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Biomedical subjects

S Weller

Publications and source records attributed to S Weller.

At least 37 records · Page 2Linked to original sources
PubMed1998

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy.

OBJECTIVE: The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir. STUDY DESIGN: In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks' gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants. RESULTS: Peak acyclovir plasma concentrations (mean +/- standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 +/- 0.7 microg/mL vs 0.74 +/- 0.6 microg/mL, P < .0001) and at steady state (3.03 +/- 1.0 microg/mL vs 0.94 +/- 0.7 microg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 +/- 3.6 h x microg/mL vs 7.71 +/- 2.5 h x microg/mL, P < .001) and at steady state (19.65 +/- 6.4 h x microg/mL versus 11.0 +/- 4.5 h x microg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected. CONCLUSION: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy.

Acyclovir↗
PubMed1998

A modular system for cemented and cementless implantation of femoral stem prostheses.

A femoral stem [BiContact, Aesculap, Germany) has been developed which is suitable for both cemented and uncemented implantation. Thus a highly standardized procedure and a standard implant for any iritraoperative finding is available. While the cemented stems have a smooth surface, the cementless implants are proximally coated with a microporous titanium plasmaspray [Plasmapore]. The strategy based on the intraoperative choice of the surgeon to use either cemented or cementless implants after bone preparation turned out to be very successful in our institution. A consecutive series of 250 cases with cemented implantation and 250 cases with uncemented implantation was analyzed in a prospective follow-up study, Pollow-up time averaged 7 years for cemented and 6.5 years for uncemented THRs. The follow-up rate was 88.7% in cases treated with cemented stems and 93.1% in cases treated with uncemented stems. The rate of aseptic loosening was 1.2% for the cemented version and 0.4-% for the uncemented stem. Radiological loosening could be observed in another 1.2% of the cemented stems and was not to be found in the uncemented cases. Our data suggest an excellent midterm stability of both the cemented and the uncemented version of the BiContact hip system. The long-term results for both the cemented and uncemented prostheses of our series are still to be evaluated.

Journal Article↗
PubMed1998

[Biological osteosynthesis].

A historic review distinguishes three periods in the treatment of fractures: The conservative period (approximate reduction and immobilization in traction or plaster cast), the mechanical and operative period (exact anatomical reduction and stable--even rigid--fracture fixation), and the biological and mechanical period (stability with strict attention to the biological environment of the bone circulation). Biological fracture fixation means: conservation of bone perfusion, protection of the soft tissue envelope and reduction of systemic stress by strengthening the host-defense mechanism. For preoperative planning, the following points have to be considered: choice of fixation method, reduction technique (open, closed, additional aids), surgical tactics (approach), and intra- and postoperative adjuvant therapy.

Combined Modality Therapy↗
PubMed1997

Autoantibodies in mice lacking terminal deoxynucleotidyl transferase: evidence for a role of N region addition in the polyreactivity and in the affinities of anti-DNA antibodies.

The generation of terminal deoxynucleotidyl transferase knockout mice (TdT0) has demonstrated that TdT is the only major activity involved in N region addition. This enzyme generates diversity by adding random nucleotides at the V-D-J junctions and by disrupting the formation of repetitive "homology-directed" junctions. Several studies have demonstrated that the Ig heavy chain third complementarity-determining region (H-CDR3) and the N region play a critical role: 1) in distinguishing between polyreactive and monospecific combining sites in natural and Ag-induced Abs; and 2) in the specificity and polyreactivity of natural autoantibodies (autoAbs) and in particular of anti-DNA Abs. To examine the impact of the lack of TdT on the natural autoAb repertoire in adult mice, we have stimulated TdT0 and TdT+ littermates with LPS. Serum studies demonstrate that TdT is not critical for the generation of B cells expressing autoAbs including anti-DNA Abs and rheumatoid factors. However, the generation of a large collection of hybridomas indicates that the frequencies of these cells are reduced in TdT0 mice mainly due to a lower incidence of polyreactivity; also, the lack of N region diversity seems to negatively affect the affinity of anti-DNA Abs. The physiologic relevance of these data is discussed.

Amino Acid Sequence↗
PubMed1997

Uncemented revision stem for biological osteosynthesis in periprosthetic femoral fractures.

Fractures around a femoral prosthesis have been treated with plating and additional cement, but this leads to further reduction of bone stock in the proximal femur. Since February 1992, we have dealt with this problem in 12 patients by revision using a long uncemented stem and distal interlocking combined with homologous bone grafting. Bony ingrowth and remodelling led to restoration of the proximal femur. After bone healing, removal of the distal interlocking screws converts the distal load transfer to the proximal anchoring of the revision stem so that osteointegration can occur in the trochanteric region. The clinical results were good in all the patients after a mean follow up of 23.5 months. This is a method which provides biological osteosynthesis and is especially indicated in younger patients.

Adult↗
PubMed1997

[Low loosening rate of a cemented titanium straight shaft prosthesis in long-term follow-up].

Aseptic loosening is still a major problem in total hip replacement. We studied the mid-term results of a straight stem femoral prosthesis made from titanium alloy (BiContact) and implanted with the use of bone cement. 250 hips in 238 patients have been implanted between 8/87 and 12/88 and followed up. 172 patients were alive and could be reached after 7 years. Two patients had to undergo revision surgery within the follow up period, and in two other patients radiolucencies could be found. A loosening rate of 1.2% and a rate of radiolucencies of another 1.2% indicate that the combination of a titanium alloy stem prosthesis with bone cement not necessarily leads to early loosening or a high loosening rate, which has been supposed by several authors. The design of the individual prosthesis seems to be of greater importance than the materials used.

Adult↗
PubMed1996

[External fixation of bones (fixateur externe) in fracture treatment].

In traumatology, we differentiate between conservative and surgical treatment. External fixation of the bone lies somewhere between the two. When deciding on the most appropriate treatment for each patient, the advantages and disadvantages must be carefully evaluated. However, there are a series of single or multiple injuries which can't be optimally treated with conservative procedures nor with invasive surgery. External fixation has become the treatment method of choice in many of these cases. The fragments to be stabilised are fixed with (so-called Schanz screws) or with (Steinmann pins) or with wires. The section which lies outside the body are attached to longitudinal rods. External fixation is a noninvasive, surgical method of fracture stabilisation with many advantages is easy to handle, has a low complication rate, can be taught anywhere, and can be used everywhere. There are great advantages in cases of soft tissue damage, in polytraumatised patients and in septic orthopedic surgery.

Equipment Design↗
PubMed1996

[Cystic bone changes. Etiology, diagnosis, therapeutic principles and personal results of treatment].

Various bone disorders become manifest as cystic lesions. The differential diagnosis must include benign and malignant tumors and also non-tumorous lesions, such as osteomyelitis. The most important and most frequent types of genuine bone cyst are juvenile bone cyst and aneurysmal bone cyst. When juvenile bone cysts occur in adults they are called solitary bone cysts. Despite intensive research the pathogenesis of bone cysts is still unknown to this day, so that successful causal therapy is impossible. The main problem in the treatment of bone cysts is their high rate of recurrence, rates ranging between 20% and 50% having been cited in the international literature. A critical review of the literature reveals few publications with helpful follow-up results. Most of the publications are case reports, and they frequently merely describe various forms of treatment. More recent reports are mainly concerned with such methods as curettage, steroid injections, and continuous decompression with perforated screws. Until the early 1980s, segmental bone resection was the treatment of choice. Because of its high complication rate it has since been abandoned. In the last analysis, the only well-established method for which long-term results obtained in studies of any size have been published, is curettage of the cyst and grafting with cancellous bone from the iliac crest. In our series, 41 patients were treated with this method, and we recorded a recurrence rate of 17.1%. Complications were rare. The risk of recurrence depended on the age of the patient. A higher recurrence rate must be expected in children under the age of 10 years. For this reason, operative treatment should not be performed until after that age if possible. Newer methods, such as steorid injections and continuous decompression by means of perforated screws, had better results in some studies, but only according to a few authors. Further research is needed to show whether our method will yield good results in the long term when applied in larger patient collectives.

Adolescent↗
PubMed1996

Evidence for a change in neural processing in phantom limb pain patients.

The present study was designed to investigate differences in neural processing of pain-related semantic information in amputees with and without chronic phantom limb pain and healthy controls. One-hundred-and-twenty words (40 neutral, 40 body-related, 40 pain-related) were presented in pseudorandom order to probe group differences in the perception of pain-related information. Visual evoked potentials (VEP) to the words were recorded from 11 scalp locations, EMG was measured at the stump and the contralateral side and bilaterally from the M. corrugator. In addition, heart rate and skin conductance responses were obtained. Both early and late VEP components were altered. Pain-free amputees showed a reduced N100 amplitude compared to phantom limb pain patients and healthy controls whereas the phantom limb pain patients displayed a significantly enhanced late positivity (500-800 msec after word onset). VEP components were unaffected by word type. The peripheral EMG responses were significantly different among the groups: phantom limb pain patients showed larger EMG reactions on the stump than on the contralateral side, whereas pain-free amputees showed the opposite effect. The data suggest an enhanced central and peripheral processing of visual stimuli in phantom limb pain patients.

Adult↗
PubMed1996

Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients.

To delineate the pathogenesis of the reduction in hemoglobin occurring in renal transplant patients treated with angiotensin converting enzyme inhibitors (ACEI) and azathioprine (AZA) a controlled, prospective trial of ACEI withdrawal was conducted. The ACEI was replaced by nifedipine or clonidine in 15 kidney transplant patients immunosuppressed with AZA and prednisone (enalapril in 14 and captopril in 1). Before and during 10 to 12 weeks after withdrawal of the ACEI, AZA metabolites, renal function parameters and hematological parameters including erythropoietin and reticulocytes were evaluated. Enalaprilat levels were measured and compared with 15 similar patients matched for transplant function and enalapril dosage immunosuppressed with cyclosporine and prednisone. AZA metabolites did not differ significantly in the presence or absence of the ACEI. Enalaprilat levels also showed no significant difference between the two patient groups treated with AZA or cyclosporine. Hematocrit and hemoglobin increased significantly from 37.5 +/- 6.4 to 39.7 +/- 3.6% (mean +/- SD, P = 0.02) and 12.8 +/- 2.2 to 13.5 +/- 1.2 g/dl, P = 0.04, respectively, 10 to 12 weeks after ACEI treatment had been discontinued. Simultaneously numbers of reticulocytes and erythropoietin concentrations rose significantly after 2, 4 and 10 weeks, with a peak at two weeks (from 14.1 +/- 3.8 to 20.6 +/- 8.0/1000, P < 0.05 and from 14.3 +/- 12.4 to 29.3 +/- 54.5 mU/ml, P < 0.05, respectively). In conclusion, ACEI-related anemia in renal transplant recipients seems to be due to the erythropoietin-lowering effect of this group of drugs. A pharmacokinetic interaction between AZA and enalapril is not likely since plasma enalaprilat levels were independent of the immunosuppressive regimen and AZA metabolite levels were unchanged in the presence and absence of the ACEI. Several mechanisms by which angiotensin converting enzyme blockade may cause a decrease in circulating erythropoietin are discussed.

Adult↗
PubMed1996

Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy.

A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.

Acyclovir↗
PubMed1996

[Revision operations after failed arthrodeses of the upper ankle joint].

Although non-union of ankle arthrodesis is reported to be a common problem there is sparse literature regarding technique and results of revision arthrodesis in this difficult situation. We performed revision arthrodesis in 22 cases, either by means of a resection-compression revision arthrodesis or a tibiotalar sliding graft. According to our experience a subtle operation technique with cancellous bone grafting and particular attention to soft tissue can achieve bone healing with good functional results in about 90% of cases.

Ankle Injuries↗
PubMed1995

[Pathologic fractures: diagnostic and therapeutic considerations and results of treatment].

Compared with bone fractures caused by trauma, pathologic fractures due to diseased bone are rare events. A pathologic fracture is one that occurs without adequate trauma and is caused by a benign or malignant bone lesion. Diagnosis of the basic disease is important for the subsequent therapy. In cases of benign bone lesions the aim of treatment is total osseus healing with complete restoration of function. In malignant pathologic fractures surgery is an essential part of the overall oncologic treatment design. In most cases it is combined with adjuvant therapy. Various surgical procedures are available for fractures at different sites and depending on whether the operation is performed with curative or palliative intent. In cases of progressive neoplastic disease stabilization is necessary to attenuate pain and to maintain mobility. Between 1983 and 1993 we treated 131 patients with 143 pathologic fractures. Conservative therapy was possible in 10 cases, while 133 fractures had to be treated surgically. Most fractures were caused by skeletal metastasis (61), solitary bone cysts (19), osteoporosis (17) and plasmocytoma (16). The most frequent localizations of pathologic fractures were humerus and femur. The favoured methods of surgical stabilization were endoprosthesis and reinforced osteosynthesis. Most fractures appeared in adolescent patients up to the age of 19 and in adults between the 5th and the 7th decade, and 57.3% of the fractures were caused by a primary or secondary malignant tumour lesion. Surgical treatment was performed in all but 1 case of malignant pathologic fractures. Of 74 patients, with malignant bone lesions 6 (8.1%), are still alive. For 68 patients who died after stabilization, the average survival time was 11.6 months; individual survival time depended on the kind of the tumour present. In 55 patients with fractures in the area of benign bone lesions complete healing was achieved, in 9 cases with conservative therapy. The rate of recurrence for solitary bone cysts treated by curettage or segment resection was 23.5%. Compared with the recurrence rates published by other authors this is a very good result.

Adolescent↗
PubMed1995

[Primary total endoprosthetic hip joint replacement in acetabulum fractures].

Conservative treatment of acetabular fractures mean a long period with immobilisation followed by quite a few of complications that are life-threatening to old patients. Besides that these fractures often cause painful posttraumatic osteoarthritis of the hip joint. Open reduction and osteosynthesis is favored more and more, but the complications described cannot be avoided absolutely by surgical treatment. The sequelae are risky reoperations and the necessity for implantation of total joint prosthesis. As shown in the enclosed case reports, total hip replacement can be emphasized as first step and as definitive surgery. Implantation of an artificial joint allows postoperative remobilisation with full weight bearing and long lasting immobilisation can be avoided. Therefore this kind of therapy is justified for treatment of old and polymorbid patients as an out of rule therapy.

Acetabulum↗
PubMed1995

[Surgical therapy of Achilles tendon rupture].

From 1980 to 1991, 314 patients with acute rupture of the Achilles tendon were treated operatively in the "Berufsgenossenschaftliche Unfallklinik Tübingen" with suture of the tendon combined with a triceps surae tendon tip-over graft and subsequent cast immobilization for 6 weeks. Analysis of these cases revealed a significant reduction of severe soft tissue complications (3.2%), which were all controllable and a very low rerupture rate (0.3%) compared with the results obtained in the relevant literature. In 223 of these patients postoperative assessment according to the scale of Holz was carried out an average of 8.1 years after injury. The results were assessed as good in 87.4%, satisfactory in 11.2% and poor in 1.4%. Compared with conservative treatment with immobilization these results are significantly better than reported in the literature. The number of patients with Achilles tendon rupture who have received conservative functional treatment with a newly developed boot is still so small that reliable statistical statements are not yet possible. Therefore, operative therapy with an established procedure should still be regarded as the method of choice for treatment of Achilles tendon rupture; the tip-over graft is a valuable complement to the tendon suture.

Achilles Tendon↗
PubMed1995

HPLC analysis of azathioprine metabolites in red blood cells, plasma and urine in renal transplant recipients.

Anemia has been frequently reported in renal transplant recipients receiving azathioprine for immunosuppression and enalapril for treatment of hypertension. During the course of a prospective trial in such patients we determined azathioprine metabolites in erythrocytes, plasma, and urine as well as erythropoietin and hemoglobin levels in order to evaluate a potential interaction between these 2 drugs, possibly leading to anemia. Two specific high performance liquid chromatography (HPLC) methods for determination of azathioprine metabolites, both employing a mercurial cellulose resin for extraction, are presented. One method using a strong anion exchange column allows detection of 6-thioguanosine di- and triphosphate (thioguanine nucleotides) in red blood cells (RBC) with a sensitivity of 30 pmol/100 microliters RBC. 6-mercaptopurine (MP) and 6-thiouric acid (TUA) in plasma and urine were analyzed simultaneously by reversed-phase HPLC with a sensitivity of 5 ng/ml. The average (median values are given) steady state concentrations of thioguanine nucleotides in erythrocytes came to 267 pmol/100 microliters RBC (range 53-613) with and to 246 pmol/100 microliters RBC (range 39-629) without concomitant enalapril medication. Mean plasma concentrations of MP and TUA 3 hours after drug intake came to 14.8 +/- 9.9 ng/ml and 398 +/- 262 ng/ml, respectively, during enalapril comedication. Withdrawal of enalapril did not influence these metabolite levels coming to 15.3 +/- 9.1 and 451 +/- 253 after stopping enalapril treatment. Thioguanine nucleotides in RBCs were neither related to the dose of azathioprine given (r = -0.113, p > 0.05) nor to hemoglobin levels (r = 0.278, p > 0.05). However, azathioprine dose/kg body weight seemed to be related to hemoglobin concentration, with and without enalapril comedication. We conclude that enalapril therapy does not influence the measured azathioprine metabolites, the reported cases of anemia may rather be due to a pharmacodynamic interaction as shown by the significant increase in erythropoietin after withdrawal of enalapril. The assays described here are suitable to study the metabolism of azathioprine in patients with various diseases.

Administration, Oral↗
PubMed1994

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Adult↗