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Biomedical subjects

A Jacobs

Publications and source records attributed to A Jacobs.

At least 37 records · Page 2Linked to original sources
PubMed2001

Enhancement of the quality of MALDI mass spectra of highly acidic oligosaccharides by using a nafion-coated probe.

Spectra of highly acidic oligosaccharides obtained by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) can be greatly enhanced in quality by coating the MALDI probe surface with a film consisting of a perfluorosulfonated ionomer (Nafion) prior to the addition of the sample-matrix mixture. For comparison, three mixtures containing highly acidic oligo- and polysaccharides derived from partial acidic hydrolysis of alginate, pectin, or carboxymethyl cellulose (CMC) were analyzed by employing probes with an uncoated gold surface or a surface coated with a Nafion or nitrocellulose film. The negative ion-mode MALDI spectra of the oligouronates (oligomers containing mannuronic/guluronic and galacturonic acid residues) obtained using uncoated or nitrocellulose-coated probes consisted of a series of broad, multiple peaks. These multiple peaks were assigned to the molecular ions of the nondissociated [M - H]- and partially sodiated [MnNa - H]-, where n = 1, 2, or 3, oligomers. In contrast, the corresponding spectra obtained with Nafion-coated probes contained only a single series of sharp peaks originating from the molecular ions ([M - H]-) of nondissociated oligomers exhibiting chain lengths of as many as approximately 15 uronic acid residues. The Nafion coating was apparently capable of removing the sodium counterions remaining in the deposit of the sample-matrix mixture on the probe, thereby greatly enhancing the signal-to-noise ratios of the peaks in the spectra. In a similar manner, higher quality spectra could also be obtained by using Nafion-coated probes for analysis of the oligouronates and CMC oligomers by positive ion-mode MALDI-MS.

Fluorocarbon Polymers↗
PubMed2001

Digital chest radiography with a large-area flat-panel silicon X-ray detector: clinical comparison with conventional radiography.

This was a radiologists' preference study to compare a digital chest radiography system that utilizes a large-area silicon flat-panel detector with conventional radiography for visualizing anatomic regions of the chest. Conventional and digital posteroanterior (PA) and lateral chest radiographs were obtained in 115 patients. The PA and lateral image pairs were compared independently by three radiologists rating the overall appearance, 11 anatomic regions in the PA, and 9 in the lateral views. Statistical analysis was performed with the Wilcoxon signed-rank test with Bonferroni-Holm adjustment (p=0.05). For the PA view, the digital system performed significantly better for the overall appearance and for all anatomic regions except for the peripheral pulmonary vasculature and hilum, where no significant difference was found. For the lateral digital images, the regions trachea, costodiaphragmatic recess, and hilum were rated significantly worse. The regions retrosternal and retrocardiac lung were rated significantly better. The other regions and the overall appearance showed no significant differences. The described digital chest radiography system showed statistically superior visualization of anatomic regions for PA and an ambiguous performance for lateral images as compared with conventional radiography. After changing some image processing parameters for the lateral view, this system may be suitable for digitalization of chest radiography.

Adult↗
PubMed2001

Characterization of the molar masses of hemicelluloses from wood and pulps employing size exclusion chromatography and matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

The molar mass parameters for arabino-4-O-methylglucuronoxylans, arabinohexenuronoxylans, 4-O-methylglucuronoxylans, hexenuronoxylans, and galactoglucomannans extracted from wood and pulps have been determined. To characterize different types of hemicelluloses, delignified wood (spruce, pine, larch, aspen, and birch) and chemical pulps (unbleached and totally chlorine-free bleached) were extracted with dimethyl sulfoxide (DMSO) or alkaline aqueous solutions. Size exclusion chromatography (SEC) with off-line matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-MS) were employed to characterize the molar masses. The hemicellulose extracts were separated by SEC into fractions each containing components with a narrow range of molar masses and the average molar mass of each fraction subsequently determined by MALDI-MS. The molar mass parameters for the hemicelluloses were then calculated on the basis of the SEC distribution curves and MALDI-MS spectra. As expected, in most cases the hemicelluloses extracted from wood (holocellulose) exhibited higher molar masses than did the corresponding hemicelluloses from chemical pulps. The molar mass parameters for hemicelluloses isolated from pulps derived from cooking samples of the same batch of softwood chips decreased in the following order: ASAM pulp > MSSAQ pulp > kraft pulp. The lowest molar masses were demonstrated by the glucuronoxylans extracted from pulps obtained by cooking with acidic sulfite. The xylans from bleached kraft pulp were characterized by molar masses that were only slightly lower than those of the corresponding xylans from unbleached pulp. The xylans extracted into DMSO exhibited somewhat lower molar masses than did the corresponding xylans extracted into alkaline aqueous solutions. In all cases the range of molar masses demonstrated by the hemicelluloses investigated was found to be rather narrow, i.e., the polydispersity index Mw/Mn was found to be approximately 1.1-1.4.

Carbohydrate Sequence↗
PubMed2001

Distribution of uronic acids in xylans from various species of soft- and hardwood as determined by MALDI mass spectrometry.

The distribution of 4-O-methylglucuronic acid residues along the polysaccharide chains of xylans isolated from birch, aspen, spruce, pine, and larch was studied here employing matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis of the oligosaccharide mixtures obtained by partial acid hydrolysis. The hydrolyzates thus obtained were analyzed by MALDI-MS or by capillary electrophoresis as well as by size exclusion chromatography in combination with MALDI-MS. In the case of all softwood xylans examined, the major portion of the 4-O-methylglucuronic acid residues were distributed regularly on every seventh or eighth xylose residue, while a minor portion of these residues were attached to adjacent xylose residues in the beta-(1-->4)-D-xylopolysaccharide chains. In contrast, the 4-O-methylglucuronic acid residues in the hardwood xylans examined were found to be distributed irregularly within the xylan. Further support for these experimental findings with the xylans was obtained by simulation of the distribution patterns of the molecular masses of oligosaccharides arising from polysaccharides with the postulated distribution of uronic acid residues.

Carbohydrates↗
PubMed2001

The dialysis diet and fluid non-adherence questionnaire: validity testing of a self-report instrument for clinical practice.

This study evaluated the validity of the dialysis diet and fluid non-adherence questionnaire (DDFQ) as a self-report instrument for clinical practice. The DDFQ was designed to measure non-adherence behaviour with diet and fluid guidelines in patients treated with hospital-based haemodialysis in Flanders (Belgium). In a multicentre cross-sectional study design, 564 patients from 10 dialysis centres in Flanders completed the DDFQ Criterion and construct validity of the instrument were substantiated using correlation techniques between the DDFQ and biochemical and biological ratings of non-adherence. The results of this study suggest that the DDFQ is a valid self-report instrument to assess non-adherence behaviour in haemodialysis patients in Flanders and probably also in other cultures.

Adult↗
PubMed2001

Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.

Clostridium difficile is most commonly associated with colonic infection. It may, however, also cause disease in a variety of other organ systems. Small bowel involvement is often associated with previous surgical procedures on the small intestine and is associated with a significant mortality rate (4 of 7 patients). When associated with bacteremia, the infection is, as expected, frequently polymicrobial in association with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported patients. Visceral abscess formation involves mainly the spleen, with 1 reported case of pancreatic abscess formation. Frequently these abscesses are only recognized weeks to months after the onset of diarrhea or other colonic symptoms. C. difficile-related reactive arthritis is frequently polyarticular in nature and is not related to the patient's underlying HLA-B27 status. Fever is not universally present. The most commonly involved joints are the knee and wrist (involved in 18 of 36 cases). Reactive arthritis begins an average of 11.3 days after the onset of diarrhea and is a prolonged illness, taking an average of 68 days to resolve. Other entities, such as cellulitis, necrotizing fasciitis, osteomyelitis, and prosthetic device infections, can also occur. Localized skin and bone infections frequently follow traumatic injury, implying the implantation of either environmental or the patient's own C. difficile spores with the subsequent development of clinical infection. It is noteworthy that except for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease do not appear to be strongly related to previous antibiotic exposure. The reason for this is unclear. We hope that clinicians will become more aware of these extracolonic manifestations of infection, so that they may be recognized and treated promptly and appropriately. Such early diagnosis may also serve to prevent extensive and perhaps unnecessary patient evaluations, thus improving resource utilization and shortening length of hospital stay.

Adult↗
PubMed2001

Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke.

OBJECTIVE: There is no known effective treatment for chronic stroke. In this report, we used positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) to map the metabolic brain response to neuronal cell implantation in the first human neuroimplantation trial for stroke. METHODS: Twelve patients (nine men, three women; mean age +/- standard deviation, 60.8+/-8.3 yr) with chronic basal ganglia infarction and persistent motor deficit underwent FDG PET within 1 week before and 6 and 12 months after stereotactic implantation of human neuronal cells. Serial neurological evaluations during a 52-week postoperative period included the National Institutes of Health stroke scale and the European stroke scale. RESULTS: Alterations in glucose metabolic activity in the stroke and surrounding tissue at 6 and 12 months after implantation correlated positively with motor performance measures. CONCLUSION: FDG PET performed as part of an initial open-label human trial of implanted LBS-Neurons (Layton BioScience, Sunnyvale, CA) for chronic stroke demonstrates a relationship between relative regional metabolic changes and clinical performance measures. These preliminary findings suggest improved local cellular function or engraftment of implanted cells in some patients.

Aged↗
PubMed2001

Heparin binding by the HIV-1 tat protein transduction domain.

The protein transduction domain from the HIV-1 tat protein (termed PTD-tat) has been fused to the C-terminus of a model cargo protein, the IgG binding domain of streptococcal protein G. We demonstrate that PG-Ctat (PTD-tat fused to the C-terminus of protein G) binds to a heparin affinity column. PG-Ctat binds with relatively high affinity, as shown by its elution at 1.6 M NaCl. The heparin binding properties of PTD-tat are consistent with the idea that heparan sulfate, an analog of heparin found at the cell surface, plays a role in the translocation of PTD-tat fusions. We suggest that the heparin-binding properties of PTD-tat can be exploited for purification of PTD-tat fusions in the absence of affinity tags.

Gene Products, tat↗
PubMed2001

Health related quality of life is improved by botulinum neurotoxin type A in long term treated patients with focal dystonia.

OBJECTIVES: The advent of botulinum neurotoxin type A (BoNT/A) gave rise to substantial progress in the treatment of focal dystonias. In the light of the high costs of the toxin and the necessity to establish valid outcome indices for this treatment apart from sheer reduction of dystonic muscle tone and posture, the impact of focal dystonia and its treatment with BoNT/A on patients' health related quality of life (HRQL) was determined. METHODS: Fifty patients with cranial and cervical dystonia treated long term with BoNT/A were enrolled in a prospective, open labelled cohort study. The HRQL was assessed using the EuroQol (EQ-5D) and the short form 36 health survey questionnaire (SF-36) at baseline before BoNT/A injections and at two follow up visits after 6 and 12 weeks covering one BoNT/A treatment period with maximum effect size at the first follow up. RESULTS: Compared with a general population sample, a considerable negative impact of focal dystonia on HRQL was found in patients under investigation. In both disease types, BoNT/A treatment led to a significant improvement in several HRQL dimensions, in particular providing moderate to marked effect sizes in the fields of mental health and pain. The impairment of HRQL due to pain as well as the BoNT/A induced improvement within this SF-36 subscore were significantly higher in patients with cervical dystonia. Under BoNT/A therapy, no correlation was found between changes of clinical outcome scores and HRQL measures. CONCLUSIONS: The data confirm that BoNT/A is able to induce a significant, but temporary amelioration of several aspects of HRQL in both types of focal dystonia. This may substantially contribute to the patients' subjective benefit from the therapy. Moreover, the data provide further arguments to accept high costs of the BoNT/A treatment in these severely handicapped patients, as a consequence of its considerable benefit on quality of life.

Aged↗
PubMed2001

Intraoperative MRI and adjuvant radiosurgery.

INTRODUCTION: For many patients with brain tumors, the ideal management strategy may be a planned subtotal resection followed by stereotactic radiosurgery (SRS). However, intraoperative visual inspection may be an inadequate measure of the amount of residual lesion. Intraoperative MRI (IMRI) may help to ensure that the goals of surgery have been achieved and that the best possible target for SRS remains. PATIENTS AND METHODS: We have operated on 68 patients using the PoleStar N-10 IMRI system (Odin Medical Technologies, Yokne'am, Israel). Benign extraaxial lesions were present in 34 patients. In 12 patients subtotal resection and adjuvant SRS were planned. Diagnoses included 5 pituitary adenomas, 4 meningiomas, 2 vestibular schwannomas, and 1 trigeminal schwannoma. Tumor resection was performed until critical structures (e.g. superior sagittal sinus) were being approached and IMRI demonstrated that the lesion was as small as possible. RESULTS: In 1 patient a surgical resection was completed, while in 11 others the plan for subtotal resection was carried out. One patient with an extensive meningioma was treated with fractionated 3-dimensional conformal fractionated radiation therapy, as her tumor remained too large for SRS. In the remaining 10 patients an ideally small target remained for SRS; 3 patients have been treated so far. CONCLUSIONS: Adjuvant SRS after subtotal tumor resection is an excellent management strategy for many patients with intracranial tumors. IMRI can ensure that the surgical goals have been reached. Future comparison of target volumes, integral volume doses, and patient outcomes are planned.

Adult↗
PubMed2001

Quantitative kinetics of [124I]FIAU in cat and man.

UNLABELLED: For the assessment of the efficacy of clinical gene therapy trials, different imaging modalities have been developed that enable a noninvasive assessment of location, magnitude, and duration of transduced gene expression in vivo. These imaging methods rely on a combination of an appropriate marker gene and a radiolabeled or paramagnetic marker substrate that can be detected by PET or MRI. Here, we assess whether the nucleoside analog 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyl-5-iodouracil (FIAU), a specific marker substrate for herpes simplex virus type 1 thymidine kinase (HSV-1-tk) gene expression, penetrates the blood-brain barrier (BBB) as an essential prerequisite for a noninvasive assessment of HSV-1-tk gene expression in gliomas. METHODS: No-carrier-added [(124)I]FIAU was synthesized by reacting the precursor 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyluracil (FAU) with carrier-free [(124)I]NaI. The course of biodistribution of [(124)I]FIAU was investigated in anesthetized cats (n = 3; organs) and in one patient with a recurrent glioblastoma (plasma and brain) by PET imaging over several hours (cats, 1-22 h) to several days (patient, 1-68 h). FIAU PET was performed in conjunction with multitracer PET imaging (cerebral blood flow and cerebral metabolic rate of O(2) in cats only; cerebral metabolic rate of glucose and [(11)C]methionine in all subjects). A region-of-interest analysis was performed on the basis of coregistered high-resolution MR images. The average radioactivity concentration was determined, decay corrected, and recalculated as percentage injected dose per gram of tissue (%ID/g) or as standardized uptake values (SUVs). RESULTS: The average chemical yield of [(124)I]FIAU synthesis was 54.6% +/- 6.8%. The chemical and radiochemical purities of [(124)I]FIAU were found to be >98% and >95%, respectively. In cats, the kinetic analysis of [(124)I]FIAU-derived radioactivity showed an early peak (1-2 min after injection) in heart and kidneys (0.20 %ID/g; SUV, 4.0) followed by a second peak (10-20 min after injection) in liver and spleen (0.16 %ID/g; SUV, 3.2) with subsequent clearance from tissues and a late peak in the bladder (10-15 h after injection). In the unlesioned cat brain, no substantial [(124)I]FIAU uptake occurred throughout the measurement (<0.02 %ID/g; SUV, <0.4). In the patient, [(124)I]FIAU uptake in normal brain was also very low (<0.0002 %ID/g; SUV, <0.16). In contrast, the recurrent glioblastoma revealed relatively high levels of [(124)I]FIAU-derived radioactivity (5-10 min after injection; 0.001 %ID/g; SUV, 0.8), which cleared slowly over the 68-h imaging period. CONCLUSION: The PET marker substrate FIAU does not penetrate the intact BBB significantly and, hence, is not the marker substrate of choice for the noninvasive localization of HSV-1-tk gene expression in the central nervous system under conditions in which the BBB is likely to be intact. However, substantial levels of [(124)I]FIAU-derived radioactivity may occur within areas of BBB disruption (e.g., glioblastoma), which is an essential prerequisite for imaging clinically relevant levels of HSV-1-tk gene expression in brain tumors after gene therapy by FIAU PET. For this purpose, washout of nonspecific radioactivity should be allowed for several days.

Animals↗
PubMed2000

Percutaneous coronary intervention in the current era compared with 1985-1986: the National Heart, Lung, and Blood Institute Registries.

BACKGROUND: Although refinements have occurred in coronary angioplasty over the past decade, little is known about whether these changes have affected outcomes. METHODS AND RESULTS: Baseline features and in-hospital and 1-year outcomes of 1559 consecutive patients in the 1997-1998 Dynamic Registry who were having first coronary intervention were compared with 2431 patients in the 1985-1986 National Heart, Lung, and Blood Institute Registry. Compared with patients in the 1985-1986 Registry, Dynamic Registry patients were older (mean age, 62 versus 58 years; P:<0.001) and more often female (32.1% versus 25.5%; P:<0.001). In the Dynamic Registry, procedures were more often performed for acute myocardial infarction (22.9% versus 9.9%; P:<0.001) and treated lesions were more severe (84.5% versus 82.5% diameter reduction; P:<0.001), thrombotic (22.1% versus 11.3%; P:<0.001) or calcified (29.5% versus 10.8%; P:<0.001). Stents were used in 70.5% of Dynamic Registry patients, whereas 1985-1986 patients received balloon angioplasty alone. Procedural success was higher in the Dynamic Registry (92.0% versus 81.8%; P:<0.001) and the rate of in-hospital death, myocardial infarction, and emergency coronary bypass surgery combined was lower (4.9% versus 7.9%; P:=0.001) than in the 1985-1986 Registry. The 1-year rate for CABG was lower in the Dynamic Registry (6.9% versus 12.6%; P:<0.001). CONCLUSIONS: Although Dynamic Registry patients had more unstable and complex coronary disease than those in the 1985-1986 Registry, their rate of procedural success was higher whereas rates of complications and subsequent CABG were lower. Results of percutaneous coronary intervention have improved substantially over the past decade.

Angioplasty, Balloon, Coronary↗
PubMed2000

Analysis of carbohydrates in wood and pulps employing enzymatic hydrolysis and subsequent capillary zone electrophoresis.

An efficient method for determining the carbohydrate composition of extractive-free delignified wood and pulp is described here. The polysaccharides in the sample are first hydrolyzed using a mixture of commercially available preparations of cellulase and hemicellulase. The reducing saccharides in the hydrolysate thus obtained are subsequently derivatized with 4-aminobenzoic acid ethyl ester and thereafter quantitated by capillary zone electrophoresis (CZE) in an alkaline borate buffer with monitoring of the absorption at 306 nm. All reducing sugars (i.e., neutral monosaccharides and uronic acids) which occur as structural elements in the polysaccharides of wood and pulp can be quantitated in a single such analytical run, which can also determine the contents of 4-deoxy-beta-L-threo-hex-4-enopyranosyluronic acid (HexA) residues present in pulps obtained from alkaline processes. CZE analyses were performed using linear regression of standard curves over a concentration range spanning approximately three orders of magnitude. Carbohydrate constituents constituting approximately 0.1% of the dry mass of the sample could be quantitated. The overall precision of this analytical procedure--involving enzymatic hydrolysis, derivatization and CZE--was good (RSD=2.2-7.5%), especially considering the heterogeneity of the wood and pulp samples. The total yield of carbohydrates (93-97%) obtained employing the procedure developed here was consistently higher than that obtained upon applying the traditional procedure for carbohydrate analysis (85-93%) (involving acid hydrolysis and gas chromatographic analysis) to the same pulps. The trisaccharide HexA-xylobiose was the only HexA-containing saccharide detected using the conditions for enzymatic hydrolysis developed here (i.e., 30 h incubation at pH 4 and 40 degrees C); whereas mixtures of HexA-xylobiose and HexA-xylotriose were obtained when the incubation was performed at pH 5 or 6.

Carbohydrates↗
PubMed2000

Helper virus-free herpes simplex virus type 1 amplicon vectors for granulocyte-macrophage colony-stimulating factor-enhanced vaccination therapy for experimental glioma.

Subcutaneous vaccination therapy with glioma cells, which are retrovirally transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), has previously proven effective in C57BL/6 mice harboring intracerebral GL261 gliomas. However, clinical ex vivo gene therapy for human gliomas would be difficult, as transgene delivery via retroviral vectors occurs only in dividing cells and ex vivo glioma cells have a low growth fraction. To circumvent this problem, a helper virus-free herpes simplex virus type 1 (HSV-1) amplicon vector was used. When primary cultures of human glioblastoma cells were infected with HSV-1 amplicon vectors at an MOI of 1, more than 90% of both dividing and nondividing cells were transduced. When cells were infected with an amplicon vector, HSVGM, bearing the GM-CSF cDNA in the presence of Polybrene, GM-CSF secretion into the medium during the first 24 hr after infection was 1026 ng/10(6) cells, whereas mock-infected cells did not secrete detectable GM-CSF. Subcutaneous vaccination of C57BL/6 mice with 5 x 10(5) irradiated HSVGM-transduced GL261 cells 7 days prior to intracerebral implantation of 10(6) wild-type GL261 cells yielded 60% long-term survivors (>80 days), similar to the 50% long-term survivors obtained by vaccination with retrovirally GM-CSF-transduced GL261 cells. In contrast, animals vaccinated with the same number of nontranduced GL261 cells or with GL261 cells infected with helper virus-free packaged HSV-1 amplicon vectors carrying no transgene showed only 10% long-term survivors. In conclusion, helper virus-free HSV-1 amplicon vectors appear to be effective for cytokine-enhanced vaccination therapy of glioma, with the advantages that both dividing and nondividing tumor cells can be infected, no viral proteins are expressed, and these vectors are safe and compatible with clinical use.

Animals↗
PubMed2000

Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor).

Preimplantation mammalian embryos in culture secrete autocrine growth factors into the surrounding medium that, in turn, stimulate the development of the embryos. The full complement of these factors is unknown. Since one hallmark of embryo development is the formation of an epithelium, the trophectoderm, we tested the hypothesis that one such embryo-derived growth factor is acrogranin (epithelin/granulin precursor), a factor that possesses growth-regulatory activities principally toward epithelial cells. We found that acrogranin mRNA was expressed in preimplantation mouse embryos with the transcript levels rising to their highest point in blastocysts, coincident with the appearance of the trophectoderm. Indirect immunofluorescence confocal microscopy of preimplantation mouse embryos at different developmental stages revealed that acrogranin immunostaining was most concentrated in the trophectoderm of blastocysts. Immunoblotting and immunoprecipitation experiments demonstrated that the embryos secreted acrogranin into the surrounding medium. To determine how altering the levels of acrogranin in the culture medium surrounding the embryos might affect embryonic growth and development, acrogranin protein levels in the culture medium were decreased with a function-blocking antibody or increased by adding the purified acrogranin to the medium. In both a concentration-dependent and a reversible manner, affinity-purified anti-acrogranin antibody significantly inhibited the development of eight-cell embryos to the blastocyst stage compared to controls (no added immunoglobulin or nonspecific IgG). Furthermore, embryo cell numbers were significantly decreased in the presence of the highest concentrations of acrogranin antibody compared to control embryos. Exogenous acrogranin added to cultures of eight-cell embryos accelerated the time for the onset of cavitation, as well as stimulating the rate of blastocoel expansion and increasing the number of trophectoderm cells compared to controls. These results indicate that acrogranin can regulate the appearance of the epithelium in the developing mouse blastocyst, the growth of the trophectoderm, and/or the function of the embryonic epithelium.

Animals↗
PubMed2000

Regulatory science: a special update from the United States Food and Drug Administration: Preclinical issues and status of investigation of botanical drug products in the United States.

A recent survey was conducted across the therapeutic divisions within the CDER, U.S. FDA regarding the number of submissions related to botanical drug products over the past ten years. The overall number of botanical submissions as expressed in the parenthesis are as follows: 1990 (1), 1991 (4), 1992 (4), 1993 (5), 1994 (6), 1995 (5), 1996 (13), 1997 (16), 1998 (10). In the total of 64 counted, 50 of them are submitted in original IND and the rest (14) in pre-IND format. The therapeutic categories are focused on dermatological and topical (19), anti AIDS/antiviral (12), oncologic (13), neuropharmacologic (8), endocrine and metabolic (3), urologic (2), tobacco (2), and cardio-renal products (1). The regulatory actions taken on these submissions showed that 68% of them are evaluated as safe to proceed for the human trials, while the rest (32%) of submissions required agency's regulatory guidance. Among the submissions that required further guidance, 81% were deficient in preclinical pharmacology/toxicology information and the rest (19%) lacks information in other areas (chemistry, clinical protocols). Following agency's guidance, 93% of the submissions that were put on hold were allowed to proceed. In summary, a total of 94% of all the botanical INDs submitted to the agency were allowed to proceed without additional animal toxicity studies conducted. In conclusion, this survey indicates that the growing public interest in botanical supplements has prompted more formal evaluation of the efficacy/safety claims of these products.

Databases, Factual↗
PubMed2000

Considerations on photochemical genotoxicity: report of the International Workshop on Genotoxicity Test Procedures Working Group.

Recent toxicological observations have caused concern regarding the need to test, for example, pharmaceuticals and cosmetic products for photochemical genotoxicity. The objective of this report is to give assistance on how to adapt existing test methods to investigate the potential of light-absorbing compounds to induce genotoxic effects on photoactivation. In general, the Organization for Economic Co-Operation & Economic Development (OECD) draft guideline on in vitro phototoxicity testing served as a basis for consideration. Concomitant exposure of the cells to the test compound and solar simulated light was considered appropriate as the initial, basic test condition. Optimization of the exposure scheme, e.g., a change of the irradiation spectrum, might be indicated depending on the initial test results. Selection of test compound concentrations should be based on results obtained with the dark version of the respective test system but might have to be modified if phototoxic effects are observed. Selection of the irradiation dose has to be performed individually for each test system based on dose-effect studies. The irradiation should induce per se a small, reproducible toxic or genotoxic effect. The report includes a specification of necessary controls, discusses factors that might have an impact on the irradiation characteristics, and gives a rationale for the omission of an external metabolic activation system. It also addresses the question that physicochemical and pharmacokinetic properties might trigger the need to test a chemical for photochemical genotoxicity. Relevant experimental observations are presented to back up the recommendations. The working group did not reach a consensus as to whether a single, adequately perfomed in vitro test for clastogenicity would be sufficient to exclude a photogenotoxic liability or whether a test battery including a gene mutation assay would be needed for product safety testing regarding photochemical genotoxicity.

Animals↗