Ethics of trial drug use: to give or not to give?

The 2014 outbreak of Ebola viral disease in some West African countries, which later spread to the USA and Spain, has continued to be a subject of global public health debate. While there is no approved vaccine or drug for Ebola cure yet, moral questions of bioethical significance are emerging even as vaccine studies are at different clinical trial phases. This paper, through a normative and critical approach, focuses on the question of whether it is ethical to give any experimental drugs to Ebola victims in West Africa or not. Given the global panic and deadly contagious nature of Ebola, this paper argues on three major compassionate grounds that it is ethical to use experimental drugs on the dying African victims of Ebola. Besides respecting patients and family consent in the intervention process, this paper argues that the use of Ebola trial drugs on West African population will be ethical if it promotes the common good, and does not violate the fundamental principles of transparency and integrity in human research ethics. Using Kantian ethical framework of universality as a basis for moral defense of allowing access to yet approved drugs. This paper provides argument to strengthen the compassionate ground provisional recommendation of the WHO's Strategic Advisory Group of Experts on Immunization (SAGE) on Ebola vaccines and vaccination.

Magnetic resonance imaging of suspected atrial tumors.

Two-dimensional echocardiography has become the standard technique for evaluation of cardiac and paracardiac mass lesions. We have used magnetic resonance imaging (MRI) as an independent assessment of cardiac-associated masses in patients with echocardiograms demonstrating sessile atrial tumors. MRI was performed in seven patients, ages 33 to 84, whose echocardiographic diagnoses included left atrial mass (five), right atrial mass (one), and interatrial mass (one). In four of the patients with a diagnosis of left atrial mass, MRI showed extracardiac compression of the atrium, simulating a tumor (hiatal hernia, tortuous descending aorta, bronchogenic cyst). MRI was entirely normal in one patient with an apparent left atrial mass. MRI elucidated extension of an extracavitary mass into the interatrial septum in two patients. One of these patients with an echocardiographic right atrial mass had extension of a lipoma into the interatrial septum without atrial tumor. MRI confirmed the echocardiographic diagnosis of an interatrial mass in the other patient. We conclude that MRI, because of its ability to define anatomic relationships and tissue characteristics, is a powerful noninvasive tool for evaluating suspected cardiac mass lesions. Although echocardiography remains the primary screening test for the detection of cardiac masses, MRI is a more specific modality for precise diagnosis. Correct MRI interpretation may obviate the need for invasive studies or surgery.

Vaginal PGE2 and intraamniotic PGF2 alpha for the termination of second trimester pregnancy.

PIP: A study was conducted in New York City over the September 1982-June 1983 period to examine the role of combinations of intraamniotic instillation of 20 mg prostaglandin E2 (E) and 20 mg vaginal prostaglandin F2 (F) for the termination of 2nd trimester pregnancies. The women seeking abortion were assigned to 1 of 5 treatment methods. The standard procedure included a medical history, physical examination, birth control and abortion counseling, laboratory tests, and a pregnancy sonogram for all participants, who were randomly assigned to the treatment methods. The standard 2nd trimester abortion method used in the Gynecology-Day Hospital of the Bronx Municipal Hospital Center was F 40 mg intraamniotic followed by intravenous oxytocin at 20-30 mU/min approximately 12 hours after the amnioinfusion. This standard method was compared to 4 others in which only 20 mg F was given in association with a 20 mg vaginal suppository of E. Most women receiving E were given lomotil and an antiemetic as prophylaxis against gastrointestinal side effects. The groups were comparable in terms of age and parity. Statistical endpoints used were the P50 cumulative abortion time, the 24 hour cumulative abortion time, and failure rate defined as no abortion in 48 hours. The lowest P50 value was obtained in the EEF group, and there was a significant difference between this group and the FF group. The 24 hour abortion rates were lowest in the EF and the FEE group. The EF group also had the highest failure rate, indicating that the total dosage was inadequate. There were multiple omissions in the recording of side effects, making it impossible to accurately report on whether the incidence of side effects changed with these regimens. On the basis of these results as well as previous data, it is postulated that PGE2 is the better agent for uterine conversion and that PGF2 acts primarily as an oxytocic agent.^ieng

Internal and external cervical os dilation with vaginal 15-methyl prostaglandin F2 alpha.

PIP: Changes in the external and internal cervical os after vaginal administration of a suppository containing 1 mg of 15-methyl prostaglandin F2alpha (PGF2alpha) were differentiated in this study of 19 pregnant women prior to a 1st trimester pregnancy termination. Mean age of the women was 20.6 +or- .99, mean parity was .68 +or- .2, and mean gravidity was 2.32 +or- .54. Pregnancies averaged 10 weeks duration. Cervical dilatation before administration averaged 6.89 +or- .45 mm in the external os and 3.37 +or- .43 in the internal os; compared to 10 +or- .44 mm in the external os and 8.05 +or- .57 mm in the internal os 3 hours after administration of suppositories. Mean additional dilatation prior to the procedure was 1.84 +or- .43 mm. 74% of the women experienced diarrhea, 37% had vomiting, 27% cramps, 21% nausea, 26% vaginal pain, and 26% bleeding prior to the procedure. The greater dilatation of the internal os found in the study is comparable to the behavior of the cervix in the uterus near term when lower segment changes often precede the dilatation of the external os.^ieng

Early pregnancy-abortion model using sulprostone.

Sulprostone has been demonstrated to be effective as a parenteral abortifacient, but not as a vaginal suppository. A vaginal preparation was given to 19 women to determine its mechanism of action, and to confirm the principle of uterine conversion as a biological model for the induction of an early abortion. The drug was administered to women with confirmed pregnancies and amenorrhea and not exceeding 49 days. A 95% success rate was obtained with an incidence of drug related side effects of 20% as opposed to the general 80-90% figure of PGE2 and F2a. The hormone profile obtained revealed a parallel fall in hCG and estradiol, and progesterone. This study confirms the value of uterine conversion, a concept that describes the change in uterine reactivity following PG administration and determines the phase when uterine activity is no longer dependent on exogenous oxytocic medication.

Immunochemical CK-MB assay for myocardial infarction.

The diagnostic efficiency of an immunochemical assay for CK-MB (I-MB) was compared with that of an electrophoretic procedure for this isoenzyme (E-MB) in 215 consecutive patients in whom acute myocardial infarction (MI) was clinically suspected. All patients were investigated with a standard protocol consisting of serial assays of total creatine kinase (CK) and lactic dehydrogenase (LD) activities, CK-MB and LD1 isoenzymes, and electrocardiograms. Technetium pyrophosphate cardiac scans were obtained for eleven patients; autopsy was performed in six cases. The diagnosis of acute MI was established in 45 patients. The coefficients of variation for the intra-assay and interassay precision of I-MB assay ranged from 2.05%-7.2%. Concordance between the I-MB and E-MB results at the decision values for acute MI was observed in 203 of 215 patients (94.4%). At the cut-off point of 10 U/L, the I-MB assay was 95.5% sensitive and 95.3% specific for acute MI; the corresponding rates for the E-MB test were 93.3% and 94.7% respectively. The test efficiency rate for I-MB assay was 95.3% and that of E-MB procedure 94.4%. A complete time-based isoenzyme protocol for the diagnosis of acute myocardial infarction has several variables; the need for interpretation of individual profiles and for the preparation of a formal report is discussed.

Dissociation between hepatosplenic and marrow iron in liver cirrhosis.

Histochemical study of tissue iron in the various parts of the reticuloendothelial system in 15 subjects with cirrhosis was performed. Stainable iron in the liver and spleen sections, generally in large quantities, was found in 13 of 15 cases. Paradoxical association of hepatosplenic siderosis with depletion of marrow iron reserves was observed in seven subjects. In all seven, gross gastrointestinal blood loss had occurred during life and the source of bleeding from one or more anatomic lesions was identified at the time of autopsy. Depletion of marrow iron reserves in these seven subjects can be attributed to two factors: first, the available marrow iron stores were used for erythropoiesis; second, the ample hepatosplenic iron deposits could not be mobilized for transport to the bone marrow. Thus, hepatosplenic iron in cases of cirrhosis seems to be sequestered from its normal metabolic pathways.

Failure of serum ferritin levels to predict bone-marrow iron content after intravenous iron-dextran therapy.

The relation between serum ferritin levels and stainable-iron deposits in the liver, spleen, and bone marrow was investigated in 36 patients with chronic renal failure who died after being on haemodialysis for 1-103 months. Elemental iron (mean, 5450 mg) had been given intravenously as iron dextran to patients in a long-term subgroup, who had been on dialysis for more than 3 months. The results of semiquantitative histochemical assessment of tissue iron in slides obtained at necropsy (scale 0 to 4+) were confirmed by chemical analyses of tissue iron. Serum ferritin levels correlated well with the degree of hepatosplenic siderosis but did not always correlate with bone-marrow iron stores in these patients. Serum ferritin concentrations were raised in 10 marrow-iron-depleted subjects (mean, 1336 ng/dl). The paradoxical association of hepatosplenic siderosis with marrow iron depletion was observed in most of the patients on dialysis for less than 40 months. The histochemical data show that the bulk of intravenously injected iron dextran is taken up by the liver and spleen; that the hepatosplenic stores fail to be mobilised to the bone marrow; and that intravenous iron-dextran therapy, by-passing the intestinal mechanism for the regulation of iron absorption, carries a high risk of long-term hepatosplenic siderosis.

Immunochemical LD1 assay for myocardial infarction.

The diagnostic efficiency of an immunochemical assay for LD1 (I-LD1) was compared with an electrophoretic procedure for this isoenzyme (E-LD1) in 100 consecutive patients hospitalized for a clinical suspicion of acute myocardial infarction (MI). All patients were investigated with a standard protocol including serial determinations of total creatine kinase (CK) and lactic dehydrogenase (LD) activities, CK and LD isoenzymes, and electrocardiograms. Thirty-two patients were diagnosed to have acute MI on the bases of positive CK-MB or EKG or both. The coefficients of variation for the intraassay and interassay precision of I-LD1 assay ranged from 3.12% to 7.69%. Direct correlation between the I-LD1 and E-LD1 was very satisfactory (r = .961; P = less than .001). When the results of these two procedures were compared in terms of decision values for acute MI, there was agreement between them in 87 patients. At the cut-off point of 90 U/L, I-LD1 assay was 100% sensitive and 89% specific for acute MI; the corresponding figures for E-LD1 were 81% and 91%, respectively. The diagnostic efficiencies of the I-LD1 and E-LD1 procedures were 93% and 88%, respectively. A substantial saving in technologist time with the I-LD1 assay over the E-LD1 procedure was documented in this study.

Primary signet-ring cell carcinoma of the urinary bladder: review of the literature and report of a case.

A case of primary signet-ring carcinoma of the urinary bladder treated with total cystectomy and clinically disease-free three years and nine months after surgery is described. The signet-ring cell carcinoma of the bladder is a rare neoplasm; among the five cases found in the literature, the neoplasms pursued a fulminant course, diffusely invaded the bladder wall without forming intraluminal growths, and could not be controlled by segmental resection, radiotherapy, and chemotherapy alone or in combinations. The pathogenesis of mucus-producing signet-ring cell carcinoma in the urinary bladder, an organ that normally contains no mucogenic elements, is discussed. The histologic evidence for the origin of this neoplasm from the totipotent urothelium is illustrated.

Intraventricular thrombosis in polycythemia vera: A cause of intractable cardiac failure.

The occurrence of thrombotic events is central to the course of polycythemia vera. Myocardial, cerebral, peripheral, and pulmonary infarctions are frequent and are consequences of throbmoses in small and medium caliber arteries. Thrombosis in large caliber arteries is a rare event. Thrombosis within the chambers of the heart has not been hitherto reported. This report documents the occurrence of massive left ventricular thrombosis in a patient with polycythemia vera. The throbmus reduced the left ventricular capacity by about 75% and caused intractable congestive heart failure.

Correlation of the diagnostic skin test with the immunoperoxidase assay in ragweed hypersensitivity.

The results of the diagnostic skin test are correlated with those obtained with an immunoperoxidase (IP) assay in 17 patients with positive histories for ragweed hay fever. The IP assay, a version of the ELISA technique, employs polystyrene microtiter plates as the solid-phase, horseradish peroxidase as the enzymatic label and O-phenylene diamine as the enzyme substrate. Concordance between the results of these two diagnostic techniques was observed in 66 patients (86%). Among the 11 patients with discordant results the modified RAST test was in agreement with the IP assay in seven and with the diagnostic skin test in four patients. In these latter four patients ragweed-specific IgE antibodies were detected by the IP or the modified RAST assays in low titers. The coefficients of variation for the IP assay ranged from 8% to 14.3%. The pros and cons of the use in vitro tests (the IP and the RAST test) and the diagnostic skin test in clinical practice of allergy are discussed.

Hemosiderosis in hemodialysis patients. An autopsy study of 50 cases.

The distribution of stainable iron stores was investigated in various organs of 50 hemodialysis patients with chronic renal disease. Massive iron deposits were found in the liver and spleen. Among 18 patients with severe hepatosplenic siderosis, iron deposits were abundant in the adrenal glands, lymph nodes, and lungs and were sparse in the heart, kidneys, and pancreas. There was an absence or scarcity of stainable iron in bone marrow of 19 pats. In five of these marrow-iron-depleted patients, serum concentrations of ferritin were high. In long-term hemodialysis patients, a variety of factors make massive iron overloads of various organs a likely occurrence, severe hepatosplenic siderosis may occur in marrow-iron-depleted patients, and serum ferritin levels in this setting may not always accurately reflect the status of marrow iron store.