Publications by authors named "Jennifer S Chen"

18 Publications

  • Page 1 of 1

Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes.

PLoS Biol 2021 03 17;19(3):e3001143. Epub 2021 Mar 17.

Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States of America.

There are currently limited Food and Drug Administration (FDA)-approved drugs and vaccines for the treatment or prevention of Coronavirus Disease 2019 (COVID-19). Enhanced understanding of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and pathogenesis is critical for the development of therapeutics. To provide insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2, we performed single-cell (sc) RNA sequencing (RNA-seq) of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface (ALI) cultures over a time course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target at the onset of infection, which we confirmed by electron and immunofluorescence microscopy. Over the course of infection, the cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III interferons (IFNs) and interleukin (IL)-6 but not IL-1. This results in expression of interferon-stimulated genes (ISGs) in both infected and bystander cells. This provides a detailed characterization of genes, cell types, and cell state changes associated with SARS-CoV-2 infection in the human airway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.3001143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007021PMC
March 2021

Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection.

J Virol 2021 Jan 13. Epub 2021 Jan 13.

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA

Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). As PGs play diverse biological roles in homeostasis and inflammatory responses, inhibiting PG production with NSAIDs could affect COVID-19 pathogenesis in multiple ways, including: (1) altering susceptibility to infection by modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; (2) regulating replication of SARS-CoV-2 in host cells; and (3) modulating the immune response to SARS-CoV-2. Here, we investigate these potential roles. We demonstrate that SARS-CoV-2 infection upregulates COX-2 in diverse human cell culture and mouse systems. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on expression, viral entry, or viral replication. In contrast, in a mouse model of SARS-CoV-2 infection, NSAID treatment reduced production of pro-inflammatory cytokines and impaired the humoral immune response to SARS-CoV-2 as demonstrated by reduced neutralizing antibody titers. Our findings indicate that NSAID treatment may influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies rather than modifying susceptibility to infection or viral replication.Public health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19). NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are critical for the generation of prostaglandins - lipid molecules with diverse roles in homeostasis and inflammation. Inhibition of prostaglandin production by NSAIDs could therefore have multiple effects on COVID-19 pathogenesis. Here, we demonstrate that NSAID treatment reduced both the antibody and pro-inflammatory cytokine response to SARS-CoV-2 infection. The ability of NSAIDs to modulate the immune response to SARS-CoV-2 infection has important implications for COVID-19 pathogenesis in patients. Whether this occurs in humans and whether it is beneficial or detrimental to the host remains an important area of future investigation. This also raises the possibility that NSAIDs may alter the immune response to SARS-CoV-2 vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00014-21DOI Listing
January 2021

An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2.

Cell Rep 2020 12 1;33(12):108528. Epub 2020 Dec 1.

Department of Microbiology, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

Soluble forms of angiotensin-converting enzyme 2 (ACE2) have recently been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We report on an improved soluble ACE2, termed a "microbody," in which the ACE2 ectodomain is fused to Fc domain 3 of the immunoglobulin (Ig) heavy chain. The protein is smaller than previously described ACE2-Ig Fc fusion proteins and contains an H345A mutation in the ACE2 catalytic active site that inactivates the enzyme without reducing its affinity for the SARS-CoV-2 spike. The disulfide-bonded ACE2 microbody protein inhibits entry of SARS-CoV-2 spike protein pseudotyped virus and replication of live SARS-CoV-2 in vitro and in a mouse model. Its potency is 10-fold higher than soluble ACE2, and it can act after virus bound to the cell. The microbody inhibits the entry of β coronaviruses and virus with the variant D614G spike. The ACE2 microbody may be a valuable therapeutic for coronavirus disease 2019 (COVID-19) that is active against viral variants and future coronaviruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705358PMC
December 2020

Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.

Cell 2021 01 20;184(1):76-91.e13. Epub 2020 Oct 20.

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574718PMC
January 2021

Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication.

bioRxiv 2020 Sep 25. Epub 2020 Sep 25.

Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). PGE , one of the most abundant PGs, has diverse biological roles in homeostasis and inflammatory responses. Previous studies have shown that NSAID treatment or inhibition of PGE receptor signaling leads to upregulation of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, thus raising concerns that NSAIDs could increase susceptibility to infection. COX/PGE signaling has also been shown to regulate the replication of many viruses, but it is not yet known whether it plays a role in SARS-CoV-2 replication. The purpose of this study was to dissect the effect of NSAIDs on COVID-19 in terms of SARS-CoV-2 entry and replication. We found that SARS-CoV-2 infection induced COX-2 upregulation in diverse human cell culture and mouse systems. However, suppression of COX-2/PGE signaling by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on expression, viral entry, or viral replication. Our findings suggest that COX-2 signaling driven by SARS-CoV-2 may instead play a role in regulating the lung inflammation and injury observed in COVID-19 patients.

Importance: Public health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NSAIDs function by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes are critical for the generation of prostaglandins, lipid molecules with diverse roles in maintaining homeostasis as well as regulating the inflammatory response. While COX-1/COX-2 signaling pathways have been shown to affect the replication of many viruses, their effect on SARS-CoV-2 infection remains unknown. We found that SARS-CoV-2 infection induced COX-2 expression in both human cell culture systems and mouse models. However, inhibition of COX-2 activity with NSAIDs did not affect SARS-CoV-2 entry or replication. Our findings suggest that COX-2 signaling may instead regulate the lung inflammation observed in COVID-19 patients, which is an important area for future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.09.24.312769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523115PMC
September 2020

A web tool for the design of prime-editing guide RNAs.

Nat Biomed Eng 2021 02 28;5(2):190-194. Epub 2020 Sep 28.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Prime editing enables diverse genomic alterations to be written into target sites without requiring double-strand breaks or donor templates. The design of prime-editing guide RNAs (pegRNAs), which must be customized for each edit, can however be complex and time consuming. Compared with single guide RNAs (sgRNAs), pegRNAs have an additional 3' extension composed of a primer binding site and a reverse-transcription template. Here we report a web tool, which we named pegFinder ( http://pegfinder.sidichenlab.org ), for the rapid design of pegRNAs from reference and edited DNA sequences. pegFinder can incorporate sgRNA on-target and off-target scoring predictions into its ranking system, and nominates secondary nicking sgRNAs for increasing editing efficiency. CRISPR-associated protein 9 variants with expanded targeting ranges are also supported. To facilitate downstream experimentation, pegFinder produces a comprehensive table of candidate pegRNAs, along with oligonucleotide sequences for cloning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-020-00622-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882013PMC
February 2021

Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection.

bioRxiv 2020 Jun 17. Epub 2020 Jun 17.

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.06.16.155101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457610PMC
June 2020

Flow cytometric identification of T13 cells in mouse and human.

J Allergy Clin Immunol 2021 Feb 21;147(2):470-483. Epub 2020 Jul 21.

Jackson Laboratory for Genomic Medicine, Farmington, Conn; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Conn. Electronic address:

Anaphylaxis is a life-threatening allergic reaction caused by cross-linking of high-affinity IgE antibodies on the surface of mast cells and basophils. Understanding the cellular mechanisms that lead to high-affinity IgE production is required to develop better therapeutics for preventing this severe reaction. A recently discovered population of T follicular helper T13 cells regulates the production of high-affinity IgE in mouse models of allergy and can also be found in patients with allergies with IgE antibodies against food or aeroallergens. Here we describe optimized protocols for identifying T13 cells in both mice and humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.04.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854882PMC
February 2021

Regulation of IgE by T follicular helper cells.

J Leukoc Biol 2020 03 22;107(3):409-418. Epub 2020 Jan 22.

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Allergies to food and environmental antigens have steeply grown to epidemic proportions. IgE antibodies are key mediators of allergic disease, including life-threatening anaphylaxis. There is now compelling evidence that one of the hallmarks of anaphylaxis-inducing IgE molecules is their high affinity for allergen, and the cellular pathway to high-affinity IgE is typically through sequential switching of IgG B cells. Further, in contrast to the previously held paradigm that a subset of CD4 T cells called Th2 cells promotes IgE responses, recent studies suggest that T follicular helper cells are crucial for inducing anaphylactic IgE. Here we discuss recent studies that have enabled us to understand the nature, induction, and regulation of this enigmatic antibody isotype in allergic sensitization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.3RI1219-425RDOI Listing
March 2020

Identification of a T follicular helper cell subset that drives anaphylactic IgE.

Science 2019 08 1;365(6456). Epub 2019 Aug 1.

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (T) cells direct the affinity and isotype of antibodies produced by B cells. Although T cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing T cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These "T13" cells have an unusual cytokine profile (IL-13IL-4IL-5IL-21) and coexpress the transcription factors BCL6 and GATA3. T13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aaw6433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901029PMC
August 2019

A ten-acious cytokine for a tenacious infection.

Sci Immunol 2019 02;4(32)

Departments of Laboratory Medicine, Immunobiology, and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Email: and

T follicular helper cells produce interleukin-10 during chronic viral infections to support the humoral response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.aaw7720DOI Listing
February 2019

Two-Factor Authentication for Type 2 Immunity.

Immunity 2018 09;49(3):381-383

Departments of Laboratory Medicine and Immunobiology and Section of Rheumatology, Allergy, and Clinical Immunology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

The initiation of type 2 responses is tightly regulated. In this issue of Immunity, Sokol et al. (2018) demonstrate that CCL8 is a critical signal that licenses dendritic cells to enter the lymph node parenchyma and induce Th2 differentiation after allergen exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2018.08.020DOI Listing
September 2018

Genetic determinants and epigenetic effects of pioneer-factor occupancy.

Nat Genet 2018 02 22;50(2):250-258. Epub 2018 Jan 22.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Transcription factors (TFs) direct developmental transitions by binding to target DNA sequences, influencing gene expression and establishing complex gene-regultory networks. To systematically determine the molecular components that enable or constrain TF activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite their classification as pioneer factors, all three TFs exhibit cell-type-specific binding, even when supraphysiologically and ectopically expressed. However, FOXA2 and GATA4 can be distinguished by low enrichment at loci that are highly occupied by these factors in alternative cell types. We find that expression of additional cofactors increases enrichment at a subset of these sites. Finally, FOXA2 occupancy and changes to DNA accessibility can occur in G-arrested cells, but subsequent loss of DNA methylation requires DNA replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-017-0034-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517675PMC
February 2018

Practice Variation in Triple Therapy for Patients With Both Atrial Fibrillation and Coronary Artery Disease: Insights From the ACC's National Cardiovascular Data Registry.

JACC Clin Electrophysiol 2016 Feb 10;2(1):36-43. Epub 2015 Nov 10.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Clinical Research Institute, Boston, Massachusetts, USA. Electronic address:

Objectives: The aim of this study was to test the hypothesis that in the United States substantial practice variation exists in triple therapy prescribing practices, unrelated to measured patient factors.

Background: Recent data have shown that the risk of bleeding on dual antiplatelet therapy and oral anticoagulation ("triple therapy") is high, although the optimal strategy for patients with atrial fibrillation and coronary artery disease remains unclear.

Methods: Using the PINNACLE (National Practice Innovation and Clinical Excellence) registry, we identified 79,875 unique patients with both atrial fibrillation/atrial flutter and myocardial infarction and/or coronary stenting within 12 months. Using triple therapy as a binary outcome variable, we created a mixed-effects logistic regression model with patient factors as fixed effects and practice site as a random effect. Patient factors included age, sex, diabetes, congestive heart failure, hypertension, peripheral arterial disease, prior stroke or transient ischemic attack, history of systemic embolization, and dyslipidemia. The model was assessed with a median odds ratio to assess practice variation after adjustment for patient factors.

Results: After adjustment for patient factors, significant practice variation was suggested by a median odds ratio of 2.78 (95% confidence interval: 2.33 to 3.23). In particular, this suggests that 2 randomly selected practices would differ in their likelihood of prescribing triple therapy for an identical patient by a factor of nearly 3.

Conclusions: In the United States, there is substantial practice variation in prescribing triple therapy to eligible patients even after adjustment for patient clinical characteristics. These results suggest that opportunities exist to improve the quality of care of this sizable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacep.2015.08.010DOI Listing
February 2016

Myoclonus associated with long-term use of diltiazem.

Am J Health Syst Pharm 2011 Sep;68(18):1707-10

College of Pharmacy, University of Minnesota, Duluth, 55812, USA.

Purpose: A case of possible diltiazem-induced myoclonus in a patient receiving long-term therapy, with residual symptoms after discontinuation, is reported.

Summary: A 61-year-old Caucasian man who had received diltiazem therapy for 5 years for the treatment of premature ventricular contractions (PVCs) was seen at a clinic for complaints of abnormal sensations and body movements that had worsened over 2 years and were sometimes triggered by an exaggerated startle response to light and startling scenes on television and in movies. After a sleep study, electroencephalography, and other evaluations to rule out neurologic and other causes of the patient's myoclonus, diltiazem therapy was discontinued; two weeks later, the man reported a 50% reduction in symptoms. At 1- and 3-year follow-up visits, the patient reported further diminution but not complete resolution of the myoclonic symptoms. In contrast to other published cases of calcium-channel-blocker-induced myoclonus, the onset of movement symptoms in this case was delayed, occurring years rather than days after the initiation of diltiazem use; the residual symptoms persisted far longer than in other reported cases. It is possible that the concomitant use of citalopram and a change in the patient's lipid-lowering medication may have contributed to or prolonged the abnormal movement symptoms in this case. Using the adverse drug reaction probability algorithm of Naranjo et al., the case was classified as possible diltiazem-induced myoclonus.

Conclusion: A 61-year-old man developed myoclonus three years after starting diltiazem therapy for PVCs. The symptoms gradually resolved after the discontinuation of diltiazem but did not stop completely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2146/ajhp100704DOI Listing
September 2011

Separation of doxorubicin and doxorubicinol by cyclodextrin-modified micellar electrokinetic capillary chromatography.

Electrophoresis 2006 Aug;27(16):3263-70

Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.

Doxorubicinol (DOXol) is a human metabolite of the chemotherapy agent doxorubicin (DOX), and is associated with dose-dependent cardiotoxicity and decreased drug efficacy. Due to the structural similarities and equal molecular charges of DOXol and DOX, their electrophoretic separation is commonly ineffective. A method for separating and detecting DOX and DOXol, as well as two DOXol enantiomers, was established using cyclodextrin-modified micellar electrokinetic capillary chromatography with laser-induced fluorescence detection. Differential DOXol production was detected in a DOX-sensitive and resistant pair of cell lines, with a 0.08 +/- 0.01 fmol limit of detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/elps.200600025DOI Listing
August 2006

Unlabeled uses of botulinum toxins: a review, part 2.

Am J Health Syst Pharm 2006 Feb;63(3):225-32

University of California at San Francisco, San Francisco, CA 94143, USA.

Purpose: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed.

Summary: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur.

Conclusion: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2146/sp/06001DOI Listing
February 2006

Unlabeled uses of botulinum toxins: a review, part 1.

Am J Health Syst Pharm 2006 Jan;63(2):145-52

Drug Information and Analysis Service, University of California at San Francisco, San Francisco, CA 94143, USA.

Purpose: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed.

Summary: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur.

Conclusion: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2146/ajhp050137DOI Listing
January 2006