Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model

Dexniguldipine-HCl (DNIG) — a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MRD) — was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303±27 pmol/mg protein; DNIG (3.3 mol/l): 1,067±174 pmol/mg protein; F4-6P, solvent: 948±110 pmol/mg protein;n=8–9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC₅₀), 0.73 vs 5.4 mol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (B) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.Abbreviations DOX doxorubicin - CSA cyclosporin A - DMSO dimethylsulfoxide - DNIG dexniguldipine-HCl - DNR daunorubicin - MDR multidrug resistance - MITO mitoxantrone - pgp170 permease glycoprotein 170 - VER R.S.-verapamil Dexniguldipine-HCl is the proposed INN for compound B859-35, the R-enantiomer of niguldipine. Segments of this work have been reported in the abstract form     

Sinus of Valsalva aneurysm or fistula: management and outcome

BACKGROUND: Few large or long-term series exist regarding the management of patients with sinus of Valsalva aneurysms or fistulas (SVAFs). METHODS: Between 1956 and 1997, 129 patients presented with a ruptured (64 cases; 49.6%) or nonruptured (65 cases; 50.4%) SVAF. The patients included 88 men and 41 women, with a mean age of 39.1 years. Associated findings included a history of endocarditis (42 cases; 32.6%), a bicuspid aortic valve (21 cases; 16.3%), a ventricular septal defect (15 cases; 11.6%), and Marfan's syndrome (12 cases; 9.3%). Operative procedures included simple plication (61 cases; 47.3%), patch repair (52 cases; 40.3%), aortic root replacement (16 cases; 12.4%), and aortic valve replacement/repair (75 cases; 58.1%). RESULTS: There were five in-hospital deaths (3.9%): four due to preexisting sepsis and endocarditis and one that followed dehiscence of the repair in a patient with Marfan's syndrome. Two patients (1.6%) had strokes during the early postoperative period. The survivors were followed up for 661.1 patient-years (5.3 years/patient). The following late complications occurred: prosthetic valve malfunction (5 cases; 3.9%), prosthetic valve endocarditis (3 cases; 2.3%), SVAF recurrence (2 cases; 1.6%), thrombosis (1 case; 0.8%), and anticoagulation-related bleeding (1 case; 0.8%). CONCLUSIONS: Resection and repair of SVAF entails an acceptably low operative risk and yields long-term freedom from symptoms. Early, aggressive treatment is recommended to prevent endocarditis or lesional enlargement, which causes worse symptoms and necessitates more extensive repair.     

Infection after cardiac transplantation: treatment and prognosis

Since July 1982, 18 patients have undergone orthotopic cardiac transplantation at the Texas Heart Institute with steroid and cyclosporine immunosuppression. There have been no deaths from infection despite 15 bacterial, 8 viral, 6 fungal and 1 protozoal infection episodes. With a total follow-up of 90 patient months (mean follow-up, 5.0 months; range 0.1 to 18 months), the incidence of infection is 33 episodes per 100 patient months (1.7 episodes per patient). Only 23 episodes (77%) required drug treatment. Compared to conventional immunosuppressive regimes, cyclosporine treatment is associated with a substantial reduction in the incidence and severity of infection in cardiac allograft recipients.     

Partial Artificial Heart (ALVAD) Use with Subsequent Cardiac and Renal Allografting in a Patient with Stone Heart Syndrome

The abdominal left ventricular assist device (ALVAD) is an order of magnitude more effective than conventional intra-aortic balloon pumping (IABP) in unloading and providing circulatory support to the failing left ventricle. This is a report of a unique case which demonstrates that in the absence of pulmonary vascular obstruction or constriction, the ALVAD can substitute for both left and right heart function. A 21-year-old patient with a congenital bicuspid aortic valve developed acute valvular endocarditis which rapidly progressed to congestive heart failure. An operation was undertaken, the mitral and aortic valves were excised and replaced by porcine heterografts, and a fistula from the right sinus of Valsalva to the right ventricle was closed. When coronary circulation was restored, irreversible ischemic contracture of the left ventricle, or "stone heart" syndrome, developed and emergency ALVAD or partial artificial heart implantation was effected. This device functioned as a total artificial heart for nearly six days, while a donor heart was sought. The patient then underwent removal of the ALVAD and cardiac and renal allografting. The transplanted heart functioned well, but the patient expired fifteen days later from gram-negative sepsis.     

Lysis of venous clots by local intraarterial Thrombolysin injection in the rat

Intravascular coagulation is the final common pathway of failure in replanted digits and "free" tissue transfers. To address this clinical problem, a model based upon intimal damage and stasis in the rat femoral vein was developed. The ability of local, intraarterially administered Thrombolysin to achieve "local" clot lysis was investigated. "Systemic anticoagulation" was measured by standard hematologic monitoring and "systemic thrombolysis" by lysis of a contralateral standard femoral vein clot. The mean drug volume required for local clot lysis was proportional to the clots' duration time; 7.8 ml required for the 30-minute, and 17.0 ml required for the 60-minute clot (p less than 0.05). Lysis was achieved by local intraarterial Thrombolysin in 87% of the clots of 30 minutes' duration and in 94% of the clots of 60 minutes' duration. Overall, just 3.6% of contralateral clots lysed (p less than 0.001). Systemic anticoagulation did not occur.     

Femorofemoral bypass: prognostic factors

During a 17-year period, femorofemoral bypass grafting was performed on 85 patients as the primary operation for unilateral iliac artery disease. Of these patients, 53 (62%) were operated on for claudication and 32 (38%) for limb salvage. There were two operative deaths (2.4%). The 5-year cumulative graft patency rate was 63.2%, and the limb salvage rate was 70%. Prognostic factors included poor runoff and distal disease, donor iliac artery stenosis prior to femorofemoral bypass grafting, and progression of disease in the donor vessel following surgery. Definitive surgical correction is safe and effective with good long-term results.     

Takayasu's arteritis: diagnostic considerations and surgical treatment

A 20-year-old white woman with Takayasu's arteritis had headaches, neck soreness, and a right carotid bruit. Corticosteroid treatment only temporarily relieved symptoms and caused Cushing's syndrome because of high dosage requirements. Progressive narrowing of the right common carotid artery occurred despite treatment. The diseased portion of the artery was successfully resected and replaced by a Dacron graft. Corticosteroid treatment was then tapered and discontinued, and the patient has remained well for 3 years. Carotid Doppler and real-time ultrasound studies performed more than 2 years after surgery showed a patent graft and no new disease process. This technique may be of value in selected cases for both prevention of cerebral ischemia and the elimination of local symptoms of the inflammatory process.     

Surgical management of 56 patients with congenital coronary artery fistulas

Over a 25-year period, 58 patients underwent evaluation or surgical treatment of coronary artery fistulas, or both, at our institution. Twenty-one patients had major associated cardiac defects, either congenital or acquired, and 9 had multiple fistulas. Fistulas to the left heart were unusual. Exertional angina and dyspnea were the most common presenting symptoms, but most young patients were asymptomatic. Seventy percent had audible heart murmurs. No operative deaths occurred in patients with isolated fistulas. Coronary artery fistulas cause symptoms due to "coronary steal" with resulting myocardial ischemia and, more rarely, marked left-to-right or left-to-left shunting. Definitive surgical correction is safe and effective, with good long-term results.