Food and Drug Administration (FDA) has approved Qutenza(TM) (capsaicin) 8% patch, the first and only product containing prescription strength capsaicin, for the management of neuropathic pain due to postherpetic neuralgia (PHN), the nerve pain which can follow shingles. Qutenza delivers a synthetic form of capsaicin, the substance in chili peppers that gives them their heat sensation, through a dermal delivery system, providing up to 12 weeks of reduced pain following a single one-hour application. It is the first product from NeurogesX to be approved by the FDA.
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Biotech Calendar: Key FDA Action Dates
Britt Stuge, PhD, PT, of Norway and colleagues recently published an article in the Physical Therapy Journal. The article includes a new tool that physical therapists can utilize to assess function in female patients who have pelvic girdle pain.
In some particular embodiments, action of one or more enzymes, for example, a kinase, a phosphatase, a protease, and/or an amidase, converts a precursor polypeptide to a biologically active polypeptide. In some embodiments, a precursor polypeptide is or comprises a zymogen and/or a proenzyme. In some embodiments, a precursor peptide is converted to an active polypeptide via one or more post-translational modification.
Pharmaceutical compositions of provided agents and/or compositions comprising such agents also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Efficacy of Qutenza® 8% patch for neuropathic
NeurogesX's early stage product pipeline includes pre-clinical compounds, which are prodrugs of acetaminophen and various opioids. The company has evaluated these compounds in vitro and in vivo.
EC50 values were determined by nonlinear curve fitting using Graph Pad Prism 6/0 software. Statistical comparisons were made using either t-test or one-way ANOVA with Tukey's posthoc test. Data were considered to be statistically significant with p<0/05.
In some embodiments, lipidation may include fluorination. In some embodiments fluorination includes the addition of one or more C6F13 chains. Without wishing to be held to a particular theory, it is thought that the presence of one or more C6F13 chains may allow a lipid entity to segregate from hydrocarbon lipid membrane components (see J. Am. Chem.
Buprenorphine – Commercial Medical Benefit Drug Policy
Genuth S. Insights from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study on the Use of Intensive Glycemic Treatment to Reduce the Risk of Complications of Diabetes. Endocrinology Practice, 2006; 12 (S1): 34-41.
The approval was granted under the FDA’s Breakthrough Therapy and Priority Review processes
Keen H, Payan J et al. Treatment of Diabetic Neuropathy With 7-Linolenic Acid. Diabetes Care, 1993; 16(1): 8-15.
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Spectrum is seeking FDA approval to expand the label for Zevalin to include consolidation therapy for patients with NHL. Zevalin is an effective drug that has been a commercial disappointment, so the company hopes the expanded FDA label will boost sales.
Prior pelvic floor surgery was recorded by approximately 8/6% of the participants. The likelihood of surgery taking place increased with age, and there was identified greater than 20% chance of prior pelvic floor surgery in the women aged 76-85 years. Higher rates of urinary and defaecatory distress were noted in women who had gone through prior surgery as well.
US FDA approval tracker: August
Balakumar P, Rohilla A et al. The Multifaceted Therapeutic Potential of Benfotiamine. Pharmacological Research, 2021; 61: 482-488.
Radicava® – Commercial Medical Benefit Drug Policy
In some embodiments, a ligand entity is or comprises a peptide with an amino acid sequence showing at least 40% sequence identity to one or more reference peptides. In some embodiments, a ligand entity is or comprises a peptide showing at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or greater sequence identity to one or more reference peptides. In some embodiments, a ligand entity is or comprises a peptide showing at least 70% sequency identity to one or more characteristic sequence elements of a reference peptide. In some embodiments, a ligand entity is or comprises a peptide showing at least 75%, 80%, 85%, 90%, 95%, or 99% or greater sequence identity to one or more characteristic sequence elements of a reference peptide. In some embodiments, a characteristic sequence element may be characterized through the use of alanine scanning or other technique for defining characteristic sequence elements. In some embodiments, a reference peptide may be or comprise one of the peptides listed in Table 1.
Also contemplated herein is pulmonary delivery of provided agents and/or compositions comprising such agents. Such agents are delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
Human embryonic kidney (HEK) 293 cells were cultured in Dulbecco's modified Eagle's medium (Life Technologies) with 10% fetal bovine serum (Atlanta Biologicals), 100 U/mL penicillin, and 100 μg/mL streptomycin. Cells were maintained at 37° C. in a humidified environment with 5% CO2.
NeurogesX Inc. Q1 2021 Earnings Call Transcript
Biological products are approved for marketing under the provisions of the Public Health Service (PHS) Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product. A biologics license application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical affects of the biologic product. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product.
Nakayama M, Izumi G, Nemoto Y, Shibata K, Hasegawa T, Numata M. Hosoya T. Suppression of N(epsilon)-(carboxymethyl)lysine generation by the antioxidant N-acetylcysteine. Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis.
Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. The American journal of clinical nutrition.
The FDA is currently reviewing the Company's new drug application (NDA) for Qutenza in PHN and has assigned a Prescription Drug User Fee Act (PDUFA) date of August 16, 2009. Qutenza, if approved by the FDA, would benefit from seven years of market exclusivity in PHN as a result of this orphan designation.
Topical Pain Relief: What Is It + How Does It Work
Hosseini A, Sharifzadeh M et al. Benefit of magnesium-25 carrying porphyrinfullerenenanoparticles in experimental diabetic neuropathy. International Journal of Nanomedicine 2021:5 517–523.
QUTENZA® 8% PATCH – Pain Specialists of
Tecentriq then is administered as an 840mg infusion once every two weeks with the doses of Cotellic maintained at 60mg/day on days 1 through 21 of each cycle and Zelboraf at 720mg twice every day. Treatment continues until melanoma worsens or the patient can no longer tolerate the drug side effects. Tecentriq has several other indications that include some bladder, breast, liver and lung cancers. The new indication was approved under Priority Review and Project Orbis, the FDA’s program for sharing information with international drug regulatory organizations to expedite the approval of oncology therapies. Check here for Tecentriq’s prescribing information, here for Cotellic’s and here for Zelboraf’s.
Actemra® Injection for Intravenous Infusion – Commercial Medical Benefit Drug Policy
Gonzalez-Clemente JM, Mauriciio D et al. Diabetic Neuropathy is Associated with Activation of the TNF-a System in Subjects with Type 1 Diabetes Mellitus. Clinical Endocrinology, 2005; 63: 525-529.
Nerve injury-induced mechanical allodynia and hypersensitivity were assessed by von Frey hairs as previously described (see Xu et al, Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury, 2021, J. Neuroimmune Pharmacol, 8: 37-41). For testing mechanical sensitivity, the plantar surface of a hindpaw was stimulated with a series of von Frey hairs (0/02-2/56 grams, Stoelting). The 50% paw withdrawal threshold (PWT) was determined using Dixon's up-down method. For paw withdrawal frequency (PWF), the same von Frey hair (0/16 g) was applied 10 times and the number of positive responses to the stimulations counted. A positive response was scored if the mouse sharply withdrew the paw or flinched upon removal of the stimulus. Cold allodynia was tested by the acetone method as previously reported (see Flatters and Bennett, Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy, 2004, Pain, 109:150-161). In brief, a drop of acetone was placed against the plantar paw of the mouse and the mouse's response monitored for the next 20 seconds. If there was no response then a score of 0 was assigned. If there was a response, this response was monitored 40 seconds in total and behavior was assigned as follows: 1, quick withdrawal or stamp of the foot; 2, prolonged withdrawal and repeated flicking of the paw; 3, repeated flicking of the paw with licking directed at the ventral side of the paw.
Grünenthal is a global leader in pain management and related diseases. As a science-based, privately-owned pharmaceutical organization, we have a long track record of bringing innovative treatments and state-of-the-art technologies to patients worldwide. Our purpose is to change lives for the better – and innovation is our passion. We are focussing all of our activities and efforts on working towards our vision of a world free of pain.
Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources — human, animal, or microorganism — and may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.
Simponi Aria® Injection for Intravenous Infusion – Commercial Medical Benefit Drug Policy
Susceptible to: An individual who is “susceptible to” a disease, disorder, or condition is at risk for developing the disease, disorder, or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition does not display any symptoms of the disease, disorder, or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition has not been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, or condition is an individual who has been exposed to conditions associated with development of the disease, disorder, or condition.
Cremon C, Stanghellini V, Barbaro MR, Cogliandro RF, Bellacosa L, Santos J. Barbara G. Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome. Alimentary Pharmacology & Therapeutics.
Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Current Pharmaceutical Design, 2008;14(10):953-61.
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Walker MJ, Morris LM et al. Improvement of Cutaneous Sensitivity in Diabetic Peripheral Neuropathy with Combination L-Methylfolate, Methylcobalamin, and Pyridoxal 5’Phosphate. Reviews in Neurological Diseases, 2021; 7(4): 132-139.
In some embodiments, a target is associated with an extracellular membrane. In some embodiments, a target is associated with an intracellular membrane. In some embodiments, a target is associated with an extracellular surface of a membrane. In some embodiments, a target is associated with an intracellular surface of a membrane.
Jacobs AM, Cheng D et al. Management of Diabetic Small-Fiber neuropathy with Combination L-Methylfolate, Methylcobalamin, and Pyridocal 5’-Phosphate. Reviews of Neurological Diseases, 2021; 8(1/2): 1-9.
Hsieh ST. Pathology and functional diagnosis of small-fiber painful neuropathy. Acta Neurologica Taiwanica, 2021;19(2):82-9.
Passive cold therapy devices operate by gravity or a hand pump without the use of a battery or electricity. Generally, they consist of a cuff or wrap and a cooler. Ice water is placed in the reservoir or cooler.
The 5 Best Topical Products For Neuropathy Relief
Kamboj SS, Vasishta RK et al. N-Acetylcysteine Inhibits Hyperglycemia-Induced Oxidative Stress and Apoptosis Markers in Diabetic Neuropathy. Journal of Neurochemistry, 2021; 112: 77-91.
The treatment is a topical, non-systemic, non-opioid pain therapy delivered in the form of a patch and is the first and only treatment of its kind to deliver prescription strength capsaicin directly into the skin. Delivered at an in-office procedure, the agent reversibly desensitizes and defunctionalizes the Transient Receptor Potential Vanilloid (TRPV1) receptor, which plays a critical role in pain signaling.
In some embodiments, anchored ligand agents enable characterization of tissue-specific activation or blockade of selected receptors while minimizing or avoiding confounding off-target effects. It is contemplated that, in some embodiments, altering construct efficacy and/or the degree of membrane adherence, long term physiological consequences of receptor activation or blockade at titrated levels can be investigated (low level vs. high level stimulation). Further, in some embodiments, the introduction of point mutations may convert tethered ligands between those that are agonist and antagonist, and capable of inducing or not inducing receptor internalization.
Averitas Pharma announces FDA acceptance of sNDA filing for Qutenza (capsaicin) 8% patch for the treatment of neuropathic pain associated with diabetic peripheral neuropathy. Morristown, NJ: Grunenthal Group.
Dyck PJ, Davies JL et al. Risk Factors for Severity of Diabetic Polyneuropathy. Diabetes Care, 1999; 22: 1479-1486.
Exemplary ligand-gated ion channel antagonists include, but are not limited to: 5-HT3 receptor antagonists. AMPA receptor antagonists, GABAA receptor antagonists, Glycine receptor antagonists, Kainate receptor antagonists, nACh receptor antagonists, NMDA receptor antagonists, P2X receptor antagonists, and Zinc-activated channel antagonists.
UnitedHealthcare Commercial Medical & Drug Policies and Coverage Determination Guidelines
Hayee MA, Mohammad QD et al. Diabetic Neuropathy and Zinc Therapy. Bangladesh Medical Reseanch Council Bull, 2005; 31(2): 62-67.
Morales-Vidal S, Morgan C et al. Diabetic Peripheral Neuropathy and the Management of Diabetic Peripheral Neuropathic Pain. Postgraduate Medicine, 2021; 124(4).
Human embryonic kidney cells (HEK293) were maintained at 37° C. in a humidified 5% CO2 atmosphere and cultured with Dulbecco's modified eagle medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. Cells were seeded into 96-well plates and grown to ˜80% confluence.
Morikawa et al (2021) stated that the Nuss procedure for surgical correction of PE often causes severe post-operative pain. Cryoanalgesia of intercostal nerves is an alternative modality for pain control. These researchers described their modification of the cryoICE™ probe that allowed for nerve ablation through the ipsilateral chest along with early results utilizing this technique. To allow for ipsilateral nerve ablation, a 20-French chest tube was cut and secured to the cryoICE probe, thus providing insulation for the malleable end of the probe. A 3-year retrospective review of patients undergoing Nuss repair at the authors’ institution was performed. Patients who received cryoanalgesia (cryo, n = 6) were compared with a historical control cohort who did not receive cryoanalgesia (non-cryo, n = 13) during Nuss repair. Hospital LOS, post-operative narcotic requirement (PNR), and highest post-operative pain score were collected. Both cohorts were similar regarding age, body mass index (BMI), and pectus index. The cryo group had a significantly less PNR (6/4 versus 17/9 doses, p = 0/05) and was discharged on average more than 1 day earlier than non-cryo patients (3/7 versus 2/2 days, p = 0/01). No complications occurred in either group.
Gerbi A, Maixent J-M et al. Fish Oil Supplementation Prevents Diabetes-Induced Nerve Conduction Velocity and Neuroanatomical Changes in Rats. The Journal of Nutrition, 1999; 129: 207-213.
Nasal delivery of a pharmaceutical composition comprising one or more provided agents is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.
Effective Date: 12/01/2021 – This policy addresses alpha1-proteinase inhibitors (Aralast NP™, Glassia™, Prolastin®-C, and Zemaira®) for chronic augmentation and maintenance therapy of emphysema due to congenital deficiency of alpha1-proteinase inhibitor (A1-PI)/alpha1-antitrypsin (AAT) deficiency. Applicable Procedure Codes: J0256, J0257.
Evkeeza™ – Commercial Medical Benefit Drug Policy
In some embodiments, an anchored ligand agent may be or comprise a membrane-tethered ligand (MTL). The use of membrane tethered ligands (MTLs) has been described as useful in characterizing a particular ligand's interaction with a receptor (see Fortin et al, Membrane-tethered ligands are effective probes for exploring class B1 G protein-coupled receptor function, 2009, PNAS 106(19): 8049-8054).
Off-Label/Unproven Specialty Drug Treatment – Commercial Medical Benefit Drug Policy
In the above depiction, the lipid entity (shown as a membrane anchor) and linker are attached via a covalent bond, shown as a dark circle. As shown, “X” and “Y” may be bioorthogonal reaction partners that can react in water without interference by other partners, or may be standard amide, ester, thioester, thioether, disulfide, oxime or hydrazone bonds. In some embodiments, “X” and “Y” are click chemistry moieties.
The particular combination of therapies (substances and/or procedures) to employ in a combination regimen will take into account compatibility of the desired substances and/or procedures and the desired therapeutic effect to be achieved. In some embodiments, provided soluble lipidated ligand agents can be administered concurrently with, prior to, or subsequent to, one or more other therapeutic agents.
Beckman JS -OONO: rebounding from nitric oxide. Circulation Research, 2001;89(4):295-7.
In some embodiments, daily oral doses of active compounds will be, for human subjects, from about 0/01 mg/kg per day to 1,000 mg/kg per day. Specific doses may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. In some embodiments, multiple doses per day are contemplated to achieve appropriate systemic levels of agents. Provided agents may be formulated into a controlled and/or sustained release form.
Grünenthal is headquartered in Aachen, Germany, and has affiliates in 30 countries across Europe, Latin America and the US. Our products are available in more than 100 countries. In 2021, Grünenthal employed around 4,900 people and achieved sales of € 1/3 bn.
In some embodiments, lipidation comprises geranylation. In some embodiments, lipidation includes geranylgeranylation.
Onpattro® – Commercial Medical Benefit Drug Policy
In some embodiments, association between a ligand entity and a lipid entity (optionally with a linker) will result in an increase in one or more of the potency, activity, or half-life of a ligand entity as compared to the ligand entity alone. In some embodiments, association between a ligand entity and a lipid entity (optionally with a linker) will result in a decrease in one or more of the potency, activity, or half-life of a ligand entity as compared to the ligand entity alone. In some embodiments, an improvement in one or more of potency, activity, and/or half-life is defined as a statistically significant improvement in one or more desired characteristics or attributes in a tethered or lipidated ligand entity as compared to the ligand entity alone in an in vitro and/or in vivo assay. In some embodiments, association between a ligand entity and a lipid entity (optionally with a linker) decreases one or more side effects associated with administration of the ligand entity alone.
In accordance with the present invention, provided lipidated ligand agents may be formulated, together with one or more pharmaceutically acceptable carriers, for delivery by any appropriate route. In some embodiments, soluble lipidated ligand entities are administered intravenously, intradermally, transdermally, orally, by inhalation, subcutaneously, and/or transmucosally.
In some embodiments, a ligand entity is or comprises a variant of a reference peptide that differs from the reference peptide by no more than 30 amino acids. In some embodiments, a variant differs from a reference peptide by no more than 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid. In some embodiments, a ligand entity is or comprises a variant of a reference peptide that differs from a characteristic sequence element of the reference peptide by no more than 30 amino acids. In some embodiments, a variant differs from a characteristic sequence element of a reference peptide by no more than 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid. In some embodiments, a reference peptide may be or comprise one of the peptides listed in Table 1.
Ziegler D. Painful Diabetic Neuropathy. Diabetes Care, 2009; 32(2): 5414-5419.
In a cross-sectional study in The Netherlands, standardized surveys of 1380 women between the ages of 45-85 years were completed for urinary and bowel distress. The women also answered questions about prior pelvic floor surgery.
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Varkonyi T and Kempler P. Diabetic Neuropathy: New Strategies for Treatment. Diabetes, Obesity and Metabolism, 2008; 10: 99-108.
The present invention provides soluble lipidated ligand agents useful in a variety of diagnostic, therapeutic and/or research contexts. In general, provided agents comprise a ligand entity associated with a lipid entity. In some embodiments, the ligand and lipid entities are associated with one another by means of a linker entity.
In some embodiments, provided soluble lipidated ligand agent(s) are utilized in a pharmaceutical formulation that is separate from and distinct from the pharmaceutical formulation containing the other therapeutic agent. In some embodiments, provided soluble lipidated ligand agent(s) are admixed with the composition comprising the other therapeutic agent. In other words, in some embodiments, provided soluble lipidated ligand agent(s) are produced individually, and the provided soluble lipidated ligand agent is simply mixed with another composition comprising another therapeutic agent.
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Xiaflex® – Commercial Medical Benefit Drug Policy
Cooper DJ, Nichol AD, Bailey M, et al; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: The POLAR Randomized Clinical Trial.
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Rizkalla SW, Tagirid L et al. Improved Plasma Glucose Control, Whole-Body Glucose Utilization, and Lipid Profile on a Low-Glycemic Index Diet in Type 2 Diavetic Men. Diabetes Care, 2004; 27(8): 1866-1872.
For example, peptidic ligand entities maybe oriented so that it is linked to the anchor entity via its amino (N) terminal end; alternatively or additionally, a peptidic ligand entity can be oriented so that it is linked to the anchor entity via its carboxy (C) terminal end. In some embodiments, a peptidic ligand entity can be truncated by one or more amino acid residues at either end or both ends. In some embodiments, a peptidic ligand entity can be extended by one or more amino acid residues at either end, or both ends. Moreover, in some embodiments, a peptidic ligand entity can be truncated by one or more amino acid residues at one end and extended by one or more amino acid residues at the other end. Alternatively or additionally, one or more amino acid residues can be replaced by one or more different amino acid residues, at any position along the peptide. Substituted amino acid residues can include naturally occurring amino acid residues, non-naturally occurring amino acid residues, or amino acid residue analogs. Furthermore, amino acid residues can be chemically modified, for example, by covalently linking a chemical substituent, such as a sugar, to the amino acid residue. Generally, each of these types of variations can be accomplished using methods and techniques well established in the fields of molecular biology and nucleic acid and peptide chemistry.
Both tSubP and I-SubP-COOH appear to activate NK1R (A) and NK3R (C) with no observed activity at NK2R (B). HEK293 cells were transiently cotransfected for 24 hours with cDNAs encoding: the designated NK receptor subtype, a 5X-SRE-Luc-pest reporter gene (pGL4/33), tethered ligand (for MTL assays, left panels), and a 3-galactosidase gene to control for transfection variability. For assessment of soluble lipidated ligand agent induced signaling, cells were stimulated with ligand for 4 hours. Luciferase activity was quantified and normalized relative to a 4 hour stimulation with 1μM soluble amidated substance P (s-SubP-NH2) on the corresponding NK receptor subtype. Abbreviations: tSubP, tethered Substance P; tCCK4, tethered CCK4; s-SubP-COOH, soluble Substance P with a C-terminal free acid; I-SubP-COOH, lipidated Substance P with a C-terminal free acid; NK1R, neurokinin 1 receptor; NK2R, neurokinin 2 receptor; and NK3R, neurokinin 3 receptor.
In some embodiments, such modifications comprise the introduction or addition or a lipidation site or sequence. In some embodiments, a lipidation site or sequence is a known lipidation site or sequence.
Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects. Alternative medicine review: a journal of clinical therapeutic.
Xolair® – Commercial Medical Benefit Drug Policy
Weber and colleagues (2021) noted that PHN is a common and potentially debilitating neuropathic pain condition. Current pharmacologic therapy can be inadequate and intolerable for patients. These researchers presented a case of a man with refractory PHN in the intercostobrachial nerve (ICBN) distribution that was successfully treated with cryoneurolysis / cryoanalgesia therapy. Given the severity of PHN and disabling pain to patients with limited options, these investigators believed that cryoablation offers an alternative that is minimally invasive, with less risk compared to other forms of neurolysis. This case-report showed an ICBN neuralgia related to PHN, which to the authors’ knowledge has not been reported in the literature and treated with cryoablation. While the authors acknowledged that additional studies are needed and the conflicting data on efficacy of cryoablation with intercostal blocks and with post-thoracotomy pain, there have been positive results for cryoanalgesia for PHN in the dermatologic literature with cutaneous use. Furthermore, the minimal risk to ICBN cryoablation given the superficial nature, as compared to intercostal blocks, whose risks include pneumothorax and vascular uptake / bleeding, allowed for the ICBN cryoanalgesia to be a viable option that should be further examined in patients who presented with features of ICBN neuralgia related to PHN.
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Wade RL and Cal Q. Impact of L-Methylfolate Combination therapy Among Diabetic Peripheral Neuropathy Patients. American Journal of Pharmacological Benefits, 2012l 4(5): 218-225.
In a recent Johns Hopkins Health Alertthe signs and symptoms of colorectal cancer are discussed. Some of the symptoms of colorectal cancer include a change in bowel status such as diarrhea, constipation,or narrow stools that last for a few weeks. Bloating, cramping, a feeling of incomplete emptying of the rectum, or inability to pass stool for a week can also be the first signs of cancer. Unfortunately for pelvic rehabilitation providers, the above symptoms can describe many of our patients who we are treating for bowel dysfunction.
Skaper SD, Facci L. Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philosophical transactions of the Royal Society of London.
Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. Journal of Diabetes Complications, 2008;22(2):83-7.
Leeuw ID, Engelen W. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg‐depleted type 1 diabetic patients (T1dm). Magnesium Research, 2004; 17(2): 109-14.
Testosterone Replacement or Supplementation Therapy – Commercial Medical Benefit Drug Policy
Administration: As used herein, the term “administration” refers to the administration of one or more agents or compositions to a subject. Administration may be by any appropriate route.
Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
This article highlights a few things in my opinion. One, anatomy is a living science, and it continues to be researched and redefined as surgeons and other disciplines find needs for sharing information and for shaping best practices. It is also important to remember that surgeons are amazing resources, and one can really "get" anatomy while observing a surgery and listening to a surgeon describe layers of fascia or muscles as they pertain to the procedure. Lastly, we can continue to be engaged in learning and re-learning anatomy, as it sets the foundation for the stories that bodies tell.
Kim et al (2021) noted that although there are reports that showed cryoanalgesia is superior to patient-controlled analgesia (PCA) for post-thoracotomy pain management in the immediate post-operative period, cryoanalgesia for thoracoscopic procedures has not been well described in the literature. In particular, when a patient lies supine, as in the Nuss procedure, the application of a thoracoscopic cryoprobe on the posterolateral intercostal nerves is difficult because of the curvature of the ribs. These researchers described a thoracoscopic transthoracic cryoanalgesia technique applied during the Nuss procedure that overcomes this access difficulty. This method facilitated a cryoprobe application without the need for additional thoracoscopic ports and improved operative field of view.
Yagihashi S, Yamagishi S et al. Pathology and Pathogenetic Mechanisms of Diabetic Neuropathy: Correlation with Clinical Signs and Symptoms. Diabetes Research and Clinical Practice, 2007; 77s: S184-S189.
An anti-frictional agent maybe included in a formulation to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
Zolgensma® – Commercial Medical Benefit Drug Policy
Effective Date: 03/01/2021 – This policy addresses the use of inhaled nitric oxide (iNO) for treating term or near-term infants with hypoxic respiratory failure or echocardiographic evidence of persistent pulmonary hypertension of the newborn (PPHN). Applicable Procedure Code: 94799.
The present invention teaches, in some embodiments, that even ligand entities that are inactive in other forms can surprisingly be rendered biologically active in a lipidated format as described herein. Furthermore, the present invention demonstrates that lipidated forms of ligand entities of interest can be identified that are sufficiently soluble in physiologically relevant contexts to permit formulation, administration, and activity of provided agents to achieve desired biological effects.
Anesthesiology News - March 2021 - Digital Edition
Head KA. Peripheral Neuropathy: Pathogenic Mechanisms and Alternative Therapies. Alternative Medicine Review, 2006; 11(4): 294-329.
Francisco GE, Tan H et al. Do Botulinum Toxins Have a Role in the Management of Neuropathy? American Journal of Physical Medicine and Rehabilitation, 2021; 91(10): 899-909.
McIlduff CE and Rutkove SB. Critical Appraisal of the Use of Alpha Lipoic Acid (Thiooctic Acid) in the Treatment of Symptomatic Diabetic Polyneuropathy. Therapeutics and Clinical Risk Management, 2021; 7: 377-385.
In addition or as an alternative to the formulations described above, provided agents and/or compositions comprising such agents maybe formulated as a depot preparation. Such long acting formulations maybe formulated with suitable polymericorhydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Krystexxa® – Commercial Medical Benefit Drug Policy
The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990), which is incorporated herein by reference.
Cameron NE, Cotter MA et al. The effects of evening primrose oil on nerve function and capillarization in streptozotocin-diabetic rats: modulation by the cyclo-oxygenase inhibitor flurbiprofen. British Journal of Pharmacology, 1993; 109 972-979.
What GAO Found The number of drug shortages remains high. Although reports of new drug shortages declined in 2021, the total number of shortages.
Oxlumo™ – Commercial Medical Benefit Drug Policy
In some embodiments, lipidation may comprise N-myristoylation. As used herein, “N-myristoylation” refers to the attachment of a myristate to an N-terminal glycine.
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Ulvi H, Aygul R et al. Effect of L_Carnitine on Diabetic Neuropathy and Ventricular Dispersion in Patients with Diabetes Mellitus. Turkish Journal of Medical Science, 2021; 40(2): 169-175.
Yu X, Zhang L, Yang X, Huang H, Huang Z, Shi L, Zhang H, Du G. Salvianolic acid A protects the peripheral nerve function in diabetic rats through regulation of the AMPK-PGC1α-Sirt3 axis. Molecules, 2021 Sep 20;17(9):11216-28.
Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient. Case Reports in Endocrinology, 2021.
In the US by the year 2050, research has estimated that pelvic organ prolapse will increase in women by 46% (WU JM 09). Rehabilitation efforts must continue to advance so that women can avoid surgery when possible, and so that women can be offered pre-surgery rehabilitation as well as follow-up post-surgically.
Funding could come via any upfront fee from a US marketing deal, however, comments from Anthony DiTonno, chief executive, suggest this is unlikely to happen at the moment. He said because the doctors who would prescribe Qutenza are highly concentrated it is proving difficult to carve the market up, so at this point NeurogesX is preparing to go it alone.
Diabetes Prevention Program Research Group. Impact of Intensive Lifestyle and Metformin Therapy on Cardiovascular Disease Risk Factors in the Diabetes Prevention Program. Diabetes Care, 2005; 28(4): 888-894.
Trogarzo® – Commercial Medical Benefit Drug Policy
A) YM022 blocks tethered CCK4-Gly mediated CCK2R signaling. HEK293 cells were cotransfected with cDNAs encoding: CCK2R, a 5X-SRE-Luc-pest reporter gene, tCCK4-Gly (as indicated), and a β-galactosidase gene to control for transfection efficiency. Four hours following transfection, cells were with treated with increasing concentrations of YM022 for 20 hours. Luciferase activity was quantified and normalized relative to a parallel preparation of CCK2R expressing cells stimulated for 4 hours with soluble amidated CCK-4 (s-CCK4-NH2, 10 μM). B) YM022 blocks s-CCK-4-Gly-COOH and I-CCK4-Gly-COOH mediated activation of CCK2R. HEK293 cells were transfected as indicated above. Twenty hours after transfection, cells were with treated with increasing concentrations of YM022 together with either 10 μM of I-CCK4-Gly-COOH or s-CCK4-Gly-COOH. Following an additional four hour stimulation, luciferase activity was quantified and normalized as outlined for panel A. Data represent the mean±SEM from 3 independent experiments, each performed in triplicate.
Pilkington et al (2021) noted that intercostal cryoablation(IC) for pain management in children undergoing Nuss Procedure has been previously described. These investigators examined post-operative outcomes following Modified Ravitch procedure for pectus disorders comparing IC to thoracic epidural (TE). This was a single-center, retrospective review of pediatric patients (age of less than 21 years) undergoing Modified Ravitch procedure (January 2021 to March 2021) with either IC (n = 9), or TE (n = 20) analgesia. Primary outcome was LOS; and secondary outcomes were inpatient opioid use (in oral morphine equivalents per kilogram; OME/kg), pain scores on each post-operative day (POD), discharge prescriptions, and complications. Pair-wise comparisons made with Mann-Whitney U test or Fisher Exact test as appropriate; 2-tailed p values of < 0/05 were considered significant. Patient characteristics were similar; LOS was shorter with IC compared to TE (4 days versus 6; p < 0/006). Post-operative opioid use was not significantly different (IC: 1/5 OME/kg versus TE: 1/1; p = 0/10). There was improved pain control on POD 2 in patients who underwent IC (median pain score of 3 versus 4; p < 0/0004). There was no difference in discharge prescription (IC: 3/3 OME/kg; TE: 4/8; p = 0/19) or complication rate (IC: 55/6 %, TE: 50 %; p = 1/0).
The present invention also provides systems for identifying, characterizing, and/or manufacturing such lipidated ligand agents. In some embodiments, provided systems utilize a membrane-tethered format to identify and/or characterize ligand, linker, and/or lipid entities of interest. In some embodiments, modular systems are provided that permit facile linkage of various ligand entities, linker entities, and/or lipid entities with one another. In some embodiments, such modular system permit ready re-assortment of components.
Every few months or so, Allergan pops up in the rumor mill. This time it's GlaxoSmithKline and Sanofi-Aventis who've been tagged as suitors for the company.
In this Example, the activation of human and mouse CMKLR1 with full length (amino acids 21-157) and C-terminal (amino acids 149-157) chemerin peptides was first compared. HEK293 cells were transiently transfected with cDNAs encoding i) human or mouse CMKLR1, ii) a SRE5x-Luc reporter gene, iii) a Gαq5i66Vchimera, and iv) a β-galactosidase control. Twenty-four hours after transfection, cells were stimulated with ligand for 4 hours and luciferase activity determined as described in Experimental Procedures. Luciferase activity was normalized relative to the maximal value observed using saturating concentrations of the corresponding soluble ligand (=100%).
Indraccolo U, Indraccolo SR, Mignini F. Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis-related pain: a meta-analysis. Annali Dell'Istituto Superiore di Sanita.
A review is the basis of FDA's decision to approve an application. It is a comprehensive analysis of clinical trial data and other information prepared by FDA drug application reviewers. A review is divided into sections on medical analysis, chemistry, clinical pharmacology, biopharmaceutics, pharmacology, statistics, and microbiology.
Adult CD1 mice (male, 25-35 g) were used for behavioral studies. Mice were group-housed and kept under a 12-hour light/dark cycle. For the neuropathic pain model, chronic construction injury was induced by ligation of the sciatic nerve under isoflurane anesthesia (see Bennett and Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, 1988, Pain, 33: 87-107). For intrathecal injection, spinal cord puncture was made with a 30G needle between the L5 and L6 level to deliver reagents (10 μl) to the cerebral spinal fluid. L-Stable Chem was synthesized as described above. RvE1 was kindly provided by Resolvyx Pharmaceuticals Inc.
Patients may experience substantial procedural pain. Prepare to treat pain with local cooling (such as a cold pack) and/or appropriate analgesic medication.
In some embodiments, one or more small molecules are encapsulated within the nanoparticle. In some embodiments, small molecules are non-polymeric. In some embodiments, in accordance with the present invention, small molecules are not proteins, polypeptides, oligopeptides, peptides, polynucleotides, oligonucleotides, polysaccharides, glycoproteins, proteoglycans, etc. In some embodiments, a small molecule is a therapeutic. In some embodiments, a small molecule is an adjuvant. In some embodiments, a small molecule is a drug.
Complement Inhibitors – Commercial Medical Benefit Drug Policy
Evcimen ND and King GL. The Role of Protein Kinase C Activation and the Vascular Complications of Diabetes. Pharmacological Research, 2007; 55: 498-510.
Expression of Gq5i66V directs signaling of the Gαi-coupled chemerin receptor to stimulation of a Gαq-dependent SRE5x-Luc-PEST reporter gene. For experiments investigating the agonist function of soluble and lipidated peptides, tethered ligand cDNA was not included in the transfection mixture. Twenty four hours after transfection, cells were stimulated with or without peptide agonist for 4 hours in serum-free medium. Ligands were synthesized as described above: recombinant human chemerin (corresponding to amino acids 21-157) was purchased from R+D systems and chemerin 145-157 was purchased from Phoenix Pharmaceuticals. Following ligand stimulation, the media was aspirated and luciferase activity measured using SteadyLite reagent and quantified using a TopCount NTX. A β-galactosidase assay was then performed following assessment of luminescence. Cleavage of 2-nitrophenyl β-D-galactopyranoside substrate was quantified after incubation of cell lysates at 37° C. for 30 to 60 minutes by measuring the optical density at 420 nm on a SpectraMax microplate reader. Luciferase reporter gene activities were normalized to corresponding β-galactosidase activity controls.
Methods and Systems for Designing and/or Characterizing Soluble Lipidated Ligand Agents
Initially, a candidate ligand entity is selected. As described herein, there is a wide range of potential ligand entities for use according to various embodiments. Examples include, but are not limited to, peptides, FDA-approved drugs, drugs under investigation for use on a particular membrane associated target, and investigational molecules shown to interact with one or more receptors, ion channels, enzymes, or transporters. In this Example, Chemerin is selected as the candidate ligand entity.
It is also well-known in the orthopedic literature that falls in the elderly increase risk for hip fracture, and 1 year mortality rates are known to be significantly higher for those who have had a hip fracture. Many rehab providers have assisted these patients in their fall recovery, and many factors are at play in making such a recovery challenging. Oftentimes a patient who has suffered a fall and a significant injury have to spend time away from their home, enter environments in which iatrogenic illnesses can occur, and experience the effects of being bed-bound or of having reduced physical activity.
This will be a single arm observational study to include 100 subjects. After a clinical decision is made to implement a single drug substitution to ATV +/- RTV, there will be an initial screening visit, at which time the study will be presented to the patient and informed consent for participation will be obtained. A number of evaluations (including blood tests) will be completed to definitively assess a subjects eligibility to participate in this protocol. The patients will continue on their current therapy and will return within the next 14 days for an enrollment visit to review the blood test results and definitively confirm study eligibility. In particular, we will ascertain the continued presence of the side effect/toxicity motivating consideration of a change in therapy. This being down, the quality of life questionnaires (MOS-HIV and ASDM) will be administered for the first time. Once again, the patient will continue on their current HAART and return within the next 14 days for a.
The backing film is imprinted with “capsaicin 8%”. Each Qutenza patch contains a total of 179 mg of capsaicin (8% in adhesive, 80 mg per gram of adhesive) or 640 micrograms (mcg) of capsaicin per square cm of patch (https://dkluchezar.ru/hack/?patch=7534).
Chirchiglia D, Chirchiglia P, Signorelli F. Nonsurgical lumbar radiculopathies treated with ultramicronized palmitoylethanolamide (umPEA): A series of 100 cases. Neurologia i Neurochirurgia Polska.
7th Day review of the Qutenza pain pain patch, from
Doctors, hospitals and federal regulators are struggling to cope with an unprecedented surge in drug shortages in the United States that is endangering cancer patients, heart attack victims, accident survivors and a host of other ill people. The paucities are forcing some medical centers to ration drugs - including one urgently needed by leukemia patients - postpone surgeries and other care, and scramble for substitutes, often resorting to alternatives that may be less effective, have more side effects and boost the risk for overdoses and other sometimes-fatal errors. Consolidation in the pharmaceutical industry has left only a few manufacturers for many older, less-profitable products, meaning that when raw material runs short, equipment breaks down or government regulators crack down, the snags can quickly spiral into shortages.
Ferring Pharmaceuticals and its partner, CSL Behring, have issued global recalls for all lots of their desmopressin nasal sprays, DDAVP® (NDC# 55566-2500-000), Stimate® (00053-6871-00) and Amring Pharmaceuticals’ authorized generic (69918-0501-05). Testing of samples found significantly higher-than-specified levels of desmopressin and benzalkonium chloride (a preservative). The risk of a desmopressin overdose or a reaction to benzalkonium could be increased. Potentially, blood levels of sodium could become too low, causing vague symptoms such as confusion, fatigue and nausea. Patients who use one of the recalled products are advised to contact their healthcare providers for an alternative treatment. Desmopressin has several FDA-approved indications that include bedwetting, central diabetes insipidus, hemophilia and von Willebrand’s disease. For more information, please look here for the FDA’s notice.
Sanchez-Ramirez GM, Caram-Salas NL et al. Benfotiamine Relieves Inflammatory and Neuropathic Pain in rats. European Journal of Pharmacology, 2006; 530: 48-53.
Adam Feuerstein writes regularly for TheStreet.com. In keeping with TSC's editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet.com. He also doesn't invest in hedge funds or other private investment partnerships.
Lee P and Chen R. Vitamin D as an Analgesic for Patients With Type 2 Diabetes and Neuropathic Pain. Archives of Internal Medicine, 2008; 168(7): 771-772.
Any of a variety of doses are contemplated as compatible with various embodiments. It is contemplated that a proper dose in a particular application will be determined in accordance with sound medical judgment.
Bone repair will be a major focus. Osiris is advancing Prochymal for inflammatory, autoimmune, and cardiovascular indications.
Qutenza works by targeting certain pain nerves in the area of skin where pain is being experienced. The Qutenza patch is applied by a physician or a healthcare professional. Clinical studies have shown that PHN pain can be reduced for up to 12 weeks following a single one-hour treatment. Up to four patches (https://dkluchezar.ru/content/uploads/files/download/qutenza-patch-fda-approval.zip) may be used and patches may be cut to conform to the size and shape of the painful area. Qutenza is a locally-acting, non-narcotic medication that is unlikely to cause drowsiness or have drug-drug interactions. Treatment with Qutenza may be repeated every three or more months as warranted by the return of pain.
Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such a CREMOPHOR®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.
Jamal GA and Carmichael H. The Effect of γ-Linolenic Acid on Human Diabetic Peripheral Neuropathy: A Double-blind Placebo-controlled Trial. Diabetic Medicine, 1990; 7(4): 319-323.
New Capsaicin Patch Helps to Reduce Diabetic Peripheral Neuropathy of the Feet
In some embodiments, lipidation comprises GPI-anchor addition. As used herein “GPI-anchor addition” refers to the linkage of glycosyl-phosphatidylinositol (GPI) to the C-terminus of a protein.
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Vincent AM, McLean LL et al. Short-Term Hyperglycemia Produces Oxidative Damage and Apoptosis in Neurons. The FASEB Journal, 2005; 19: 638-640.
Feldman EL, Stevens MJ et al. A Practical Two-Step Quantitative Clinical and Electrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy. Diabetes Care, 1994; 17(11): 1281-1289.
In some embodiments, soluble lipidated ligand agents show a solubility under physiologically relevant conditions that is reasonably comparable to that of the unlipidated form of the ligand entity. In some embodiments, a lipidated ligand agent shows a solubility that is not reasonably comparable to that of the unlipidated form of the ligand entity. In some embodiments, a lipidated ligand agent shows solubility that is statistically significantly different from that of the unlipidated form of the ligand entity. In some embodiments, a soluble lipidated ligand agent will show a solubility that is 5%, 10%, 20%, 30%, 40%, or greater than that of the unlipidated form of the ligand entity. In some embodiments, a soluble lipidated ligand agent will show a solubility that is 5%, 10%, 20%, 30%, 40%, or lower than that of the unlipidated form of the ligand entity. In some embodiments, provided soluble lipidated ligand agents are soluble under physiologically relevant conditions in that they do not violate Lipinski's Rule.
Noor R, Mittal S, Iqbal J. Superoxide dismutase -applications and relevance to human diseases. Medical Science Monitor, 2002;8(9):RA210-5.
Alternatively or additionally, in some embodiments, provided soluble lipidated ligand agents may self-localize, at least to a degree, for example as a result of inclusion of a localization moiety. For clarity, in some embodiments, a lipid entity may be or comprise a localization moiety, particularly given that certain lipid entities may themselves show preferential localization in vivo. To give but one example, in some embodiments, a lipid entity may be comprised of lipids that are preferentially found in and/or associate with a certain location or site (or plurality thereof) in vivo. Alternatively or additionally, in some embodiments, a ligand entity may be or comprise a localization entity, particularly given that certain ligand entities may themselves show preferential localization in vivo.
Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if its administration to a relevant population is statistically correlated with a desired or beneficial therapeutic outcome in the population, whether or not a particular subject to whom the agent is administered experiences the desired or beneficial therapeutic outcome.
At the time it looked as if NeurogesX had dodged a delay bullet when the FDA agreed to its proposed study using an approved combination of 2/5% lidocaine and 2/5% prilocaine, and also with a surprisingly low number of only 24 trialists. The results of this small substitute trial read out on July 24 and showed that all patients were able to wear the patch for the requisite 60 minutes.
The diagonal cut in the release liner is to aid in its removal. Peel a small section of the release liner back, and place the adhesive side of the patch on the treatment area.
Sibal L, Law HN et al. Cardiovascular risk Factors Predicting the Development of Distal Symmetrical Polyneuropathy in People with Type 1 Diabetes. Annals of the New York Academy of Sciences, 2006’ 304-318.
In clinical trials, increases in blood pressure occurred during or shortly after exposure to Qutenza. The changes averaged less than 10 mm Hg, although some patients had greater increases and these changes lasted for approximately two hours after patch removal. Increases in blood pressure were unrelated to the pretreatment blood pressure but were related to treatment-related increases in pain. Monitor blood pressure periodically during the treatment and provide adequate support for treatment related pain.
Bernaskova M, Schoeffmann A, Schuehly W, Hufner A, Baburin I, Hering S. Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists. Bioorganic & Medicinal Chemistry.
Provided agents and/or compositions comprising such agents and optionally other therapeutics maybe administered per se (neat) or in the form of a pharmaceutically acceptable composition, and furthermore may be utilized, in some embodiments, in the form of a salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
Denosumab is the most important drug in the company's late-stage pipeline. Approval for osteoporosis, and later for certain cancer indications, could re-invigorate earnings growth after a couple of flat years.
Mindfulness meditation has been demonstrated in research trials to alter perceived pain, reduce depression, and decrease stress. Results of a pilot study were recently published in support of mindfulness meditation for women with chronic pelvic pain.
Hicks, C. W, & Selvin, E. (2021). Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Current diabetes reports, 19(10), 86. Accessed July 6, 2021.
Clotting Factors, Coagulant Blood Products & Other Hemostatics – Commercial Medical Benefit Drug Policy
Fujita H, Fujishima H, Chida S, Takahashi K, Qi Z, Kanetsuna Y, Breyer MD, Harris RC, Yamada Y, Takahashi T. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. Journal of the American Society of Nephrology, 2009;20(6):1303-13.
Fahmy E, Amer H et al. Estimation of Serum Homocysteine Level in Patients with Type 2 Diabetic Neuropathy. Egyptian Journal of Neurology Psychiatry and Neurosurgery, 2021; 47(1): 59-66.
Tethered agonist induced signaling was assessed in HEK293 cells 24 hours after transfection. For soluble and lipidated peptides, 20 hours following transfection, cells were stimulated for an additional 4 hours. For antagonist assays, CP 99994 or YM022 (Tocris) were added concurrently with soluble agonist for 4 hours. With tethered ligands, antagonists were added 4 hours after transfection; activity was assessed following an additional 20 hour incubation. Quantification of luciferase and β-galactosidase activities were performed as previously described (see Fortin et al, Discovery of dual-action membrane-anchored modulators of incretin receptors, 2021, PLoS One6:e24693). Data were analyzed by nonlinear curve fitting using Graph Pad Prism 5/0 software.
De Caterina R and Madonna R. n-3 Fatty Acids in the Treatment of Diabetic Patients. Diabetes Care, 2007l 30(4): 1012-1026.
In some embodiments, provided lipidated ligand agents comprise a linker entity. In some embodiments, association of the ligand entity and lipid entity with a linker does not alter the three dimensional conformation of either the ligand entity or the lipid entity as compared to the ligand entity and lipid entity alone. In some embodiments, association with a linker results in an alteration of the three dimensional structure of at least one of the ligand entity and lipid entity.
The early approval of Ultragenyx’s Dojolvi for long-chain fatty acid oxidation disorders yesterday takes the first-to-market approval tally so far in 2021 to 29. That is well above the 18 new arrivals given a greenlight at the halfway point last year. However, as the FDA continues to shift resources and focus on pandemic-specific treatments, approval goals and timelines could well be knocked in the coming months.
In some embodiments, a ligand entity is or comprises an enzyme ligand, such as a substrate. In some embodiments, an enzyme ligand associates with one or more known membrane-associated enzymes. Non-limiting exemplary enzymes to which certain embodiments may associate include: kinases, peptidases, proteinases, and cyclo-ligases.
Maximum Dosage and Frequency – Commercial Medical Benefit Drug Policy
In some embodiments, provided methods allow for the identification and/or characterization of one or more previously unknown properties of one or more precursor polypeptides. In some embodiments, provided methods allow for characterization of precursor polypeptides and the biological function a precursor polypeptide may be capable of exerting on a target. In some embodiments, provided methods allow for the characterization of a previously unknown property of a precursor polypeptide, such as a new binding affinity or even new binding site.
FDA to Review Capsaicin Patch for Painful Diabetic
Maiwand MO, Makey AR, Rees A. Cryoanalgesia after thoracotomy. Improvement of technique and review of 600 cases.
In some embodiments, a ligand entity is or comprises a small molecule. In general, any small molecule that binds appropriately to a target of interest and is subject to lipidation as described herein may be utilized in accordance with the present invention.
Data from in vitro cytochrome P450 inhibition and induction studies show that capsaicin does not inhibit or induce liver cytochrome P450 enzymes at concentrations which far exceed those measured in blood samples. Therefore, interactions with systemic medicinal products are unlikely.
In some embodiments, solid compositions of a similar type may be employed as fillers in soft and/or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
In some embodiments, a peptidic ligand entity is or comprises one or more sequence elements. In some embodiments, a sequence element is or comprises a lipidation site.
In order to develop a soluble lipidated ligand agent from an MTL/MTP, the ligand entity, in the most desirable or advantageous orientation, is associated with a lipid entity, in some embodiments, with the use of a linker. In this Example, the linker used is polyethylene glycol (PEG), specifically PEG8 and the lipid entity used is palmitic acid. In various embodiments, a variety of linkers and/or lipid entities may be used in order to determine the most desirable combinations for use in creating one or more soluble lipidated ligand agents.
All commercial reagents were used without further purification. N-tert-butoxycarbonyl (N-Boc) protected D- and L-amino acids, and 4-hydroxymethylphenylacetamidomethyl (PAM) resin modified with N-Boc-L-Ser (Boc-L-Ser-PAM) were purchased from Chemimpex. HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) was procured from Novabiochem. Monodisperse, hetero-bifunctional polyethylene glycol (PEG), N-Fmoc-PEG8-propionic acid and the unnatural amino acid Boc-(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (N-Boc-L-Tic-OH) were from AAPPTec. Palmitic acid was purchased from Sigma Aldrich. Hydrogen fluoride was from Matheson Tri-Gas. Solvents for reversed-phase high performance liquid chromatography (RP-HPLC) had the following composition: Solvent A, H2O/CH3CN/Trifluoroacetic acid (TFA) (99/1/0/1); Solvent B, CH3CN/H2O/TFA (90/10/0/07).
In the stump, the corresponding amputated nerve was located with a nerve stimulator. With correct placement and stimulation, the PLP could then be reproduced or exacerbated. A small dose of local anesthesia was then injected, resulting in the disappearance of the PLP. If a peripheral nerve injection gave temporary relief, the final treatment was cryoanalgesia at this location. Evaluation of 5 patients, followed for at least 2/5 years, yielded the following results: 3 patients had excellent results (100 %, 95 %, and 90 % decrease in complaints, respectively), 1 patient had an acceptable result (40 % decrease), and 1 patient had only a 20 % decrease in pain. The authors concluded that although both central and peripheral components are likely involved in PLP, treatment of a peripheral pain locus with cryoanalgesia should be considered. These researchers proposed the identification of a peripheral etiology may help match patients to an appropriate therapy, and cryoanalgesia may result in long-term relief of PLP.
Coutaux A. Non-pharmacological treatments for pain relief: TENS and acupuncture. Joint, Bone, Spine: Revue du Rhumatisme.
Qutenza offers physicians a different way to effectively treat neuropathic pain associated with diabetic peripheral neuropathy. Qutenza, a specially formulated patch, delivers prescription strength capsaicin directly to the skin during an in-office procedure. Thereby, it can reversibly desensitize and defunctionalize the TRPV1 (Transient Receptor Potential Vanilloid 1) receptor, which plays a critical role in pain signaling.
Erythropoiesis-Stimulating Agents – Commercial Medical Benefit Drug Policy
It has been previously shown that chemerin is rapidly inactivated in vivo by proteases. To further enhance the activity and half-life of the lipidated chemerin analog, we substituted a proteolysis-resistant chemerin sequence into our construct. HEK293 cells were transiently transfected with cDNAs encoding i) human or mouse CMKLR1, ii) a SRE5x-Luc reporter gene, iii) a Gαq5i66V chimera, and iv) a β-galactosidase control. Twenty-four hours after transfection, cells were stimulated with increasing concentrations of various ligands for 15 minutes. Selected wells were then washed three times with serum-free media and plates were further incubated for 4 hours. Luciferase activity, determined as described in Experimental Procedures, was normalized relative to the maximal value observed using saturating concentrations of s-Stable Chem in cells that were unwashed (=100%).
Approval History Drug history at FDA
Mizukami H, Ogasawara S et al. Methylcobalamin Effects of Diabetic Neuropathy and Nerve Protein Kinase C in Rats. European Journal of Clinical Investigation, 2021; 41(4): 442-450.
According to our data, generics prescriptions in 2003 accounted for only 20% of the overall prescription volume. In contrast, generics accounted for more than 40-60% in some OECD countries , even though the generics markets are not totally comparable. It is therefore possible that our results could not be replicated exactly in other countries due to differences in the nature of the generics market. We found that the variations in substitution rates across the cantons were similar to those observed across European countries (36% in Germany, 8% in France and 4% in Spain, for instance) during the same period. Adjusting for potential disparities in health status, prescriptions or prescribers characteristics did not alter these variations, which suggests that the impact of cultural aspects such as prescribing behaviours or beliefs about generic substitution may be as important as national policies. This interpretation is confirmed by the finding that hospital physicians substituted less, and.
Qutenza Dosage and Administration
Neuropathic pain associated with diabetic peripheral neuropathy (DPN), or diabetic nerve pain, is a progressive and debilitating complication of diabetes that will affect approximately more than 5 million Americans in 2021 and is expected to double by 2030. Patients with diabetic nerve pain typically experience symptoms of numbness, tingling, as well as shooting or stabbing sensations that most often affect the lower extremities.
For example, in some embodiments, the present invention provides a first collection of potential ligand entities, each of which is attached to a chemically reactive moiety of a first type. In some embodiments, the present invention also provides a second collection of potential lipid entities, each of which is attached to a chemically reactive moiety of a second type, wherein reaction between the first and second types of chemically reactive moieties generates a covalent linkage. In some embodiments, such first and second types of chemically reactive moieties are so-called “click chemistry” moieties.
Tesfaye S, Chaturvedi N et al. Vascular Risk Factors and Diabetic Neuropathy. New England Journal of Medicine, 2005; 352: 341-350.
Upneeq Approved by FDA
Plasmids encoding either the human (University of Missouri cDNA Resource Center) or the mouse (Origene) chemerin receptor cDNA were purchased and subcloned into pcDNA1/1. Full length human chemerin cDNA (encoding pre-prochemerin corresponding to amino acids 1-163) was purchased from Sino Biological. The chemerin coding region was PCR amplified and subcloned into a type II membrane-tethered ligand (MTL) backbone as previously described. The corresponding MTL cDNA encodes a TNFα transmembrane domain, a ‘GN’ repeat linker containing a c-Myc tag (to monitor MTL expression levels), and the chemerin peptide at the C-terminus. The TNF-α transmembrane domain, by virtue of it being a type II transmembrane domain (TMD), positions the MTL such that the C-terminus of the construct projects into the extracellular space. This orientation is optimal for the study of chemerin since the C-terminal end of the peptide has been shown to be important for activity at CMKLR1. MTLs encoding pre-prochemerin (amino acids 1-163), full length chemerin (amino acids 21-157), and the C-terminal 9 amino acids of chemerin (149-157) were generated in addition to a negative control MTL (including the amino acid sequence of human galanin). To assess variant chemerin sequences, degenerate oligonucleotides (‘NNKNNK’) were used to introduce variability at positions corresponding to the 2 carboxy terminal residues of chemerin 149-157 (amino acids 156 and 157). The nucleotide sequences of all receptor and tether constructs were confirmed using automated DNA sequencing followed by analysis with VectorNTI (Invitrogen).
Vaccines – Commercial Medical Benefit Drug Policy
In some embodiments, improved half-life under relevant physiological conditions is statistically significantly different half-life as compared to a non-lipidated form of the ligand entity. In some embodiments, improved half-life under relevant storage conditions is statistically significantly greater half-life as compared to a non-lipidated form of the ligand entity.
In some embodiments, lipid entities are attached at a plurality of different locations on a particular ligand entity In many embodiments that utilize a peptide ligand entity, a lipid entity is attached at one or the other end of the ligand entity. Attachment of the lipid entity (and/or the linker entity) does not preclude interaction of the ligand entity with its target.
Copper-containing complexes which catalyze such reactions include, but are not limited to, copper bromide (CuBr), copper chloride (CuCl), copper sulfate (CuSO4), copper iodide (CuI), [Cu(MeCN)4](OTf), and [Cu(MeCN)4](PF6). Organic and inorganic metal-binding ligands can be used in conjunction with metal catalysts and include, but are not limited to, sodium ascorbate, tris(triazolyl)amine ligands, tris(carboxyethyl)phosphine (TCEP), and sulfonated bathophenanthroline ligands. Other such catalysts, for instance other copper catalysts or ruthenium- or silver-based catalysts, are known in the art, as are various methodologies for making and using the same.
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Ziegler D, Sohr CGH et al. Oxidative Stress and Antioxidant Defense in Relation to the Severity of Diabetic Polyneuropathy and Cardiovascular Autonomic Neuropathy. Diabetes Care, 2004; 27: 2178-2183.
Once a candidate ligand entity (here, Chemerin) is selected, at least two versions of tethered forms of the ligand entity are created to associate with a target. In this Example, the target is CMKLR1. Both versions comprise a membrane tether, which in this Example is a transmembrane domain of either herpes simplex virus type 1, or tumor necrosis factor-α (TNFα).
Margolis DJ, Malay DS, Hoffstad OJ, Leonard CE, MaCurdy T, de Nava KL, Tan Y, Molina T, Siegel KL. Incidence of Diabetic Foot Ulcer and Lower Extremity Amputation Among Medicare Beneficiaries, 2006 to 2008: Data Points #2. 2021 Feb 17. Data Points Publication Series [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2021.
Ophthalmologic Policy: Vascular Endothelial Growth Factor Inhibitors – Commercial Medical Benefit Drug Policy
In some embodiments, a ligand entity is covalently bound to a lipid entity. In some embodiments, the ligand entity and lipid entity are directly covalently bound to one another, while, in other embodiments, the ligand entity and the lipid entity are indirectly covalently bound. As a specific, non-limiting example, in some embodiments, a ligand entity is covalently bound to a linker, and the linker is covalently bound to the lipid entity.
The hose exchanges cooled ice water between the cooler and the cuff which covers the injured area. Elevating the cooler fills and pressurizes the cuff. Compression is controlled by gravity and is proportional to the elevation of the cooler.
Talaei A, Siavash M, Majidi H, Chehrei A. Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. International Journal of Food Sciences and Nutrition, 2009;60 Suppl 5:71-6.
Two studies evaluated the pharmacodynamic effects of Qutenza on sensory function and epidermal nerve fiber (ENF) density in healthy volunteers. Consistent with the known pharmacodynamic effects of capsaicin on TRPV1-expressing nociceptive nerve endings, reduced ENF density and minor changes in cutaneous nociceptive function (heat detection and sharp sensation) were noted one week after exposure to Qutenza. ENF density reduction and sensory changes were fully reversible.
For example, as is well known by those of ordinary skill in the art, certain amino acids are typically classified as similar to one another as “hydrophobic” or “hydrophilic” amino acids, and/or as having “polar” or “non-polar” side chains. Substitution of one amino acid for another of the same type may often be considered a “homologous” substitution.
The present invention establishes specifically that such a membrane-tethered format can usefully reveal desirable attributes and/or characteristics of ligand entities, which ligand entities can then function effectively when incorporated into soluble lipidated ligand agents as described herein. In some particular embodiments, where both the ligand entity and the membrane tether are or comprise polypeptides, a membrane-tethered ligand entity conjugate can be prepared through recombinant technology.
Evenity® – Commercial Medical Benefit Drug Policy
In comparison, ‘FS’ and ‘VA’ both activated mouse CMKLR1 with both ‘SL’/‘GP’ showing partial agonist activity and ‘GH’ showing no effect. Again, negative control tethered galanin did not activate either receptor. Since the endogenous Chem 149-157 sequence showed the highest activity as a tether, we chose to utilize this sequence in follow-up experiments.
Qutenza: Approval of a “DESI-inspired” Drug
Cooper and colleagues (2021) stated that after severe traumatic brain injury (TBI), induction of prophylactic hypothermia has been suggested to be neuro-protective and improve long-term neurologic outcomes. These researchers examined the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe TBI. The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multi-center, randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments (EDs) after severe TBI. The first patient was enrolled on December 5, 2021, and the last on November 10, 2021. The final date of follow-up was May 15, 2021. There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33° C to 35° C) for at least 72 hours and up to 7 days if intra-cranial pressures were elevated, followed by gradual re-warming. Normothermia targeted 37° C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician.
Rituximab – Commercial Medical Benefit Drug Policy
In some embodiments, a peptidic ligand entity is or comprises a precursor peptide. Another of the advantages of some embodiments is that lipidation of a precursor peptide may allow the precursor peptide to exert a desired biological effect, for example, an effect normally associated with the activated form of the peptide, without undergoing the modifications normally thought to be required to activate the precursor peptide. In some embodiments, a soluble lipidated precursor peptide is able to bind to its target and exert a biological effect when the precursor peptide alone is not able to do so.
Somatostatin Analogs – Commercial Medical Benefit Drug Policy
Isolated: As used herein, the term “isolated” refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% of the other components with which they were initially associated. In some embodiments, isolated agents are about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components.
Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0/5-2/5% w/v); and phosphoric acid and a salt (0/8-2% w/v). Suitable preservatives include benzalkonium chloride (0/003-0/03% w/v); chlorobutanol (0/3-0/9% w/v); parabens (0/01-0/25% w/v) and thimerosal (0/004-0/02% w/v).
Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
After removal of Qutenza, generously apply Cleansing Gel to the treatment area and leave on for at least one minute. Remove Cleansing Gel with a dry wipe and gently wash the area with mild soap and water and dry thoroughly.
Bansal V, Kalita J et al. Diabetic Neuropathy. Postgraduate Medical Journal, 2006; 82: 95-100.
Sepsas et al (2021) studied patients undergoing thoracotomy to compare the effects of cryoanalgesia, combined with intravenous patient-controlled analgesia (IVPCA), against IVPCA alone during the 4 days following surgery. A total of 50 patients were randomized into 2 groups: an IVPCA group (n = 25) and an IVPCA-cryo group (n = 25). Subjective pain intensity was assessed on a verbal analog scale at rest and during coughing. The intensity and the incidence of post-thoracotomy pain, numbness, epigastric distension and/or back pain, the analgesic requirements, as well as the blood gas values and respiratory function tests were evaluated up to the 2nd post-operative (post-op) month. Hemodynamic data and episodes of nausea and/or vomiting were recorded over the 4 post-op days.
17-Alpha-Hydroxyprogesterone Caproate – Commercial Medical Benefit Drug Policy
Han T, Bai K et al. A Systematic Review and Meta-Analysis of Alpha-Lipoic Acid in the Treatment of Diabetic Peripheral Neuropathy. European Journal of Endocrinology, 2021; 167: 465-471.
Romeo L, Intrieri M, D'Agata V, Mangano NG, Oriani G, Ontario ML, Scapagnini G. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, induces heme oxygenase in rat neurons and acts as an effective neuroprotective agent against oxidative stress. Journal of the American College of Nutrition, 2009;28 Suppl:492S-499S.
In some embodiments, each of the plurality of compositions has a different release profile, such as provided by various enteric coatings, for example. In some embodiments, each of the plurality of compositions has a similar release profile.
Effective Date: 04/01/2021 – This policy addresses the use of Benlysta® (belimumab) injection for intravenous infusion for the treatment of systemic lupus erythematosus (SLE) and active lupus nephritis (LN). Applicable Procedure Code: J0490.
The acquisition includes all uses and thus provides full rights, and intellectual property, for the asset. In consideration, Spectrum will pay to Altair a total of $750,000 in restricted common stock.
The most pronounced attenuation of mucus metaplasia was seen in mice treated with I-Stable Chem. To further assess the effects of I-Stable Chem, the inflammatory response in the lung using H+E staining and BALF analysis of leukocytes was performed.
To aid dissolution of a therapeutic into an aqueous environment, a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctylsodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.
If approved dostarlimab will be a latecomer to the PD-1 class. Fortunately endometrial cancer is not as competitive as some tumour types: Merck’s Keytruda is the only PD-1 with endometrial cancer on its label, but in tumours that are not MSI-H or mismatch repair-deficient, a different population to Glaxo’s dostarlimab. However, Keytruda is also approved in MSI-H tumours irrespective of tumour type.
De Grandis D and Minardi C. Acetyl-L-Carnitine (Levacecarnine) in the Treatment of Diabetic Neuropathy. Drugs Research and Development, 2002; 3(4): 223-231.
Self-Administered Medications – Commercial Medical Benefit Drug Policy
In some embodiments, a ligand entity is or comprises a receptor ligand, such as a GPCR ligand. According to various embodiments, a variety of freely soluble as well as membrane-associated receptor ligands may be used.
According to various embodiments, a linker may be selected based, at least in part, on application-specific factors. Non-limiting examples of such factors include the specific chemistries of a particular ligand entity/lipid entity combination, the efficacy of a particular linker in in vitro or in vivo models, the desired degree of solubility, and distance required for a ligand entity to reach a target. In some embodiments, a linker, for example, a non-peptidic linker, has a length of between about 2 Å and 175 Å, inclusive. In some embodiments, a linker is between 30 Å and 150 Å, inclusive.
Lemtrada – Commercial Medical Benefit Drug Policy
Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
Cui XP, Li BY, Gao HQ, Wei N, Wang WL, Lu M. Effects of grape seed proanthocyanidin extracts on peripheral nerves in streptozocin-induced diabetic rats. Journal of Nutritional Science and Vitaminology (Tokyo), 2008;54(4):321-8.
Alternatively or additionally, pharmaceutically acceptable excipients such as cocoa butter and/or suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be utilized. Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md, 2005; incorporated herein by reference) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
According to the website, there are currently 1,966 drug shortages and 52 anticipated drug shortages in Canada. The site lists, but does not analyze the shortages. Among drugs that continue to face shortages are tamoxifen, commonly prescribed for women with estrogen positive breast cancer. For weeks, patients have reported difficulty filling their prescriptions. Apotex, which is the countrys biggest supplier of tamoxifen, expects to have supply available as soon as possible, said Jordan Burman, vice-president of global corporate communications. The company had initially said the drug would be available by the end of January, but after working with Health Canada has since.
A product number is assigned to each drug product associated with an NDA (New Drug Application). If a drug product is available in multiple strengths, there are multiple product numbers.
Bestard JA and Toth CC. An Open-label Comparison of Nabilone and Gabapentin as Adjuvant Therapy or Monotherapy in the Management of Neuropathic Pain in Patients with Peripheral Neuropathy. Pain Practice, 2021; 11(4): 353-368.
Farvid MS, Homayouni F et al. Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation. Diabetes Research and Clinical Practice, 2021; 93: 86-94.
US FDA approval tracker: January
Golbidi S, Badran M et al. Diabetes and Alpha Lipoic Acid. Frontiers in Pharmacology, 2021; 2.
Entyvio® – Commercial Medical Benefit Drug Policy
The lipidated SubP peptide (I-SubP-COOH) included a KGG spacer coupled to the N-terminus to allow attachment of the corresponding PEG8/palmitic acid. In comparison, the lipidated CCK4 analog (I-CCK-Gly-COOH) contains only a GG spacer used for subsequent anchoring.
Significant investment has been directed to development of additional such agents. Of particular interest are agents susceptible to tissue-specific delivery.
The candidate soluble lipidated ligand agents, here chemerin-PEG8-palmitic acid agents, are then tested in an assay similar to the luciferase assay described above. However, since soluble lipidated ligand agents are not capable of expression from a cDNA, they must be added to the test system exogenously. Other components of the system, such as the target and luciferase reporter, may be introduced via cDNA transfection as described previously and above. The activity of the candidate soluble lipidated ligand agent is then assessed in a manner similar to the MTL/MTP. Comparison is made between the SMAL and a non-lipidated and/or non-tethered forms of the ligand entity (peptide alone, peptide plus linker vs. SMAL).
FDA Approved Drugs: August
Glidants that might improve the flow properties of a drug during formulation and to aid rearrangement during compression might be added. Such glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.