Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline.

Proarrhythmias due to drug-induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late-stage development.

Ultrastructural localization of aluminum in hepatocytes of hemodialyzed patients.

The livers of 7 hemodialyzed patients have been studied by electron microscopy and electron probe X-ray microanalysis. In 6 patients dialyzed for a long time (at least 39 months), aluminum has been detected in high concentrations in phagolysosomes of hepatocytes; in these lysosomes aluminum is associated with phosphorus. In 2 of these 6 patients, a very large number of aluminum inclusion bodies were found inside hepatocytes and this aluminum accumulation was associated with severe ultrastructural lesions of the cells.

[Prevention and treatment of cytomegalovirus infections after graft of allogenic bone marrow].

Cytomegalovirus (CMV) infection is the most frequent cause of lethal infection after bone marrow transplantation. Viremia occurs in 50% of patients seropositive for CMV before transplantation. Interstitial pneumonitis due to CMV occurs in 10% to 20% of patients with 85% mortality.

[Trial treatment of severe Raynaud's phenomenon with prostacyclin (PGI2)].

Severe forms of Raynaud's phenomenon are very disabling. In a randomized, single-blind trial, we have evaluated the effects of PGI2, a natural compound with strong vasodilator and anti-platelet activities, in 14 patients presenting with Raynaud's phenomenon. The patients received a 24-hour infusion of either PGI2 in doses of 10 mg/kg.

[Determination of the dose-response curve for atracurium dibesylate in the anesthetized adult].

The mechanical response of the adductor pollicis to a 0.15 Hz stimulation of the ulnar nerve was studied in 35 unpremedicated adult patients (mean age 38 yr) under general anaesthesia using thiopentone, fentanyl and a N2O/O2 mixture under mechanical ventilation. PaCO2, pH, K, Ca, Mg plasma levels and temperature were in the normal range.

Serum IgE in primary glomerular diseases.

Serum IgE was measured by RIST test in 181 adult subjects, with log transformation. In 24 controls the geometric mean was 109 IU/ml, with an upper limit (geometric mean +/- 2 SD) of 460 IU/ml. 157 cases of glomerulonephritis (GN) classified according to light and immunofluorescence microscopy were studied.

[Muscle relaxant effect of atracurium in patients with chronic renal failure].

The muscle relaxant effect of atracurium was monitored by measuring the strength of the adductor pollicis muscle (TH) elicited by supramaximal stimulation of the ulnar nerve at the wrist. In order to facilitate tracheal intubation, a dose of 0.6 mg X kg-1 was administered in 10 patients with complete renal failure.

Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir.

In a double-blind controlled study, oral acyclovir was compared with placebo in 39 consecutive patients undergoing bone-marrow transplantation. Acyclovir was given at a dose of 200 mg every 6 h from 8 days before to 35 days after bone-marrow transplantation. Pharmacokinetic studies showed good absorption of the drug, despite intestinal damage related to chemoradiotherapy or gut graft-versus-host disease.

The effects of chronic renal insufficiency on the pharmacokinetics of doxycycline in man.

The pharmacokinetics as well as erythrocyte and plasma protein binding of doxycycline were studied in fifteen patients with various renal function impairments after oral doxycycline polyphosphate single administration. Plasma half-life (t 1/2), area under the plasma concentration-time curve (AUC), urinary excretion, renal clearance, erythrocyte and plasma protein binding (%) were regressed vs creatinine clearance. No significant correlations were observed between t 1/2 or AUC and renal function nor plasma protein binding and plasma albumin concentrations.

[Acute renal insufficiency in spontaneous septicemia of renal origin. Analysis of a series of 17 patients].

Seventeen recent cases of spontaneous renal septicemia with acute renal failure are reviewed, confirming the need for a diagnostic and therapeutic strategy to restore the fluid balance, if necessary with the aid of an artificial kidney, and the urgency of treating local infection and the pathogenic agents involved. The case review also suggest that the high mortality rate of this infection, estimated by some observers at 50 p. cent, can be greatly reduced by early radical urological treatment.

A hypereosinophilic syndrome with retinal arteritis and tuberculosis.

A 35-year-old man was initially seen with a decrease in visual acuity, renal insufficiency, and elevation of the eosinophil count in the blood. The ocular syndrome was caused by extensive arterial occlusions of the retina. The subsequent apparition of cardiac, pulmonary, and neurologic signs fulfilled the criteria for the diagnosis of hypereosinophilic syndrome (HES).

[Suppression of proliferative allogenic response in patients receiving a programmed series of transfusions prior to renal graft].

The effects on the lymphocytic proliferative allogenic response of a protocol of planned blood transfusions have been studied in 12 patients with chronic renal failure. This study was prospective and the experiments were performed before kidney grafting. The results were then compared with the clinical results of the graft.

[Scintigraphy with technetium dimercaptosuccinic acid (99 m TC DMSA). Contribution to the functional assessment of individual kidneys (author's transl)].

Renal uptake of 99m Tc DMSA was used to evaluate the renal function of 16 healthy subjects (controls) and 115 patients with various urinary tract diseases. Scintigraphic examination was carried out 6 hours after an intravenous injection of the product. In the 16 controls Tc DMSA uptake was 25.

[Surgical methods of cadaver nephrectomy prior to kidney transplantation (author's transl)].

Surgical technique during donor's binephrectomy is one of the most important parameters conditioning early success after kidney transplantation. Experimental studies showed that tractions on the renal pedicle during kidney removal had a detrimental effect upon renal cortical vascularization and subsequent kidney function. Cortical vasoconstriction is equivalent to acute warm ischemia and therefore impedes prolonged kidney preservation.

[Removal of kidneys for transplantation. Experience in a French general teaching hospital (author's transl)].

A law issued on december 22, 1976 and aimed at increasing the number of kidney transplantations in France authorizes the removal of kidneys from deceased persons of full age provided they had not expressed refusal while still alive; for decreased persons under age, removal is subject to written consent of the legal representative. In a general teaching hospital of whose than 1 000 beds, 21 kidneys donors were operated upon between January 1, 1971 and December 31, 1975 (an average of 4.2 per year).

[Significance of lymphocytotoxic antibodies in kidney transplantation revisited (author's transl)].

Lymphocytotoxic antibodies against peripheral blood lymphocytes (LT anti-PBL) were investigated in sera obtained before and after 148 kidney transplantations. Reactivity was assayed on a panel of unrelated donor cells and, in 15 cases, on the kidney donor's lymphocytes. Pretransplant LT anti-PBL, whether they persisted or not after grafting, were of no prognostic value.

[Diagnostic value of computerized tomography in severe renal tissue infections (author's transl)].

A patient with severe acute pyonephritis and septicaemia had persistent symptoms of infection despite appropriate chemotherapy. Although no obstruction was seen on ascending ureteropyelography, exploratory lumbar incision was considered. However, computerized tomography (CT scan) failed to show any obstacle or collection of pus but indicated diffuse infection of kidney.