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Biomedical subjects

H Schaefer

Publications and source records attributed to H Schaefer.

At least 19 recordsLinked to original sources

Comparison of transepidermal water loss and spectroscopic absorbance to quantify changes of the stratum corneum after tape stripping.

The objective and quantitative application of tape stripping in pharmaceutics and dermatopharmacokinetics requires the determination of the exact position of each removed tape strip inside the stratum corneum (SC) and/or the determination of the relative SC thickness. In this study, transepidermal water loss (TEWL) and the optical spectroscopic data of the corneocytes were measured simultaneously during the complete removal of the SC by tape stripping. The spectroscopic data quantitatively reflect the amount of corneocytes removed by the individual tape strips, whereas TEWL and 1/TEWL are not sensitive enough to measure the relatively small changes in the SC thickness realized by the removal of the individual strips. The relative SC thickness can be determined directly by the spectroscopic data, while the 1/TEWL values require a second independent method. The results demonstrate the importance of tape stripping characterizing the behaviour of topically applied substances.

Adhesives↗

Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.

Conventional treatment or autologous transplantation has not been able to achieve long-term remission in patients with multiple myeloma (MM). Nonmyeloablative allogeneic transplantation might offer an option for cure without the high mortality associated with conventional conditioning. Here we present a retrospective analysis of patients with high-risk MM treated with nonmyeloablative allogeneic transplantation. In all, 52 patients with relapsed MM or high-risk features at diagnosis received 2 Gy TBI alone (n=3) or with fludarabine (n=49) as conditioning. Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. Regimen-related toxicity was low. Acute graft-versus-host disease II-IV occurred in 37% of patients, and 70% experienced chronic graft-versus-host disease (cGvHD). Median follow-up was 567 days, and transplant-related mortality was 17% in total. Estimated progression-free and overall survival at 18 months was 29.4 and 41.1%, respectively. Patients with cGvHD had a significantly higher progression-free survival, as did patients with up to eight cycles of pretreatment chemotherapy vs those with nine or more. In this highly pretreated patient group, disease control was unsatisfactory and our results suggest that a potential strategy might be to perform allogeneic transplant earlier in the course of the disease.

Adult↗

[Penetration of microparticles into human skin].

The efficacy of the penetration of microparticles into the human skin depends on the size and the type of the formulation with which they are topically applied. Microparticles with a diameter of >1 microm barely penetrate into the human skin. They are located on the skin surface and form a film which, for instance, can be used for camouflage or protection against UV radiation in sunscreens. While the penetration of the microparticles in the lipid layers of the stratum corneum is limited, they penetrate efficiently into the hair follicles up to a depth >2 mm, providing their diameter is <1.5 microm. Thus, microparticles can be used for drug delivery into the hair follicles.

Drug Carriers↗

Penetration profile of microspheres in follicular targeting of terminal hair follicles.

The transfollicular administration of pharmacologically active molecules is of current therapeutic interest, mainly with regard to delivery to specific sites of the hair follicle (HF) and the reduction of hepatic metabolism and systemic toxicity. HF are privileged pathways for specific molecules depending on formulations, which enter faster into these shunts than through the stratum corneum. The aim was to optimize the delivery of fluorescent microspheres into the HF, thereby, developing a standardized protocol for follicular targeting with microspheres. The number of HF showing penetration, as well as the depth of penetration, was determined. Freshly excised skin samples with terminal HF were divided into groups, with or without prior treatment with cyanoacrylate skin surface stripping-technique (CSSS). Thereafter microspheres at a size of 0.75-6.0 microm were applied according to the developed standardized protocol. Skin biopsies were obtained, shock-frozen, and sectioned in 5 microm slices. We demonstrated a selective penetration route of the microspheres into the HF. Optimal microsphere size proved to be approximately 1.5 microm, with a 55% rate of all HF, and with a maximum penetration depth of >2300 microm. Without previous CSSS treatment of the skin, the transfollicular microsphere penetration was below 27% with a maximum penetration depth of 1000 microm. Thus, the basis for follicular targeting of essential structures containing stem cells for keratinocytes, melanocytes, and mast cells has been laid.

Administration, Topical↗

False negative findings in intraoperative SEP monitoring: analysis of 658 consecutive neurosurgical cases and review of published reports.

OBJECTIVES: To determine the sensitivity of intraoperative monitoring in neurosurgical operations using somatosensory evoked potentials and to identify reasons for false negative findings and possible settings with an increased risk for monitoring failure. METHODS: SEP monitoring of 658 neurosurgical operations was analysed. The target of monitoring was the function of a hemisphere in 251 cases, the brain stem in 198 cases, and the spinal cord in 209 cases. RESULTS: In 27 cases (4.1%), monitoring was classified as false negative. Further analysis showed that five of these patients had experienced delayed neurological damage. Among the remaining 22 false negative cases, 14 had a minor neurological deficit and eight had severe neurological damage. Overall sensitivity and negative predictive value of SEP monitoring was 79% and 96%, respectively. For the detection of severe neurological damage the corresponding figures were 91% and 98%. Sensitivity of monitoring varied depending on the target of monitoring and the type of lesion. Monitoring was less likely to detect neurological damage in surgery for infratentorial tumours with brain stem compression, small lesions of the motor cortex, and small vessel damage during aneurysm surgery. CONCLUSIONS: SEP monitoring has acceptable sensitivity for detecting neurological damage during different neurosurgical procedures. Distinct settings with an increased risk of monitoring failure can be identified. In these cases measures to enhance the sensitivity of monitoring should be considered.

Adolescent↗

[Follicular penetration. An important pathway for topically applied substances].

The knowledge of penetration pathways in and through the skin is a prerequisite for the development and optimization of topically applied drugs and cosmetics. Skin penetration has been assumed to occur via diffusion though the lipid domains of the stratum corneum. Recent studies show that the skin appendages, especially the hair follicles, play an important role in skin penetration processes. Topically applied substances cannot enter all follicles. We discuss the reasons for the phenomenon of open and closed hair follicles.

Administration, Cutaneous↗

Talampanel, a new antiepileptic drug: single- and multiple-dose pharmacokinetics and initial 1-week experience in patients with chronic intractable epilepsy.

PURPOSE: Talampanel (LY300164), a potent and selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-receptor antagonist, is a potential new antiepileptic drug (AED). This study examines the single- and multiple-dose pharmacokinetics, safety, and tolerability of talampanel in patients with intractable epilepsy and assesses the potential for pharmacokinetic interaction. METHODS: Eleven of 14 patients entered into the study completed. Fourteen patients were evaluated for safety, 13 patients were used in the single-dose, and 11 patients in the multiple-dose pharmacokinetic analysis. Each patient initially received a single 35-mg dose of talampanel followed by the measurement of pharmacokinetic profiles. A 21-day t.i.d. dosing regimen was then determined for each patient based on his or her initial pharmacokinetic profile. Adverse events were recorded by patients or their carers. RESULTS: After oral ingestion, talampanel was rapidly absorbed, with maximal plasma concentrations achieved within 1-3 h. Talampanel concentrations in patients taking enzyme-inducing AEDs were 50% lower than those seen in healthy volunteers. Mean talampanel t1/2 values were 3.0 h compared with 4.2 h in healthy volunteers. After multiple-dose and steady-state, talampanel t1/2 values were increased to 5.6 h Talampanel and valproic acid (VPA) appear to inhibit each other's metabolism mutually. Talampanel had no effect on plasma concentrations of other AEDs. Multiple-dose talampanel administration was associated with nonlinear pharmacokinetics. No serious adverse events were reported; the most frequently reported being dizziness, ataxia, drowsiness, and headaches CONCLUSIONS: Talampanel dosing strategies may be reliant on concomitant AED medication, as enzyme-inducing AEDs enhance, whereas VPA inhibits its metabolism. Talampanel was well tolerated, although adverse events occurred at lower doses compared with those in healthy subjects, probably because of the additive effect of concomitant AEDs.

Administration, Oral↗

Benefit and risk of organic ultraviolet filters.

Modern sunscreen products provide broad-spectrum UV protection and may contain one or several UV filters. A modern UV filter should be heat and photostable, water resistant, nontoxic, and easy to formulate. Identification of a substance that meets these criteria is as difficult as discovering a new drug; hundreds of new molecules are synthesized and screened before a lead candidate is identified. The most important aspect in the development of a new UV filter is its safety. In our laboratories, the safety of new ultraviolet filters is assessed by an initial in vitro screen including photostability, cytotoxicity, photocytotoxicity, genotoxicity, and photogenotoxicity tests. These tests are performed in mammalian, yeast, and bacterial cell systems. Skin penetration potential is measured in vitro using human skin or, when required by regulations, in vivo. Because modern sunscreens are selected on the basis of their retention on and in the stratum corneum and are formulated as poorly penetrating emulsions, they generally have very low to negligible penetration rates. The safety and efficacy of UV filters are regulated and approved by national and international health authorities. Safety standards in the European Union, United States, or Japan stipulate that new filters pass a stringent toxicological safety evaluation prior to approval. The safety dossier of a new UV filter resembles that of a new drug and includes acute toxicity, irritation, sensitization, phototoxicity, photosensitization, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, and, in the United States, photocarcinogenicity testing. The margin of safety of new UV filters for application to humans is estimated by comparing the potential human systemic exposure with the no-effect level from in vivo toxicity studies. Only substances with a safe toxicological profile and a margin of safety of at least 100-fold are approved for human use. Finally, prior to marketing, new UV filters undergo stringent human testing to confirm their efficacy as well as the absence of irritation, sensitization, photoirritation, and photosensitization potential in man. UV filters not only protect against acute skin injury, such as sunburn, but also against long-term and chronic skin damage, including cellular DNA damage, photoinduced immune suppression, and, by extension, skin cancer. The protection provided by modern sunscreens against UV-induced skin cancer was shown in animal photocarcinogenicity studies and confirmed by numerous in vitro, animal, and human investigations: UV filters protect the p53 tumor suppressor gene from damage and prevent UV-induced immune suppression. Recent studies suggest that sunscreens protect against precursor lesions of skin cancer, such as actinic keratoses. Additional benefits of ultraviolet filters include prevention of photodermatoses, such as polymorphic light eruption, and, possibly, photoaging. Modern sunscreens are safe for children and adults. Percutaneous penetration and irritation rates of topically applied substances in children and adults are similar. The principal protective measure is to keep children out of the sun and/or to cover them with protective clothes; however, sunscreens are a safe and effective and often the only feasible defense of children against UV radiation. In conclusion, sunscreens are safe protective devices that undergo stringent safety and efficacy evaluation.

Adult↗

Nasal glioma presenting as capillary haemangioma.

UNLABELLED: We report the case of a 5-month-old female infant with a congenital nasal tumour originally attributed to a capillary haemangioma. Doppler-flow ultrasound imaging revealed a solid mass surrounded by mildly enlarged vessels which had a flow pattern atypical of haemangioma. Histology showed non-malignant gliomatous cells with low proliferative activity. A diagnosis of nasal glioma was thus established and the patient underwent cranial MRT which excluded intracranial communication of the nasal glioma. Nasal gliomas arise from a skull defect, originating from the defective closure of the anterior neuroporus. They represent encephaloceles which have lost their intracranial connection. Nasal gliomas usually present shortly after birth as an intranasal obstruction or, as in our case, as a mostly extranasal tumour. CONCLUSION: Nasal glioma is often misdiagnosed as a capillary haemangioma. It can be distinguished from the latter by Doppler-flow ultrasonography. Magnetic resonance imaging is required to exclude intracranial communication.

Diagnosis, Differential↗

Lyme borreliosis in rhesus macaques: effects of corticosteroids on spirochetal load and isotype switching of anti-borrelia burgdorferi antibody.

Experimental Borrelia burgdorferi infection of rhesus monkeys is an excellent model of Lyme disease and closely parallels the infection in humans. Little is known about the interaction of host immunity with the spirochete in patients with chronic infection. We hypothesized that rapid development of anti-B. burgdorferi antibody in immunocompetent nonhuman primates (NHPs) is the major determinant of the reduction of the spirochetal load in Lyme borreliosis. This hypothesis was tested by measurement of the spirochetal load by PCR in association with characterization of the anti-B. burgdorferi humoral immune response in immunocompetent NHPs versus that in corticosteroid-treated NHPs. Although anti-B. burgdorferi immunoglobulin G (IgG) antibody was effectively inhibited in dexamethasone (Dex)-treated NHPs, anti-B. burgdorferi IgM antibody levels continued to rise after the first month and reached levels in excess of IgM levels in immunocompetent NHPs. This vigorous production of anti-B. burgdorferi IgM antibodies was also studied in vitro by measurement of antibody produced by B. burgdorferi-stimulated peripheral blood mononuclear cells. Despite these high IgM antispirochetal antibodies in Dex-treated NHPs, spirochetal loads were much higher in these animals. These data indicate that Dex treatment results in interference with isotype switching in this model and provide evidence that anti-B. burgdorferi IgG antibody is much more effective than IgM antibody in decreasing the spirochetal load in infected animals.

Animals↗

Investigation of follicular penetration of topically applied substances.

The influence of specific follicle properties, sebum production and hair growth on the follicular penetration of topically applied substances was investigated. The behavior of follicles identified in selected skin areas of volunteers was analyzed by various tape stripping and staining methods in combination with laser scanning microscopy. Furthermore hair growth in the selected skin areas was determined. A correlation between sebum production, hair growth activity and follicular penetration was observed.

Administration, Topical↗

The role of follicular penetration. A differential view.

Textbooks describe percutaneous absorption through normal skin as diffusion through the stratum corneum barrier, i.e., in a simplified view, as a physiochemical interaction of a penetrating compound with the horizontal multilayer lipid structures and the underlying corneocytes within the horny layer. Hair follicles and sweat glands are vertical structures and are considered of little importance since 'they represent a small and insignificant percentage of the skin surface'. To this integral view, a differentiated hypothesis is proposed: the more perfect the barrier function of the horny layer, the greater the relative role of the imperfections within the skin as a defence organ. Three kinds of imperfections should be taken into account: (1) the follicular apparatus of hair follicles; (2) the sweat glands, and (3) microlesions in the interfollicular horny layer. Each of these can theoretically represent a vertical pathway for percutaneous absorption, i.e. a 'shunt'.

Animals↗

Correlation of the local distribution of topically applied substances inside the stratum corneum determined by tape-stripping to differences in bioavailability.

Tape-stripping and optical spectroscopy are used as a suitable combined method to determine the horny layer profile. Firstly, typical ultraviolet filter substances are used as active substances which are fixed inside the horny layer. Secondly, clobetasol propionate was applied topically in two formulations, Temovate Cream and Temovate and Emollient. The measured changes in the local distribution of the drug inside stratum corneum reflect the observed differences in the biological response visualized as blanching. The concentration of the drug in deeper parts of the horny layer proposes the existence of a small channel available for the percutaneous absorption. The observed low intensity blanching is correlated to the follicle orifices of the skin. After application of Temovate and Emollient, a lateral spreading of the drug must be taken into account.

Administration, Topical↗

Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of lyme disease.

Lyme borreliosis is caused by infection with the spirochete Borrelia burgdorferi. Nonhuman primates inoculated with the N40 strain of B. burgdorferi develop infection of multiple tissues, including the central (CNS) and peripheral nervous system. In immunocompetent nonhuman primates, spirochetes are present in low numbers in tissues. For this reason, it has been difficult to study their localization and changes in expression of surface proteins. To further investigate this, we inoculated four immunosuppressed adult Macaca mulatta with 1 million spirochetes of the N40 strain of B. burgdorferi, and compared them with three infected immunocompetent animals and two uninfected controls. The brain, spinal cord, peripheral nerves, skeletal muscle, heart, and bladder were obtained at necropsy 4 months later. The spirochetal tissue load was first studied by polymerase chain reaction (PCR)-ELISA of the outer surface protein A (ospA) gene. Immunohistochemistry was used to study the localization and numbers of spirochetes in tissues and the expression of spirochetal proteins and to characterize the inflammatory response. Hematoxylin and eosin and trichrome stains were used to study inflammation and tissue injury. The results showed that the number of spirochetes was significantly higher in immunosuppressed animals. B. burgdorferi in the CNS localized to the leptomeninges, nerve roots, and dorsal root ganglia, but not to the parenchyma. Outside of the CNS, B. burgdorferi localized to endoneurium and to connective tissues of peripheral nerves, skeletal muscle, heart, aorta, and bladder. Although ospA, ospB, ospC, and flagellin were present at the time of inoculation, only flagellin was expressed by spirochetes in tissues 4 months later. Significant inflammation occurred only in the heart, and only immunosuppressed animals had cardiac fiber degeneration and necrosis. Plasma cells were abundant in inflammatory foci of steroid-treated animals. We concluded that B. burgdorferi has a tropism for the meninges in the CNS and for connective tissues elsewhere in the body.

Animals↗

Local treatment of hepatic metastases with low-level direct electric current: experimental results.

BACKGROUND: Several authors have recently reported encouraging results from low-level direct current therapy in easily accessible malignant tumors. However, antitumoral effects in colorectal metastases have not been investigated experimentally. METHODS: Using an animal model with induced hepatic metastases, we analyzed the effectiveness and the tumor growth dynamics after direct current application. Three weeks after induction tumor volumes were estimated with magnetic resonance imaging (MRI). Then direct current (80 C/cm3) was applied in the treatment group by means of one anode in the tumor center and four cathodes peripherally. In the control group electrodes were placed without applying current. Tumor growth dynamics was analyzed with MRI after 3 and 5 weeks. After this all animals were killed, and the livers histologically examined. RESULTS: After 5 weeks MRI showed a 1.6-fold tumor enlargement in the treatment group versus a 2.9-fold enlargement in the control group (Student t test, P=0.0051). The histopathologic analysis of the treated livers yielded a 21% complete response rate and a 78% partial response rate. No necroses were found in the control group. CONCLUSIONS: These results confirm the effectiveness of low-level direct current application as a potential modality for the treatment of hepatic metastases.

Animals↗

Experimental low-level direct current therapy in liver metastases: influence of polarity and current dose.

Several authors recently reported on the successful local treatment of malignant disease with low-level direct current therapy. However, antitumoral effects in colorectal metastases has not been investigated experimentally. The aim of the present study was to assess the effectiveness of this therapy and the influence of polarity and current dose. Colorectal metastases were established in BD IX rats by the injection of colon cancer cells under the liver capsule. After three weeks, the liver tumor volumes were determined by magnetic resonance imaging of the liver. Low-level direct current therapy was applied via five platinum electrodes. Four different applications were used: 60 C/cm(3), anode at the center; 60 C/cm(3), cathode at the center; 80 C/cm(3), anode at the center; and 80 C/cm(3), cathode at the center. In the control group, five electrodes were placed without applying any direct current. All animals were sacrificed on postoperative day 7. Liver metastases were histologically examined for vital tumor cells. Statistical analysis was performed with chi(2)-test. The mean initial tumor diameter before treatment was 3.6 +/- 1.4 mm (volume: 25.2 +/- 9.7 mm(3)). Histological examination of the removed livers revealed significant destruction of the metastases with localized necroses in all treatment groups; 37% had a complete response rate and 63% a partial response rate. There were no significant necroses in the control group (P < 0.0001). The best treatment results were obtained in the group with an anode at the center and a current dose of 80 C/cm(3). Direct current therapy offers a new and safe method for the local treatment of liver metastases. We were able to observe that tumor damage is related to current dose but not to the polarity of the central electrode.

Animals↗