Multiple-dose pharmacokinetics and safety of two regimens of quinupristin/dalfopristin (Synercid) in healthy volunteers.

Quinupristin/dalfopristin (Q/D) is a novel streptogramin antibiotic for the treatment of severe gram-positive infections. The purpose of this open, nonrandomized, parallel-group, phase I trial was to evaluate Q/D pharmacokinetics after single and repeated doses under the two different dosing regimens corresponding to the effective doses and to evaluate tolerability. Two groups of 10 healthy volunteers received multiple 1-hour intravenous infusions of 7.5 mg/kg Q/D either every 8 or 12 hours for 4 or 5 days, respectively. Plasma concentrations of Q, D, and metabolites were determined using high-performance liquid chromatography and selective microbiological assays. The two regimens q8h and q12h lead to the same disposition profile after single and repeated administration. Single-dose data confirmed the high plasma clearances of Q and D (about 0.90 l/h/kg) obtained previously. Unchanged drugs were the main components in plasma, with each of the three metabolites representing about 20% (in terms of the AUC ratio) of the parent drugs. Comparable steady-state concentrations were reached from day 2 of both regimens. A similar moderate increase in Cmax and AUC (about 20%) of parent drugs was observed between the first and last day of treatment. This phenomenon, which was also observed for the metabolites, was not expected considering the short terminal disposition half-lives of the parent drugs and trough plasma concentrations of all components mostly below the limits of quantitation at steady state, whatever the dosing regimen. The clearances of parent drugs at steady state were about 20% lower as compared with that observed following the first drug administration (statistically significant difference). No trend suggesting a treatment effect on any laboratory parameter, vital signs, or electrocardiographic parameters was identified. However, 80% of subjects reported venous adverse events probably related to treatment.

Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group.

AIMS: The objectives of this study were to assess the safety, pharmacokinetic and pharmacodynamic profiles, and antiviral efficacy of pegylated interferon-alpha2b monotherapy in patients with chronic hepatitis C. METHODS: Fifty-eight patients (38 men, 20 women; age range, 25 to 65 years) with compensated chronic hepatitis C were enrolled in this open-label, randomized, active controlled study. Patients received 0.035 to 2.0 microg/kg pegylated interferon-alpha2b subcutaneously weekly or the active control, interferon-alpha2b 3 million IU subcutaneously three times/week, for 24 weeks. Safety and antiviral efficacy assessments were performed during treatment and in a subsequent 4-week follow-up period. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. RESULTS: Pegylated interferon-alpha2b produced dose-related reductions in white blood cells, neutrophils, and platelets, and dose-related increases in oral temperature, serum neopterin, and serum 2'5'-oligoadenylate synthetase activity, which were qualitatively similar to those produced by nonpegylated interferon-alpha2b. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in pegylated interferon-alpha2b- and nonpegylated interferon-alpha2b-treated groups. Dose-related antiviral activity, as measured by loss of detectable serum hepatitis C virus RNA (<100 copies/mL), was noted at the end of treatment and after 4 weeks of follow-up. Both pegylated and nonpegylated interferon-alpha2b were rapidly absorbed, with maximal concentrations occurring approximately 8 to 12 hours after dose administration. Pegylated interferon-alpha2b had sustained maximal serum concentrations for 48 to 72 hours after dose administration, whereas nonpegylated interferon-alpha2b concentrations declined rapidly. Volume of distribution for both compounds was similar (approximately 1 L/kg). Pegylated interferon-alpha2b elimination half-life was approximately 10-fold greater, and mean apparent clearance was one tenth that of nonpegylated interferon-alpha2b. CONCLUSIONS: Pegylated and nonpegylated interferon-alpha2b safety and pharmacodynamic profiles were comparable. Pegylated interferon-alpha2b demonstrated delayed clearance compared with nonpegylated interferon-alpha2b, consistent with once-weekly administration.

A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group.

The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 microg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron-induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous infusion and intracavernous administration with and without a penile tourniquet.

The concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an alpha-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites, tmax was significantly increased after i.c. administrations and Cmax was significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 +/- 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 +/- 20.9, 61.4 +/- 12.2, and 58.7 +/- 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of approximately 25% and seemed to increase the efficacy of the drug in healthy volunteers.

Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses.

OBJECTIVE: The concentration-time profiles of specific metabolites of moxisylyte, an alpha-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). RESULTS: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. CONCLUSION: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.

Multiple-dose pharmacokinetics of ceftibuten after oral administration to healthy volunteers.

The pharmacokinetics of ceftibuten in plasma and urine were investigated after oral administration. Twelve healthy subjects were treated orally twice daily with 400 mg of the drug for 7 days; on day 8, the subjects received a last dose of 400 mg of ceftibuten. Ceftibuten and its metabolite, the trans isomer of ceftibuten, were assayed in plasma and urine by a specific HPLC method with UV detection. Ceftibuten was rapidly absorbed, as evidenced by the mean time to the maximum observed cis-ceftibuten concentration of 2.4 h. To describe the drug intake process, a Weibull model was used. For the metabolite, the mean time to maximum concentration in plasma was 3.25 h. Mean values for the terminal half-life in plasma were 2.17 h for cis-ceftibuten and 3.19 h for trans-ceftibuten. The overall elimination half-life, tmax, and total and renal clearances of cis-ceftibuten were invariant with respect to duration of dosing. The area under the plasma concentration versus time curve from 0 to infinity and the Cmax of this drug were significantly higher on day 8 than the values predicted from the elimination half-life computed on day 1 of treatment and the dosing interval. The pharmacokinetic parameters of trans-ceftibuten were invariant with respect to duration of dosing. Ceftibuten was well tolerated; there were no clinically significant adverse clinical events. The results from the present study indicate that the levels of cis-ceftibuten in plasma as well as in urine remain above the MICs for susceptible organisms over the dosing interval.

High-performance liquid chromatographic determination of ceftibuten and its metabolite in biological fluids: applications in pharmacokinetic studies.

An HPLC method with UV detection was developed for the analysis of ceftibuten (cis-isomer) and its metabolite (trans-isomer of ceftibuten) in plasma and urine. The detection was performed at 254 nm. The procedure for the plasma assay involves the addition of an internal standard (ceftazidime), followed by treatment of the samples with acetonitrile and dichloromethane. The urine samples, after dilution (10- to 40-fold), were analyzed by a column-switching technique without internal standard. The proposed technique is reproducible, selective, reliable, and sensitive. Linear detector responses were observed for the calibration curve standards in the ceftibuten conentration range of 0.10 to 20 mg/L for plasma and 0.10 to 50 mg/L for urine, and in the metabolite concentration range of 0.20 to 4 mg/L for plasma and 0.20 to 16 mg/L for urine. The limit of quantitation is 0.1 mg/L for ceftibuten and 0.2 mg/L for the transisomer in plasma and urine. The reproducibility of the analytical method according to the statistical coefficients is approximately 7%. The accuracy of the method is good; that is, the relative error is < 5%. The methods were applied to pharmacokinetic studies of ceftibuten after multiple oral administration (400 mg every 12 h for 8 days) to healthy volunteers.

[Late sequelae of severe injuries to the viscerocranium: clinical, radiographic and CT findings]. / Spätfolgen schwerer Gesichtsschädelverletzungen: klinische, röntgenologische und computertomographische Befunde.

After 1 to 7 years the late results of the surgical treatment of 21 patients with partly severe viscerocranial fractures have been evaluated by means of clinical as well as radiographic and CT examinations (with special thin sections and reconstructions). In demonstrating fractures and hemorrhages or mucosal swelling in the sinuses CT was found to be superior--except for fractures of the floor of the orbita and the nasal bone. Clinical dysfunctions and disorders included among others impaired eye motility (5), optic nerve lesions (2), bone prominences (14; predominantly at the orbital margins, in one case resulting in severe deformity of the face), dental and functional masticatory disorders (10), sinus problems and headache (11). The number of fractures that could be demonstrated by radiography and CT was reduced from 336 to 186, and that of fragment dislocations even to less than a quarter of the original figure. Apart from mucosal swelling and 2 hemorrhages, the sinuses--although in some cases severely injured--were well pneumatized again.

Intramyocardial distribution of hydroquinidine in the dog.

Hydroquinidine concentrations were measured simultaneously in the plasma and in right atrial and ventricular biopsy samples of four dogs in the steady state after eight days of oral sustained release hydroquinidine administration. The right ventricular concentrations were greater than the plasma concentrations in all samples (ratio 5.02(2.2)). In necropsy samples the ventricular concentrations were higher than the atrial concentrations, (ratio 1.54(0.36); p less than 0.01) and than the concentration in the sinus node region (7.72(1.85) ng.g-1 vs 4.21(2.6) ng.g-1). This study shows that intramyocardial pharmacokinetic measurements are possible and may help towards a better understanding of antiarrhythmic agents, particularly those with cumulative myocardial effect.

Vascular structure enhances regional resistance responses in mild essential hypertension.

Forearm blood flow (FABF) and forearm vascular resistance (FAVR) responses to sequential regional infusions of norepinephrine (NE) and angiotensin II (Ang II) were examined in 24 hypertensive and 18 matched normotensive subjects. Sensitivity to both vasoconstrictors, defined as the percentage increase in FAVR in response to the lowest dose of each agonist, was similar in the two groups. Also, the FABF response curve to the full range of both agonists did not differ between hypertensives and normotensives by analysis of variance (ANOVA). While the FAVR responses at the lowest doses of both NE and Ang II were similar in hypertensives and normotensives, FAVR responses in hypertensives diverged progressively from the normotensive response pattern, P less than 0.01 according to ANOVA. The hypertensives achieved greater maximum FAVR levels at the highest doses of both agonists, P less than 0.05 according to repeated measures ANOVA. After 10 min of ischaemic exercise, FAVR was higher in hypertensives than in normotensives (2.24 +/- 0.10 versus 1.87 +/- 0.08; P = 0.02, respectively). This value for FAVR was termed the minimum FAVR (mFAVR). The overall response pattern characterized by increased mFAVR, unchanged threshold sensitivity, steeper slope, greater maximum response and similarity of responses to both NE and Ang II is most consistent with a structural augmentation of resistance responses. A model was used in an effort to increase understanding of the vessel morphology. This model suggested that an increased wall/lumen ratio, perhaps without an actual increase in vascular smooth muscle mass, played an important role in the observed FAVR pattern.

Mechanism of increased alpha adrenergic vasoconstriction in human essential hypertension.

Multiple components of vascular alpha adrenergic responsiveness were investigated in twenty-four men with mild hypertension and eighteen age- and weight-matched normotensive controls. Arterial plasma norepinephrine (paNE), an index of sympathetic drive, was increased in hypertensives compared to normotensives (mean +/- SE), 199 +/- 24 vs. 134 +/- 11 pg/ml, P less than 0.02. The effective concentration of intra-arterial (iaNE) increasing forearm vascular resistance (FAVR) 30% (NE-EC30, an index of vascular alpha-receptor sensitivity) was similar in normotensives and hypertensives, 9 +/- 1 vs. 13 +/- 3 ng/100 ml per min, respectively, P greater than 0.3. The phentolamine induced reduction in FAVR, an index of vascular alpha-tone, was greater in hypertensives, -21.3 +/- 1.8 vs. normotensives, -14.9 +/- 1.2 U, P less than 0.02. We interpret these data as evidence for normal vascular alpha-receptor sensitivity to norepinephrine in mild hypertensives. Consequently, the increased sympathetic drive in mild hypertensives explains the elevated vascular alpha-tone. Although vascular alpha-receptor sensitivity to iaNE was normal, the FAVR responses at high doses (reactivity) were greater in hypertensives to regional infusion of both NE and angiotensin II. This "nonspecific" enhancement of vascular reactivity is probably explained by structural vascular changes in hypertensives.

[Risk of hepatitis in fibrin adhesion (author's transl)]. / Hepatitisrisiko bei der Fibrinklebung in der HNO-Chirurgie.

A prospective trial was performed on 146 patients, in whom fibrin tissue adhesive was applied during operations. 130 patients, who had received no fibrin glue, served as a control group, and were submitted to the same examinations as the first group of probands. In both groups we could not see any infections with hepatitis B.

[Computerized axial tomography in ORL diseases. Indications and advantages (author's transl)]. / Computertomographie bei Erkrankungen des HNO-Bereiches Indikation und Aussagekraft. I. Innerer Gehörgang, Kleinhirnbrückenwinkel, Schädelbasis.

Computerized axial tomography enables the accurate diagnosis of acoustic neuromas by non-invasive means, and it should therefore be used after conventional radiological methods. Small neuromas often only show non-specific signs and in these patients contrast cysternography is still necessary. Up to the present glomus jugulare tumours were diagnostically confirmed by angiography. Now the CT scan is recommended not only for diagnosis, but also for after-treatment follow-up and recognition of recurrent tumour growth. Tumours that infiltrate the skull base should be assessed by this method since the extent of the lesion can be exactly measured.

[Adenotonsillectomy in children with cleft palate. Indication, procedure, and results of 20 operations (author's transl)]. / Adenotonsillektomie bei Kindern mit Lippen-Kiefer-Gaumen-Spalte (LKG). Indikation, Ausführung und Ergebnisse von 20 Operationen.

Between 1972 and 1978 adenotonsillectomy was performed in 20 children with cleft palate. There was a reduction in the infection rate with a reduced incidence of hearing loss and maxillary sinusitis. A slight risk of speech impairment has been reported but is acceptable with regard to the advantages. When indicated, a scrupulous adenotonsillectomy in cleft palate children is justified.

[Closure of recurrent perforations of the tympanic membrane (author's transl)]. / Verschluss von kleinen Rezidivperforationen nach Tympanoplastic mit einem neuen Fibrinklebstoff.

In 20 patients with recurrent perforations of the tympanic membrane after tympanoplasty, closure was attempted with a fibrin tissue adhesive and in 15 this was successful. This method is recommended for the office out-patient treatment of recurrent tympanic membrane perforations.

[Endonasal sinus surgery with endoscopic control for recurrent sinusitis in children (author's transl)]. / Die endonasale Kieferhöhlenoperation mit endoskopischer Kontrolle als Therapie der chronisch rezidivierenden Sinusitis im Kindesalter.

Since 1976, 35 transnasal operations of the maxillary sinus with endoscopic control were performed in children as treatment for chronic sinusitis. After luxation of the inferior turbinate, a mucosal flap was developed to expose the lateral bony nasal wall. A sinus fenestra was then created to allow endoscopic control of the antrum during the operation. Gross pathological alterations of the mucosa were removed while most of the lining mucosa was preserved for recovery. 30 of the 35 children were followed from 4--18 months after surgery. 28 were without any discomfort. Although X-ray studies in many of the patients revealed mucosal swelling four weeks after surgery, the maxillary sinuses were well aerated 8 weeks after operation. Transnasal sinusotomy under endoscopic control is considered to be the treatment of choice for chronic sinusitis in adults and can now also be considered to be the treatment for similar disease in children.