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

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.     

Unlabeled uses of nebulized medications.

PURPOSE: The uses, dosing recommendations, benefits, and disadvantages of unlabeled drugs administered by nebulization are reviewed. SUMMARY: Nebulization is gaining popularity as a treatment alternative, and many drugs are used unlabeled in a nebulized form, including the opioids, lidocaine, magnesium sulfate, amphotericin B, and colistin. The opioids are frequently used to treat dyspnea in end-stage diseases. Common dosages include 1-2 mg every two hours as needed for hydromorphone and 25-50 microg every two hours for fentanyl citrate. Lidocaine can be used to relieve bronchoconstriction and cough symptoms as well as acting as a local anesthetic. It is typically given in a dose between 20 and 160 mg. Nebulized magnesium sulfate can be used in managing acute asthma and is given in dosages between 125 and 250 mg every 20 minutes, with no more than four consecutive doses. Nebulized amphotericin B can be used to prevent infections in immunocompromised patients. A typical amphotericin B regimen is 25 mg every 24 hours. Nebulized colistin is being studied in the prevention and treatment of gram-negative infections and in patients awaiting lung transplants. Colistin is often given as 75 mg every 12 hours to combat infections. CONCLUSION: Unlabeled nebulization of opioids, lidocaine, magnesium, amphotericin B, and colistin is an alternative method of treatment for patients with pulmonary problems or infections or for those undergoing bronchoscopy. More research is needed to develop guidelines for their use since nebulization may provide benefits to many patients who otherwise cannot be treated or would be at risk of systemic adverse effects of the drugs.     

Postoperative pain management: a practical review, part 1.

PURPOSE: The pharmacotherapy and assessment of postoperative pain in general pharmacy practice settings are reviewed. SUMMARY: Numerous factors related to all levels of society and the health care system contribute to suboptimal treatment of postoperative pain, despite awareness of this challenge for at least the past 30 years and the availability of potent analgesics and tools to help clinicians care for persons with postoperative pain. The consequences of acute pain include clinical, economic, and patient-reported outcomes; thus, improving the treatment of postoperative pain has the potential to improve health care from a broad perspective. Opioids remain the cornerstone of treatment of postoperative pain. Multimodal analgesia also has the potential to improve the pharmacotherapy of postoperative pain. In addition to the appropriate use of drugs, it is important that clinicians be comfortable with equianalgesic dosage conversion, helping ensure that analgesic-related adverse effects are minimal, assessing pain and function, and incorporating this information into patient care. CONCLUSION: Providing optimal management of postoperative pain is a vital goal for all health care providers. There is substantial potential for pharmacists to help meet this goal.     

Perioperative use of botulinum toxins

Botulinum toxins are not commonly thought of as adjuncts to surgical procedures. This article reviews some of the perioperative uses of botulinum toxins.     

From the Uppsala monitoring centre: a review of viewpoint part 1 and part 2.

The core task of the Uppsala Monitoring Centre (UMC) is the collection and processing of adverse drug reaction reports from member countries of the WHO Programme for International Drug Monitoring to detect early signals of potential drug hazards. Also a high priority is the communication of information about drug safety issues to the widest possible professional and general audiences in order to improve patient safety and welfare. The publication of the two parts of the publication Viewpoint represents a pioneering effort to provide easily accessible information on international pharmacovigilance for lay and specialist readers.     

Postoperative pain management: a practical review, part 2.

PURPOSE: The pharmacotherapy and assessment of postoperative pain in general pharmacy practice settings are reviewed. SUMMARY: Numerous factors related to all levels of society and the health care system contribute to suboptimal treatment of postoperative pain, despite awareness of this challenge for at least the past 30 years and the availability of potent analgesics and tools to help clinicians care for persons with postoperative pain. The consequences of acute pain include clinical, economic, and patient-reported outcomes; thus, improving the treatment of postoperative pain has the potential to improve health care from a broad perspective. Opioids remain the cornerstone of treatment of postoperative pain. Multimodal analgesia also has the potential to improve the pharmacotherapy of postoperative pain. In addition to the appropriate use of drugs, it is important that clinicians be comfortable with equianalgesic dosage conversion, helping ensure that analgesic-related adverse effects are minimal, assessing pain and function, and incorporating this information into patient care. CONCLUSION: Providing optimal management of postoperative pain is a vital goal for all health care providers. There is substantial potential for pharmacists to help meet this goal.     

Oxaliplatin: a review of approved uses

INTRODUCTION: Oxaliplatin, a second-generation platinum analog, has evolved as one of the most important therapeutic agents in colorectal cancer (CRC) treatment. It has had a major impact on the management and outcome of this disease. AREAS COVERED: The pharmacokinetic and pharmacodynamic data of oxaliplatin are reviewed in this paper. It also discusses the current clinical data regarding the use of oxaliplatin in early colon cancer, locally advanced rectal cancer, and in the metastatic setting, with a particular reference to its combination with monoclonal antibodies, and strategies for prevention of cumulative toxicity. EXPERT OPINION: Oxaliplatin has proven beneficial in the treatment of CRC and can currently be regarded as one of the three most important chemotherapeutic drugs used in the treatment of both metastatic disease and adjuvant therapy in stage II/III after resection. With regards to a median overall survival of more than 20 months, and a median progression-free survival for first-line treatment of about 9 - 10 months, the majority of patients will receive all three compounds (oxaliplatin, fluoropyrimidines and irinotecan) during the course of their disease. At the moment there are no drugs in late clinical development which might be able to substitute oxaliplatin in its unique role in CRC.     

The medicinal chemistry of botulinum, ricin and anthrax toxins

The potential use of weapons of mass destruction (nuclear, biological or chemical) by terrorist organizations represents a major threat to world peace and safety. Only a limited number of vaccines are available to protect the general population from the medical consequences of these weapons. In addition there are major health concerns associated with a pre-exposure mass vaccination of the general population. To reduce or eliminate the impact of these terrible threats, new drugs must be developed to safely treat individuals exposed to these agents. A review of all therapeutic agents under development for the treatment of the illnesses and injuries that result from exposure to nuclear, biological or chemical warfare agents is beyond the scope of any single article. The intent here is to provide a focused review for medicinal and organic chemists of three widely discussed and easily deployed biological warfare agents, botulinum neurotoxin and ricin toxins and the bacteria Bacillus anthracis. Anthrax will be addressed because of its similarity in both structure and mechanism of catalytic activity with botulinum toxin. The common feature of these three agents is that they exhibit their biological activity via toxin enzymatic hydrolysis of a specific bond in their respective substrate molecules. A brief introduction to the history of each of the biological warfare agents is presented followed by a discussion on the mechanisms of action of each at the molecular level, and a review of current potential inhibitors under investigation.     

Use of botulinum toxins in cancer therapy

A recent study has demonstrated for the first time that botulinum neurotoxin (BoNT) briefly opens tumour vessels, allowing more effective destruction of cancer cells by radiotherapy and chemotherapy. This review discusses the implications of BoNTs in cancer treatment. After briefly reviewing the different BoNT serotypes, their pharmacological activities and their general use in medicine, the authors focus on their possible application in cancer and describe how BoNTs have been used so far to treat spasm related to tumour or to therapies. By dissecting the mechanisms of action leading to a potentiation of anticancer therapy, it can be seen that BoNTs act by an effect on the tumour microenvironment rather than by a direct cytotoxic effect on tumour cells.     

Viscum articulatum Burm. f.: a review on its phytochemistry,pharmacology and traditional uses

Objectives

The aim of this study was to review and highlight traditional and ethnobotanical uses, phytochemical constituents, IP status, biological activity and pharmacological activity of Viscum articulatum.

Methods

Thorough literature searches were performed on Viscum articulatum, and data were analysed for reported traditional uses, pharmacological activity, phytochemicals present and patents filed. Scientific and patent databases such as PubMed, Science Direct, Google Scholar, Google patents, USPTO and Espacenet were searched using different keywords.

Key findings

Viscum articulatum has been traditionally used in different parts of the world for treatment of various ailments. Almost all the parts such as leaves, root, stem and bark are having medicinal values and are reported for their uses in Ayurvedic and Chinese system of medicine for the management of various diseases. Modern scientific studies demonstrate efficacy of this plant against hypertension, ulcer, epilepsy, inflammation, wound, nephrotoxicity, HIV, cancer, etc. Major bioactive phytochemicals include oleanolic acid, betulinic acid, eriodictyol, naringenin, β‐amyrin acetate, visartisides, etc.

Conclusions

Side effects of allopathic medicines have created a global opportunity, acceptance and demand for phytomedicines. Viscum articulatum could be an excellent source of effective and safe phytomedicine for various ailments if focused translational efforts are undertaken by integrating the existing outcomes of researches.

     

Towards new uses of botulinum toxin as a novel therapeutic tool

The uses of botulinum toxin in the fields of neurology, ophthalmology, urology, rehabilitation medicine and aesthetic applications have been revolutionary for the treatment of patients. This non-invasive therapeutic has continually been developed since first discovered in the 1970s as a new approach to what were previously surgical treatments. As these applications develop, so also the molecules are developing into tools with new therapeutic properties in specific clinical areas. This review examines how the botulinum toxin molecule is being adapted to new therapeutic uses and also how new areas of use for the existing molecules are being identified. Prospects for future developments are also considered.     

ADP-ribosylation of cerebrocortical synaptosomal proteins by cholera, pertussis and botulinum toxins

Certain microbial toxins ADP-ribosylate G proteins that may be related to those postulated to participate in secretion, whilst botulinum neurotoxins, produced by Clostridium botulinum, block Ca2(+)-dependent neurotransmitter release. Thus, botulinum, pertussis and cholera toxins were examined for ADP-ribosyl transferase activity using isolated nerve terminals. Although type D botulinum, cholera and pertussis toxins exhibited such enzymic activity, this was not detectable with types A or B botulinum neurotoxins or their individual chains, in any synaptosomal fraction. Botulinum type D and pertussis toxins ADP-ribosylated proteins with mol. wt approximately 24,000 and 42,000 respectively, whereas cholera toxin modified several proteins including a 51,000/47,000 mol. wt doublet. Pre-incubation of synaptosomes with type A, B or D toxins did not inhibit type D-induced labelling in the corresponding lysate. Similar pre-incubations with cholera or pertussis toxins reduced ADP-ribosylation of their substrates. Hence, under conditions in which these botulinum toxins were shown to block Ca2(+)-dependent transmitter release no ADP-ribosylated substrate was produced in the intact nerve terminals. Moreover, direct correlation was not found between the concentration dependencies of type D toxin for protein modification and inhibition of [3H]noradrenaline release from synaptosomes. These collective findings implicate C3, a non-neurotoxic contaminant of type D, in the enzymic action. The substrate for type D toxin was found in the cytosolic fraction and to a lesser extent in synaptic membranes, the reverse of the situation for pertussis toxin. A combination of the membranes and cytosol was required for maximal labelling of the 51,000/47,000 doublet by cholera toxin. Purified synaptic vesicles contained proteins labelled by type D and pertussis toxins but lacked major cholera toxin substrates. Future research will determine the possible involvement of these toxin-susceptible vesicular proteins in transmitter release.