A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Transposition of the great arteries and isolated origin of the sinus node artery

We report the cases of 2 newborns who underwent at 7 days of age an arterial switch operation for transposition of the great arteries with a rare coronary anomaly: the left and right coronary arteries originated with a single ostium from sinus 1 and the sinus node artery had an isolated origin from sinus 2. The sinus node artery was reimplanted into the new aorta in both patients. Both babies were discharged in sinus rhythm. Preserving the vascularization of the sinus node may avoid the occurrence of postoperative atrial rhythm disturbances.     

Growth of the hypoplastic aortic arch after simple coarctation resection and end-to-end anastomosis.

Surgical treatment of a hypoplastic aortic arch associated with an aortic coarctation is controversial. The controversy concerns the claimed need to surgically enlarge the diameter of the hypoplastic arch, in addition to resection and end-to-end anastomosis. The purpose of this prospective study is to determine the fate of the hypoplastic aortic arch after resection of the aortic coarctation and end-to-end anastomosis. Between July 1, 1988, and January 1, 1990, 15 consecutive infants less than 3 months of age with an aortic coarctation were evaluated echocardiographically. A Z-value was calculated, being the number of standard deviations the aortic arch differs from the expected value, derived from a control group. Eight of these 15 infants had a hypoplastic aortic arch with a mean Z-value of -7.14 +/- 1.39. The other seven infants had a "normal" aortic arch with a mean Z-value of -1.85 +/- 1.08. All 15 infants underwent simple coarctation resection and end-to-end anastomosis. Six months after operation the mean Z-value increased significantly in those with a hypoplastic arch to -1.08 +/- 0.69 (p less than 0.0001) and in those with a "normal" aortic arch to 0.106 +/- 0.99 (p = 0.004). No infant died in our series (0%; CL 0% to 12%) and a recoarctation developed once (12.5%; CL 2% to 36%). Therefore we believe that simple resection and end-to-end anastomosis is the operation of choice for aortic coarctation associated with a hypoplastic aortic arch despite the presence of a ventricular septal defect and that enlargement of the hypoplastic aortic arch is not necessary.     

Splenic Abscess Complicating Infective Endocarditis: Three Case Reports

We present three case-reports of splenic abscess in patients who were initially diagnosed with bacterial endocarditis. In all cases the diagnosis of splenic abscess was based on the findings of abdominal CT scan or MRI. All patients were treated by laparotomy and splenectomy. Two patients fully recovered and one patient, who suffered from splenic rupture and massive blood loss before surgery, died.

Splenic abscess is a well-described but rare complication of infective endocarditis. Rapid diagnosis and treatment are essential as its course can prove fatal.

Abdominal CT scan or MRI should be performed if there is clinical suspicion of splenic abscedation. Immediate splenectomy combined with appropriate antibiotics and valve replacement surgery is the treatment of choice. Splenic tissue is very fragile — especially if the abscess is located subcapsular — and a splenic rupture can result from minimal trauma. If the patient’s general state allows it, it is best to perform splenectomy prior to valve replacement surgery to prevent re-infection of the valve prosthesis. A combined one-stage procedure is also an option.     

Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts: comparison of Echovist-200 and Echovist-300, timing of the Valsalva maneuver,and general recommendations for the performance of the test

BACKGROUND AND PURPOSE: Cardiac right-to-left shunts (RLS) can be identified by transesophageal echocardiography (TEE) as well as by transcranial Doppler ultrasound (TCD) using contrast agents, such as Echovist-200 or Echovist-300 in conjunction with a Valsalva maneuver (VM) as provocation procedure. Both Echovist preparations are in use. Currently, the appropriate timing of the VM is still under debate. Methods: Sixty-four patients were investigated by both TEE and bilateral TCD of the middle cerebral arteries. The following protocol was applied in a randomized way: (1) no VM, (2) VM for 5 s starting with the beginning of Echovist-300 injection, (3) VM for 5 s starting 5 s after the beginning of Echovist-300 injection, (4) VM for 5 s starting 10 s after the beginning of Echovist-300 injection, and (5) VM for 5 s starting 5 s after the beginning of Echovist-200 injection. Results: In 27 patients, an RLS was demonstrated by both TEE and contrast TCD (shunt-positive). Twenty-two patients were negative in both investigations, no patient was positive on TEE but negative on TCD, 15 patients were only positive on at least one TCD investigation but negative on TEE. Tests 3 and 5 were the most appropriate ones; test 3 was slightly superior to test 5. Conclusions: TCD using Echovist-300 or Echovist-200 is a sensitive method to identify TEE-proven cardiac RLS. To achieve the best diagnostic accuracy, the VM should be performed for a duration of 5 s starting at 5 s following the beginning of contrast injection.