Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A). OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care. MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As. RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92). CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

[Targeted therapies in Pyoderma gangrenosum: deciphering pathophysiology and improving disease management]. / Pyoderma gangraenosum: durch zielgerichtete Therapieansätze besser verstehen und behandeln können.

The immune response is a central process during wound healing. Malfunctions often lead to chronic inflammation, barrier disorders, and ulcerations of the skin. The underlying pathomechanisms are complex and the subject of current dermatological research. The care of wound healing disorders is still inadequate and urgently needs improved therapy concepts. For several years now, the development of modern immunomodulators has enabled the targeted regulation of specific signaling cascades, and their effectiveness in the treatment of wound healing disorders has been proven in numerous case studies. Thus, their use not only leads to more efficient therapeutic approaches, but also provides deeper insight into the pathomechanistic importance of specific signaling pathways in inflammatory and degenerative diseases of the skin, which are poorly understood so far. Pyoderma gangrenosum, an autoinflammatory disease, provides a good example to illustrate the progress in therapy and pathomechanistic understanding through the use of new immunomodulators and is explained in more detail in the following article.

Safety and persistence of orally administered human Lactobacillus sp. strains in healthy adults.

The aim of the study was to evaluate the safety and persistence of selected Lactobacillus strains in the gastrointestinal tract (GIT) of healthy adult volunteers after oral consumption of high doses of lactobacilli to identify potential candidates for probiotic and biotechnological applications. In the first phase of the study, nine individuals consumed capsules containing Lactobacillus gasseri 177 and E16B7, Lactobacillus acidophilus 821-3, Lactobacillus paracasei 317 and Lactobacillus fermentum 338-1-1 (each daily dose 1×1010 cfu) for 5 consecutive days. Data on gut health, blood parameters, and liver and kidney function were collected. The persistence of Lactobacillus strains was assessed by culturing combined with arbitrarily primed polymerase chain reaction (AP-PCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) on days 0, 5, 8, 10 and 20 from faecal samples. All strains survived gastrointestinal passage and were detected on the 5th day. L. acidophilus 821-3 was detected in four volunteers on the 8th day (4.3 to 7.0 log10 cfu/g) and in two on the 10th day (8.3 and 3.9 log10 cfu/g, respectively). In the second phase of the study, five additional volunteers consumed L. acidophilus 821-3 (daily 1×1010 cfu) for 5 consecutive days. The strain was subsequently detected in faeces of all individuals using real-time PCR on the 10th day (range 4.6-6.7; median 6.0 log10 cell/g) in both phases of the study for at least 5 days after discontinuation of consumption. The administration of high doses of different Lactobacillus strains did not result in any severe adverse effects in GIT and/or abnormal values of blood indices. Thus, the strain L. acidophilus 821-3 is a promising candidate for probiotic and biotechnological applications. Further studies will be performed to confirm the strain persistence and safety in a larger number of individuals.

Characterization of oral lactobacilli as potential probiotics for oral health.

INTRODUCTION: Intestinal lactobacilli have been successfully used as probiotics to treat gastrointestinal disorders, but only limited data are available for the probiotic properties of oral lactobacilli to combat oral diseases. We aimed to characterize oral lactobacilli for their potential probiotic properties according to the international guidelines for the evaluation of probiotics, and to select potential probiotic strains for oral health. METHODS: The study included 67 salivary and subgingival lactobacilli of 10 species, isolated from healthy humans. All strains were identified using amplified ribosomal DNA restriction analysis, tested for antimicrobial activity against oral pathogens, tolerance of low pH and bile content. Thereafter, the lysozyme tolerance and antibiotic susceptibility of 22 potential probiotic strains were assessed. RESULTS: The majority of strains suppressed the growth of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Streptococcus mutans, but none inhibited Candida albicans. The lowest pH tolerated by lactobacilli following 4 h of incubation was pH 2.5, but none of the strains grew at this pH. All strains tolerated a high concentration of lysozyme (10 mg/ml) and half of the strains tolerated a high concentration of human bile [5% volume/volume (V/V)]. Four Lactobacillus plantarum and two Lactobacillus oris strains expressed resistance to tetracycline and/or doxycycline. CONCLUSIONS: Strains of L. plantarum, Lactobacillus paracasei, Lactobacillus salivarius, and Lactobacillus rhamnosus expressed both high antimicrobial activity and high tolerance of environmental stress. The absence of transferable antibiotic-resistance genes in L. plantarum strains remains to be confirmed. These results suggest a potential for oral lactobacilli to be used as probiotics for oral health.

Partially hydroxylated 2,5-disubstituted bis-tetrahydrofurans from carbohydrates

The diverse bioactivities of annonaceous acetogenins have recently attracted increasing interest. Many of these natural products contain one or more 2,5-disubstituted tetrahydrofuran rings as a core unit; these are important for the bioactivity, since it is believed that these anchor the compounds to the surface of the membrane. Therefore, the synthesis of functionalized bis-tetrahydrofurans is an important task and we have developed a synthetic pathway to all four diastereomeric, partially hydroxylated bis-tetrahydrofurans, that is, 3,6:7,10)-dianhydro-2,8,9-trideoxy-L-erythro-D-ido-undecitol (1), 3,6:7,10-dianhydro-2,8,9-trideoxy-D-threo-D-ido-undecitol (2), 3,6:7,10-dianhydro-2,8,9-trideoxy-L-threo-D-ido-undecitol (3), and 3,6:7,10-dianhydro-2,8,9-trideoxy-D-erythro-D-ido-undecitol (4) starting from D-glucose. The reaction of the aldose with Meldrum's acid led to the C-glycosidic 3,6-anhydro-1,4-lactone 6, which was converted to the aldehyde building block 2,5-anhydro-3,4,7-tri-O-benzyl-6-deoxy-aldehydo-D-ido-heptose (11). Chain elongation of 11 with the Grignard reagent derived from 1-bromo-3-butene gave the diastereomers 3,6-anhydro-1,4,5-tri-O-benzyl-2,8,9,10,11-pentadeoxy-L-glycero-D-ido-undec-10-enitol (12) and 3,6-anhydro-1,4,5-tri-O-benzyl-2,8,9,10,11-pentadeoxy-D-glycero-D-ido-undec-10-enitol (13). The relative threo configuration of the major product 12 was confirmed by X-ray structure analysis. Epoxidation and subsequent cyclization afforded the cis and trans diastereomers 19 and 20, respectively, in a 1:1 ratio. Subsequent cleavage of the protecting groups and separation of the isomers furnished the target compounds in good overall yields.

Substrate specificity of sheep liver sorbitol dehydrogenase.

The substrate specificity of sheep liver sorbitol dehydrogenase has been studied by steady-state kinetics over the range pH 7-10. Sorbitol dehydrogenase stereo-selectively catalyses the reversible NAD-linked oxidation of various polyols and other secondary alcohols into their corresponding ketones. The kinetic constants are given for various novel polyol substrates, including L-glucitol, L-mannitol, L-altritol, D-altritol, D-iditol and eight heptitols, as well as for many aliphatic and aromatic alcohols. The maximum velocities (kcat) and the substrate specificity-constants (kcat/Km) are positively correlated with increasing pH. The enzyme-catalysed reactions occur by a compulsory ordered kinetic mechanism with the coenzyme as the first, or leading, substrate. With many substrates, the rate-limiting step for the overall reaction is the enzyme-NADH product dissociation. However, with several substrates there is a transition to a mechanism with partial rate-limitation at the ternary complex level, especially at low pH. The kinetic data enable the elucidation of new empirical rules for the substrate specificity of sorbitol dehydrogenase. The specificity-constants for polyol oxidation vary as a function of substrate configuration with D-xylo> D-ribo > L-xylo > D-lyxo approximately L-arabino > D-arabino > L-lyxo. Catalytic activity with a polyol or an aromatic substrate and various 1-deoxy derivatives thereof varies with -CH2OH > -CH2NH2 > -CH2OCH3 approximately -CH3. The presence of a hydroxyl group at each of the remaining chiral centres of a polyol, apart from the reactive C2, is also nonessential for productive ternary complex formation and catalysis. A predominantly nonpolar enzymic epitope appears to constitute an important structural determinant for the substrate specificity of sorbitol dehydrogenase. The existence of two distinct substrate binding regions in the enzyme active site, along with that of the catalytic zinc, is suggested to account for the lack of stereospecificity at C2 in some polyols.

Crystal and molecular structures of beta-cellobiosylnitromethane and of beta-maltosylnitromethane heptaacetate.

The structures of the title compounds have been determined by X-ray crystallography, using direct methods, and have been refined to conventional final residual factors of R = 0.063 and R = 0.046, respectively.

A sensitive bedside urine test for human chorionic gonadotrophin in suspected ectopic pregnancy.

An ultrasensitive modification of the Tandem Icon urine test for human chorionic gonadotrophin was used by clinicians, without special training, in the evaluation of 51 women with suspected ectopic pregnancy. There were 2 false-positive results. No negative results occurred in the presence of ectopic or ongoing pregnancy. A negative result (the majority of cases) is useful for excluding the diagnosis of ectopic pregnancy. The need for observation in hospital and diagnostic surgery can be greatly reduced by the use of this test in the ward or outpatient department.

Regulation of metabolic branch points of aromatic amino acid biosynthesis in Pichia guilliermondii.

The regulatory properties of the enzymes involved in the aromatic amino acid biosynthesis of Pichia guilliermondii were investigated and compared with the regulatory pattern found in other yeast species. 3-Deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) synthase, anthranilate synthase, chorismate mutase and prephenate dehydrogenase are key regulatory enzymes in P. guilliermondii. Two distinctly regulated isozymes of DAHP synthase, the initial pathway enzyme, which is inhibited by tyrosine or phenylalanine were separated by DEAE-cellulose chromatography and were characterized. Tryptophan is an excellent feedback inhibitor of anthranilate synthase, the first definite step in tryptophan biosynthesis. There are two controlled enzymes within the specific synthesis of phenylalanine and tyrosine, chorismate mutase and prephenate dehydrogenase. Chorismate mutase exhibits a balanced allosteric responsivity to phenylalanine and tyrosine, when these are used as inhibitor; tryptophan acts as an allosteric activator. Tyrosine is an effective inhibitor of prephenate dehydrogenase, whereas the activity of prephenate dehydratase is not affected by any of the aromatic amino acids. The synthesis of the enzymes in the yeast was not repressed by any single exogenous aromatic amino acids, nor by combinations of the same.

Tick-bite fever in pregnancy. A case report.

Despite the frequency of tick-bite fever in southern Africa and its doubtless occurrence in pregnancy, this report documents the first case in a pregnant woman. Consequently, the natural history of tick-bite fever in pregnancy and concomitant placental involvement must be regarded as conjectural. Accordingly a register has been opened by the Department of Obstetrics and Gynaecology, University of the Witwatersrand, for recording similar cases. At this stage of our knowledge, erythromycin 500 mg 6-hourly until 3-5 days after defervescence is the therapy of choice for such patients.

[Palliative disconnection of the kidney by transcatheter arterial embolization (author's transl)]. / Paliative Funktionsausschaltung der Niere durch arterielle Katheterembolisation.

To eliminate urine production of one Kidney transcatheter embolization of the renal artery was performed in 11 patients with mallignant tumors in the area of the pelvis; in addition to the abave procedure in 9 patients a urinary; diversion by transrenal catheter and a ureteric ligation of the opposite side was also carried out. The therapy is of palliative character and signifies the smallest intervention possible to most treat effectively involuntary urination caused by urine fistulas, painful pollakisuria caused by shrinking bladders, and to treat painful hydronephrosis caused by tumors and the like.

[Detection of acetamide in the thermal degradation products of chitin (author's transl)]. / Nachweis von Acetamid beim thermischen Abbau von Chitin.

Thermal degradation of chitin, which is a constituent of some foods, yields as main volatile compound acetamide (9% of dry weight) a fact with possible physiological implications. Thermal analysis shows decomposition beginning at 200 degrees C.

[Arteriography in old age--an assessment of the risks and technique (author's transl)]. / Arteriographie in höherem Alter--Untersuchungen zu Risiko und Technik.

Of 1,263 arteriograms performed over a period of two and a half years, there were 166 patients aged 70 years or more. The indications, angiographic findings and results have been examined retrospectively. In seven patients only was it impossible to carry out the examination because of advanced vascular disease in the pelvis. Most examinations could be performed as planned. In three patients there were minor complications without consequence. In one patient the external iliac artery was occluded following catheter angiography, but this was disobliterated during a subsequent operation which would have been carried out in case. The severity of vascular calcification as seen on plain films gives no indication regarding the difficulties during catheterisation. If aortography by catheter is impossible, we demonstrate the aorta retrogradely by a counter-current technique, using the Hettler instrument. The Hettler technique does not increase the risk and has certain advantages for the examination of older patients.