 63.6% response rate and questionnaires were evaluated for 408 patients. There were 192 events assessed as being adverse reactions from a group of nine types of neurological events in 112 patients. Paraesthesiae, ataxia, vertigo and tremor were the most common (7-9%). The overall rate of neurological reactions was 27.5%. The individual reactions are examined as are dose relationships.

Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.

OBJECTIVES: To examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy. DESIGN: Data mining using bayesian statistics implemented in a neural network architecture. SETTING: International database on adverse drug reactions run by the World Health Organization programme for international drug monitoring. MAIN OUTCOME MEASURES: Reports mentioning antipsychotic drugs, cardiomyopathy, or myocarditis. RESULTS: A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation. CONCLUSIONS: Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. The study shows the potential of bayesian neural networks in analysing data on drug safety.