The Good Clinical Practice guideline and its interpretation - perceptions of clinical trial teams in sub-Saharan Africa.

OBJECTIVES: To explore the advantages and challenges of working with the Good Clinical Practice (GCP)-International Conference of Harmonization (ICH) E6 guideline and its interpretation from the perspective of clinical trial teams based in sub-Saharan Africa. METHODS: We conducted 60 key informant interviews with clinical trial staff at different levels in clinical research centres in Kenya, Ghana, Burkina Faso and Senegal and thematically analysed the responses. RESULTS: Clinical trial teams perceived working with ICH-GCP as highly advantageous and regarded ICH-GCP as applicable to their setting and efficiently applied. Only for informed consent did some clinical trial staff (one-third) perceive the guideline as insufficiently applicable. Specific challenges included meeting the requirements for written and individual consent, conditions for impartial witnesses for illiterates or legally acceptable representatives for children, guaranteeing voluntary participation and ensuring full understanding of the consent given. It was deemed important to have ICH-GCP compliance monitored by relevant ethics committees and regulatory authorities, without having guidelines applied overcautiously. CONCLUSION: Clinical trial teams in sub-Saharan Africa perceived GCP as a helpful guideline, despite having been developed by northern organisations and despite the high administrative burden of implementing it. To mitigate consent challenges, we suggest adapting GCP and making use of the flexibility it offers.

Prevalence and genotyping of tick-borne encephalitis virus in questing Ixodes ricinus ticks in a new endemic area in western Switzerland.

Tick-borne encephalitis virus (TBEV) is the causative agent of tick-borne encephalitis (TBE) and causes neurological disease in humans in Eurasia. TBEV is transmitted by ticks of the genus Ixodes. Currently 10,000-12,000 clinical cases are reported annually in approximately 30 TBE endemic countries. Since 1990 the epidemiology of TBE is characterized by a global increase of clinical cases and an expansion of risk areas. Similar trends are also observed in Switzerland but few studies confirmed the emergence of new TBE foci by detecting viral RNA in field-collected ticks. In this study, free-living Ixodes ricinus (L.) ticks from one nonendemic and three new TBE endemic regions located in the Western part of Switzerland were screened during four consecutive years (2007-2010) for the presence of TBEV. A total of 9,868 I. ricinus ticks (6,665 nymphs and 3,203 adults) were examined in pools for TBEV by real-time reverse transcription polymerase chain reaction. Our results confirmed the presence of viral RNA in 0.1% (6/6120) of questing ticks collected in one new endemic region. Among TBE endemic sites, the minimal infection rate per 100 ticks tested ranged from 0.21 (1/477) to 0.95 (1/105). Four positive samples were sequenced and phylogenetic analysis of the NS5 gene showed that all TBEV nucleotide sequences belonged to the European subtype and were split into two distinct lineages originating probably independently from two distinct foci located North-East and East of the study region.

Microclimate and the zoonotic cycle of tick-borne encephalitis virus in Switzerland.

The focal distribution of tick-borne encephalitis virus (TBEV; Flaviviridae, Flavivirus) appears to depend mainly on cofeeding transmission between infected Ixodes ricinus L. nymphs and uninfected larvae. To better understand the role of cofeeding ticks in the transmission of TBEV, we investigated tick infestation of rodents and the influence of microclimate on the seasonality of questing I. ricinus ticks. A 3-yr study was carried out at four sites, including two confirmed TBEV foci. Free-living ticks and rodents were collected monthly, and microclimatic data were recorded. A decrease in questing nymph density was observed in 2007, associated with low relative humidity and high temperatures in spring. One site, Thun, did not show this decrease, probably because of microclimatic conditions in spring that favored the questing nymph population. During the same year, the proportion of rodents carrying cofeeding ticks was lower at sites where the questing nymph density decreased, although the proportion of infested hosts was similar among years. TBEV was detected in 0.1% of questing ticks, and in 8.6 and 50.0% of larval ticks feeding on two rodents. TBEV was detected at all but one site, where the proportion of hosts with cofeeding ticks was the lowest. The proportion of hosts with cofeeding ticks seemed to be one of the factors that distinguished a TBEV focus from a non-TBEV focus. The enzootic cycle of TBEV might be disrupted when dry and hot springs occur during consecutive years.

Efficacy of 10-day melarsoprol schedule 2 years after treatment for late-stage gambiense sleeping sickness.

In 2000, we reported that a new short treatment schedule of melarsoprol was not worse than the longer and demanding standard treatment for late-stage human African trypanosomiasis. This alternative schedule was assessed in an open, randomised clinical equivalence trial of 500 patients in Angola. 24 h after treatment, all patients were parasite free. Of 442 patients, 12 (3%) had relapsed after 1 year, of whom seven (3%) had had standard treatment and five (2%) the alternative treatment. After 2 years, 23 (5%) relapsing patients were reported, 11 (5%) in the standard treatment group and 12 (6%) in the new group. The results at the 2-year follow-up support and strengthen our previous findings.

New drugs for the treatment of human African trypanosomiasis: research and development.

Chemotherapy of human African trypanosomiasis is problematic because of the high frequency of severe adverse events, the long duration and high cost of treatment, and an increasing number of treatment-refractory cases. New cost-efficient, easy-to-use drugs are urgently needed. Whereas basic research on potential drug targets is anchored in academia, the complex, highly regulated and very expensive process of preclinical and clinical drug development is almost exclusively in the hands of pharmaceutical companies. Jennifer Keiser, August Stich and Christian Burri here review, from the angle of industrial drug research and development, the past ten years of research activities at different stages of the development of trypanocidal drugs, and assess future prospects. The absence of compounds in clinical development Phases I-III indicates no new drugs will become available in the next few years.

Investigations of the metabolites of the trypanocidal drug melarsoprol.

BACKGROUND: Melarsoprol remains the first-choice drug for trypanosomiasis (human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse reactions, we investigated the metabolism of this 50-year-old organoarsenic compound. RESULTS: The half-life of melarsoprol determined by HPLC was <1 hour compared with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating the existence of active metabolites. One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes. The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours. Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy. Because of the poor pharmaceutical properties of melarsoprol, the therapeutic potential of melarsen oxide was investigated. In a rodent model of acute infection, 20 of 20 mice were cured (0.1 to 1 mg/kg intravenously or 2.2 mg/kg intraperitoneally). In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier. CONCLUSION: The prospects for the future of trypanosomiasis treatment are deplorable. Investigations on the improvement of the use of the old drugs are therefore required. The results of this study may build a basis for further research on the cause of severe adverse reactions.

The influence of various carbon fibre braiding techniques and methods of fixation on the extensibility of ligament prostheses.

An alloplastic ligament prosthesis with carbon fibres should not only be biocompatible but should also restore the biomechanical function of a natural system, which includes restoring its elasticity. Tests with new types of braided carbon fibre strands showed their elastic extensibility to increase with increasing number of filament tows and increasing braid angle. The best results were obtained with 32 tows and a 43 degrees braid angle. This strand type was tested in vitro as a medial collateral ligament prosthesis with two methods of fixation in human knees and, in like manner, in vivo in sheep knees. Biomechanical tests in vitro using human cadaver knees and sheep knees after 12 weeks' implantation showed an elasticity similar to that of normal natural ligaments.

An automated biological assay to determine levels of the trypanocidal drug melarsoprol in biological fluids.

For the investigation of the pharmacokinetic properties of a drug, methods for sensitive and precise quantification are a prerequisite. Only few functional methods exist for the determination of the trypanocidal drug melarsoprol in biological fluids: A bioassay which requires microscopical evaluation and two HPLC methods, which require sample extraction and are difficult to automatize due to the drug's properties. We report the development of an automated biological assay, based on the fluorescent dye Alamar blue. To validate the assay for melarsoprol, 108 serum and 37 cerebrospinal fluid (CSF) samples were spiked with melarsoprol at concentrations of 17-92 ng/ml for CSF and 17 ng/ml-2.2 microg/ml for serum. The precision (repeatability) expressed as the interday average coefficient of variation was 9.9% for serum and 18.8% for CSF samples over the respective concentration range. The accuracy (measurement for the systematic error) of the test was 99.4% for serum and 96.4% for CSF. The assay's limit of quantitation with the use of the trypanosome stock STI 704 BABA was 4 ng/ml for both serum and CSF samples.

Pharmacokinetics of melarsoprol in uninfected vervet monkeys.

The level of the trypanocidal drug melarsoprol was determined in serum and cerebrospinal fluid (CSF) of six healthy vervet monkeys after intravenous application of the drug following a standard treatment schedule and a recently suggested alternative protocol. The maximum serum levels measured were about 3 micrograms/ml. A three-compartment model was used to analyze the serum data. The mean residence time calculated for melarsoprol in serum was 18 h, the volume of distribution was 3.6 l/kg and the clearance was 3.5 ml/min*kg. In the CSF the drug levels were generally very low, not exceeding 55 ng/ml, and the adaptation of the drug levels was found to be very low. The comparison of the drug concentrations required to eliminate trypanosomes in vitro and the drug concentrations reached in the CSF during treatment revealed that the latter might be insufficient in some cases to eliminate all trypanosomes from this site. The peak serum levels during alternative application of the drug were lower compared to those during empirical treatment. No evidence for drug cumulation in the body was found. The results of this study are compared with recent pharmacokinetic data from human patients, and discussed in the context of the problem of relapses and reactive encephalopathy occurring after treatment of sleeping sickness.

Treatment of late stage sleeping sickness caused by T.b. gambiense: a new approach to the use of an old drug.

Melarsoprol is the standard treatment of late stage trypanosomiasis. The development of treatment schedules was previously purely empirical. Generally melarsoprol is given in 3 series of three to four consecutive injections, given every 24 hours, with an interval of about one week between the series. Based on pharmacokinetic analysis, computer simulations and extensive literature research covering all schedules previously used and tested, a new schedule, consisting of ten daily consecutive doses of 2.16 mg/kg of the drug was suggested. The pharmacokinetic model was validated in uninfected vervet monkeys. No unexpected drug accumulation and no systemic toxic effects were observed. In a pilot clinical trial in Congo RDC a small group of T. b. gambiense patients (n = 11) was treated successfully with the new schedule. In an open randomised clinical trial conducted in 500 patients in Angola the clinical efficacy and safety of this new concise treatment were compared to those of standard protocol treatment. Parasitological cure 24 hours after treatment was 100% in both groups. Statistical analysis yielded no significant differences for adverse events between the two treatment protocols. The new schedule reduces the amount and cost for the drug by about one third, and those for hospitalisation by about half.

[Surgical therapy of pelvic tumors]. / Die chirurgische Therapie von Beckentumoren.

Results in 72 patients with primary tumors of the pelvis and in 140 patients with metastases are reported. Classification, localization, type of resection and reconstruction including bone grafts, osteosynthesis and internal hemipelvectomy are described. In benign and low grade malignant bone tumors continuity resections and pelvic reconstructions give good oncological and functional results. In high grade malignant bone tumors and soft tissue sarcomas the 5-years-survival rate is only 37% respectively 19%. Metastases of the pelvis and proximal femur are treated by combinations of metal implants and bone cement as well as by different types of total hip prostheses.

[Physical flow studies of new surgical aspiration drains]. / Strömungsphysikalische Untersuchungen neuer chirurgischer Saug-Drainagen

Mathematical and experimental results demonstrate that the customary Redon drain as well as the improved Neo-Redovac drain develop suction only over a short initial distance. The above mentioned innovation of three additional oval holes does not increase efficiency. The disadvantage of rapidly diminished suction is overcome in the "Ulmer Drain", in which equidistant openings of continually increasing aperture are aligned towards the drain end.

[Stable soft tissue reconstruction using an autochthonous muscle flap transposition and simultaneous bone reconstruction in post-traumatic and osteitis defects of the lower extremity]. / Stabile Weichteilwiederherstellung durch autochthone Muskellappentransposition und simultanen Knochenaufbau bei posttraumatischen und osteitischen Defekten an der unteren Extremität.

Posttraumatic soft tissue and bone defects can pose problems for the surgeon. Autogenous bone from the iliac crest may be used to fill bone defects. To achieve bone healing, a well vascularized recipient site for the graft is important. Local muscle flaps or distant microvascular flaps improve vascularity by introducing a fresh blood supply. Cellular and humoral antibodies are more effective and allow quicker revascularisation of the transplanted graft. 49 soft tissue defects were treated by local muscle flaps. In 14 cases the soleus, in 28 the gastrocnemius, in three the tibialis anterior, in two the abductor hallucis, and in two the gracilis muscle was transposed. 38 cases had posttraumatic osteitis, in eight the defect was merely a soft tissue defect and in three due to tumour excision. In 24 patients a combination of soft tissue repair and cancellous bone grafting was performed. Four flaps failed because of total or partial necrosis. In all cases full weight bearing on the leg with good soft tissue cover was achieved.

[Taurolin gel in treatment of osteitis (author's transl)]. / Taurolin - Gel in der Osteitis-Behandlung.

Removal of septic foci in putrid infection of the bone is an important step in the treatment of post-traumatic osteitis. The methods employed so far, such as through-drainage and siphonage, as well as gentamycin-PMMA chains, have very obvious drawbacks although they have definitely achieved favourable results. Taurolin Gel , a preparation consisting of denatured collagen in combination with the chemotherapeutic Taurolin 4%, is theoretically capable of eliminating these drawbacks. Clinical application appeared justified on the basis of good results obtained with the drainage solution of Taurolin, as well as in the course of experiments. Results have been obtained mostly in a single application in 50 cases documented and followed up; these results were equivalent to those obtained by means of the other methods. In consideration of the advantages with regard to application and effect, the authors believe that testing of this substance on a larger scale should be recommended.

[Nebacetin and taurolin as intraoperative disinfectant solutions in surgery of the locomotor system (author's transl)]. / Nebacetin und Taurolin als intraoperative Spüllösungen bei Eingriffen am Bewegungsapparat.

The anti-infective preventive action of intraoperative disinfection with physiological solution containing antibiotics, appears to be firmly established, judging from numerous publications. Since germs are showing a world-wide increasing resistance, the search for antibiotics which continue to be effective must be kept up, but alternative suggestions are equally necessary. Some publications have already been presented indicating that success similar to that previously obtained with antibiotics is possible by using disinfectants in the prophylaxis and treatment of infections. Hence, a comparative study was conducted using the non-absorbable broad-spectrum antibiotic Nebacetin and the disinfectant Taurolin in a 1% solution with a group of patients subjected to a total of 7699 major and minor surgical operations. Prospectively, early infections during the stay of the patient in the hospital, als well as disturbed wound healing, were included. No significant difference was found in the number of infections and the rate of disturbed wound healing. Indirectly, it is possible to conclude with the help of results from literature that the disinfectant Taurolin is suitable as an addition to intra-operative rinsing in the prophylaxis of infections.

[Postoperative knee joint mobilization in catheter peridural anesthesia following arthrolyses of the knee joint]. / Postoperative Kniegelenksmobilisation in Katheterperiduralanästhesie nach Arthrolysen des Kniegelenks.

The results of arthrolysis of a stiff knee are often poor due to post-operative pain preventing early active mobilization that is so essential. Adequate analgesia may be ensured by the use of continuous anaesthesia via an epidural catheter, and in combination with continuous passive motion such analgesia is able to maintain, and often improve, the range of movement obtained at surgery. 22 patients treated in this way showed an improvement in the range of movement of between 39 and 120 degrees. Patients with post-traumatic knee stiffness achieved an average improvement in the range of movement of 93%, while those with stiffness following infection only improved by 55% on the average. The pre-operative loss of movement does not appear to determine the end result: the aetiology of the stiffness is more important.

[Carbon fiber reinforced polysulfone implants for tumor surgery of the spine]. / Kohlenstoffaser-verstärkte Polysulfon-Implantate für die Tumor-Chirurgie an der Wirbelsäule.

Anterior tumor removal, cord decompression and spinal stabilization gain in significance in surgical treatment of vertebral tumors. An implant system, consisting of a basket as vertebral body replacement, plates and screws, was developed using carbon fibre reinforced polysulfone. This system allows to perform individually shaped, stable and short-distance spine fusions from an anterior approach. Moreover its radiolucence facilitates postoperative care and irradiation. Operative technique and clinical experience are demonstrated in two patients.

[Load stability in relation to the osteosynthesis method, course and complications in open lower-leg fractures with severe soft tissue lesions ]. / Belastungsstabilität in Abhängigkeit von Osteosyntheseverfahren, Verlauf und Komplikationen bei offenen Unterschenkelfrakturen mit schwerem Weichteilschaden.

The external fixator ("fixateur externe") is today's method of choice in the treatment of lower leg fractures with severe damage to the soft parts. The various application techniques and angles of application of this device entail varying stability and are characterized by certain advantages and drawbacks. Basing on detailed biomechanical studies and experience with patients, the authors prefer the rectangular mode of application using Schanz screws. If the type of fracture allows, a combination of minimal osteosynthesis and external tensor is used; this can significantly enhance the stability. In 42 patients of a total of 56 during 1978-1980 with second-grade and third-grade open fractures of lower leg, combination with minimal osteosynthesis was effected (traction screw). Of 44 patients followed up, 19 achieved stability to load within an average period of 19.8 weeks. If there is no osseous bridging 10-12 weeks after initial treatment, additional measures such as spongiosaplasty and changeover to stable inner fixation with plates become necessary. Following plate osteosynthesis with additional spongiosaplasty, full load was permissible on the average 14 weeks after this procedure in 23 patients. The course was more complicated in the case of the 2 remaining patients; it took up to 45 weeks until full load became permissible.

[Resorbable implants for refixation of osteochondral fragments in joint surfaces]. / Resorbierbare Implantate zur Refixierung von osteochondralen Fragmenten in Gelenkflächen.

Resorbable pins made of solid polydioxanone (PDS) were tested for refixation of osteochondral fragments. In both medial femoral condyles of sheep osteochondral fragments were chiselled and refixed by 3 PDS pins. After 3 months the sheep were sacrificed and healing of the fragments investigated histologically and biomechanically. Fragment dislocation was not seen in any of the cases and the cartilage surface could be described as normal. The strength of the bone healing zone reached 80% of the strength of the normal bone. The contact surface between fragment and subchondral bone showed complete bony healing. Only the border of the cartilage flake was still visible. The PDS pins had not been completely biodegraded after 3 months.

[Complications at removal sites of autologous cancellous bone transplants]. / Komplikationen an den Entnahmestellen autologer Spongiosatransplantate.

1022 autologous bone transplants were performed at the University clinic of Ulm in the years 1971-1977. The cancellous bone deposits removed were localized in the anterior and posterior iliac crest, the trochanter major, the tibial head as well as the distal radius. Since some patients had postoperatively experienced difficulty in the healing of the cancellous bone removal sites, we decided to investigate these complications by means of questionnaires, clinical re-examinations as well as X-ray controls (3-9 years after removal). During the early postoperative phase (2 months), approximately one-fifth of the patients had complained about pain at the removal site. 3.1% had more or less pronounced hematomas in the scar regions, but surgical evacuation of the hematoma was necessary in only 0.28%. Additionally, 2 cases of infection as well as one femoral neck fracture following cancellous bone removal from the greater trochanter were observed. At the time of re-examination, performed 3-9 years after cancellous bone removal, only 3.9% of the patients complained of largely weather-influenced pains in the vicinity of the cutaneous scars. Sensibility disorders in the area innervated by the N. Cutaneous femoralis lateralis, were found in all those 7 patients who, in the course of cancellous bone removal from the iliac crest, had received skin incisions extending ventrally beyond the spina iliaca anterior superior. The X-ray controls showed more or less pronounced changes in the bone structure at the removal sites of cancellous bone deposits in nearly all patients, but correlation could only be determined between the radiological alterations at the anterior iliac crest donor site and the respective complaints of the patients.