The present invention is a physical pathogen reduction method and apparatus for controlling or eliminating transfusion-transmittable infections. This purely physical technique does not involve the use of heat, chemicals and/or irradiation, each of which has significant drawbacks in the pathogen reduction of human plasma. The invention inactivates both nonenveloped and enveloped viruses as well as pathogenic bacteria and parasites in units of human plasma, while retaining the natural biological activity. integrity and potency of the treated plasma. The method uses critical, near-critical or supercritical fluids for viral and pathogen reduction of units of donor blood plasma, using novel blood plasma bags. The apparatus is in the form of a bench-top or mobile transportable unit, which can be used in hospitals, blood banks, medical facilities and hot zones in developing countries for the clearance of viruses from human plasma.
The present invention is for a continuous-flow pathogen reduction apparatus and method, based purely on pathogen inactivation physical principles, for controlling or eliminating trans fusion-transmittable infections from emerging pathogens, pandemic viruses, and bioterrorism threats. The invention inactivates both nonenveloped and enveloped viruses as well as pathogenic bacteria and parasites in human plasma and biologies, while retaining the natural bioactivity, integrity and potency of the treated biologic. The method uses critic al, near-critical or supercritical fluids for viral and pathogen reduction of plasma and biologies. The apparatus is designed to rapidly process high volumes of plasma and biologies with high levels of pathogen reduction in a continuous flow fashion.
A61L 2/24 - Apparatus using programmed or automatic operation
A61L 2/00 - Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lensesAccessories therefor
3.
METHOD AND APPARATUS FOR INACTIVATING PATHOGENS IN UNITS OF WHOLE BLOOD USING SUPERPARAMAGNETIC NANOPARTICLES COATED WITH CHEMILUMINESCENCE REAGENTS AND BROAD-SPECTRUM ANTI-VIRAL THERAPEUTICS
A method and apparatus for reducing or inactivating pathogens in units of whole blood. A plurality of superparamagnetic nanoparticles (SPN) is coated with a mixture of chemiluminescence light-generating compounds and photodynamic broad-spectrum anti-viral compounds, and the mixture in introduced into a bag of whole blood. A rapidly-changing electromagnetic field is applied to the bag to cause uniform distribution of the nanoparticles within the whole blood throughout all regions of the blood bag, including the opaque interior of the bag. The blood is processed for a predetermined processing time period, during which the chemiluminescence light activates the broad-spectrum antiviral capacity of the photodynamic compounds to achieve reduction or inactivation of pathogens throughout the blood bag. After the processing time is elapsed, the nanoparticles are removed from the processed blood by a magnetic field. The processed blood may be washed by conventional means, to remove residual reagents, and transferred into a new, sterile blood bag.
This invention is for improved extracting, separating, and manufacturing pharmaceutical grade CBD and other cannabinoids following current Good Manufacturing Practices (cGMP) of the US FDA for use in clinical trials for central nervous system (CNS) and peripheral nervous system (PNS) disorders such as pain, opioid use disorder, anxiety, epilepsy, nausea and vomiting, Multiple sclerosis and other indications by the National Institute of Health (NIH) and other researchers. This invention first established optimum conditions for the selective SuperFluids™ [supercritical fluids and near-critical fluids with or without polar co-solvents such as alcohols] fractionation of Cannabis sativa to isolate CBD, CBDA, Δ9-THC, Δ9-THCA and other cannabinoids Δ9-THC; then defined SuperFluids™ chromatographic purification conditions for the further purification of CBD, CBDA, Δ9-THC, Δ9-THCA with absolute purities >98.5%. This invention is for methods and apparatus to manufacture pharmaceutical-grade CBD and CBDA (98.5% to 100% with <0.3% Δ9-THC) from Cannabis sativa, hemp and marijuana utilizing SuperFluids™ selective extraction and chromatographic purification technologies, and the manufacture of other bioactive cannabinoids such as Δ9-THC, Δ9-THCA, Δ8-THCA, CBG, CBGA, CBC, CBN and their mixtures for future preclinical and clinical research, and their therapeutic use.
A method is disclosed for producing targeted nanoencapsulated therapeutics in a microgravity environment using supercritical, critical and near-critical fluids with and without polar cosolvents. Using the disclosed technology, nanosomes for delivering Bryostatin-1 and other Bryoids are produced in microgravity. The resulting nanosomes are smaller, more uniform, with a higher surface area to volume than those produced in gravity-based environments and have an average diameter between 0.001 to 20.000 nanometer. The resultant therapeutics may be used for treating chronic diseases such as cancer, HIV, and Alzheimer's disease.
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 31/35 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
A61K 47/24 - Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
The present invention is directed to methods and apparatus for creating a sustained release pathogen vaccine for COVID-19, influenza, HIV and other infectious human and animal viruses and pathogens using supercritical, critical, or near-critical fluids with or without polar cosolvents for simultaneously inactivating virions and pathogens, and encapsulating the inactivated virions and pathogens in biodegradable polymer nanospheres for administration to a patient. The present invention continuously inactivates SARS-CoV-2, influenza, HIV and other infectious human and animal viruses and pathogens, and nanoencapsulates the inactivated virions and pathogens in biodegradable polymer nanospheres to provide a safe and effective sustained-release vaccine, especially for the frail and elderly.
This invention is for methods to quantify the inhibition of 5-HT induced contraction of human intestinal smooth muscle and an assay to measure the effects of compounds on nausea, irritable bowel syndrome and irritable bowel disease. This invention can be used to measure the incidence and severity of nausea, and can be used as quality control assay for developing and releasing medications for controlling nausea and emesis.
This invention relates to a composition of matter using enhanced gingerols for treating nausea and emesis associated with cancer chemotherapy, pregnancy, elective surgery, radiation therapy, motion sickness, and drug medications, use and schedule of use as well as methods of making. A method of making the enhanced gingerols features supercritical, critical and near-critical fluids with and without polar cosolvents. The capsules include an enhanced extract of ginger rhizome wherein said ginger rhizome has a starting mass and said extract has a 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol mass and said ratio of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol mass to starting mass is 90-100%.
C07D 493/22 - Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
Embodiments of the present invention are directed to dosage forms for treating inflammation and rejection in transplantation injuries, graft versus host disease and stem cell transplants with Bryostatin-1, Bryostatin-1 analogs and pharmaceutically acceptable salts thereof.
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
A61K 47/28 - Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
A61K 47/22 - Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
11.
Thermal conversion of CBDA and other carboxylic cannabinoids
Cannabis biomass to convert carboxylic acids prior to extraction and purification. Alternatively, and preferably because of manufacturing cost and product stability, the carboxylic acids can be first extracted and purified. They can be utilized in the carboxylic acid form or stored in a stable manner until converted to cannabinoids for use in medicine. This invention provides an efficient method for their conversion utilizing a high-pressure reactor under inert conditions.
C07C 37/50 - Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
C07C 37/74 - SeparationPurificationStabilisationUse of additives by physical treatment by distillation
C07C 39/19 - Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
12.
METHODS FOR AND PRODUCTS FROM ENCAPSULATION OF DRUGS IN NANOPARTICLES IN A MICROGRAVITY ENVIRONMENT
This invention relates to methods for and products from precision manufacturing targeted nanoencapsulated drugs in a microgravity environment utilizing green, environmental-friendly SuperFluids™. Based on these methods, nanoparticles formulation of molecules such as, but not limited to, Bryostatin-1 and other Bryoids, manufactured and lyophilized in a gravity-based environment, will be smaller and more uniform with a higher surface area to volume ratio, approaching ‘picometer dimensions’ in a microgravity environment. Once frozen in Space, these enhanced nanoparticles, ‘picoparticles’ approaching ‘picometer dimensions’ will also find utility on Earth to treat ‘orphan’ and chronic diseases such as cancer, HIV and Alzheimer's disease. The methods feature SuperFluids™ which are supercritical, critical and near-critical fluids with and without polar cosolvents.
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 47/24 - Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
A61K 31/35 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
Embodiments of the present invention are directed to articles of manufacture and methods of making such articles having utility for the delivery of cannabinoids, naltrexone and a combination of cannabinoids and naltrexone as a therapeutic. One embodiment of the present invention directed to the article of manufacture comprises a lyophilized sphere having a diameter of about 100 to 500 nanometers having a shell comprising a biodegradable polymer containing a cannabinoid, naltrexone and a combination of a cannabinoid and naltrexone in a deareated buffer. A featured cannabinoid is cannabidiol (CBD).
Embodiments of the present invention are directed to formulations and methods of treating folic acid deficiency and morning sickness. The dosage form has an effective amount, of a folic add with an effective amount of a gingerol composition to suppress nausea and/or gastric distress and to promote hematopoiesis.
A61K 9/48 - Preparations in capsules, e.g. of gelatin, of chocolate
A61K 47/44 - Oils, fats or waxes according to two or more groups of Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
A61K 47/22 - Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
A61K 47/24 - Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
A61K 47/14 - Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
SUPERFLUIDS DISRUPTION OF SACCHAROMYCES CEREVISIAE (YEAST), CELL WALL DISINTEGRATION INTO NANOPARTICLES AND FRACTIONATION INTO BETA-GLUCANS, CHITIN AND MANNANS (MANNOPROTEINS)
The present invention is directed to methods and apparatus for and products from disrupting, removing intracellular proteins, enzymes and nucleic acids, spray drying, lipid extraction, and making nanoparticles of Saccharomyces cerevisiae (yeast) cell wall followed by acid and/or enzymatic hydrolysis to produce Beta (β)-glucans, chitin and mannans (mannoproteins). The process and apparatus feature critical, supercritical, or near critical fluids for disruption of yeast and making yeast cell wall nanoparticles. The product materials retain full activity and are devoid of residual processing chemicals such as solvents, salts, or surfactants.
Embodiments of the present invention are directed to dosage forms for treating inflammation and rejection in transplantation injuries, graft versus host disease and stem cell transplants with Bryostatin-1, Bryostatin-1 analogs and pharmaceutically acceptable salts thereof.
C07D 493/22 - Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61P 25/00 - Drugs for disorders of the nervous system
40 - Treatment of materials; recycling, air and water treatment,
Goods & Services
Manufacturing Services for others in the field of pharmaceutical agents; Manufacturing services for others in the field of enhanced therapeutics for treating cancers and their side effects, infectious diseases, namely, HIV and Influenza and CNS disorders; Manufacturing services for others in the field of quality of life medicines for health maintenance
Embodiments of the present invention are directed to formulations and methods of treating folic acid deficiency and morning sickness. The dosage form has an effective amount, of a folic add with an effective amount of a gingerol composition to suppress nausea and/or gastric distress and to promote hematopoiesis.
A61K 31/495 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
A61K 31/325 - Carbamic acidsThiocarbamic acidsAnhydrides or salts thereof
A61K 31/167 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen atom of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
A61K 31/20 - Carboxylic acids, e.g. valproic acid having a carboxyl group bound to an acyclic chain of seven or more carbon atoms, e.g. stearic, palmitic or arachidic acid
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61P 25/14 - Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
A61P 25/00 - Drugs for disorders of the nervous system
C07D 493/22 - Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
For the Board of Supervisors of Louisiana State University and Agricultural and Mechanical College (USA)
Inventor
Alexander, Jonathan Steven
Carpenter, April C.
Castor, Trevor Percival
Abstract
Embodiments of the present invention are directed to methods and dosage forms for treating inflammation and rejection in transplantation injuries with Bryostatin-1, Bryostatin-1 analogs and pharmaceutically acceptable salts thereof.
A61K 47/14 - Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
A61P 37/06 - Immunosuppressants, e.g. drugs for graft rejection
C07D 493/22 - Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 31/20 - Carboxylic acids, e.g. valproic acid having a carboxyl group bound to an acyclic chain of seven or more carbon atoms, e.g. stearic, palmitic or arachidic acid
A61K 31/325 - Carbamic acidsThiocarbamic acidsAnhydrides or salts thereof
A61K 31/167 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen atom of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
A61K 31/4045 - Indole-alkylaminesAmides thereof, e.g. serotonin, melatonin
A61K 47/68 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
This invention is for formulations of analogs of the non-toxic and inert Vitamin D3, its non-toxic and mostly inert pre-hormone and its toxic and biologically active hormone, and for using these formulations for preventing and treating certain cancers such as breast, prostate, ovarian, kidney, renal and other cancers, Vitamin D deficiency, autoimmune disease such as Multiple Sclerosis, hypertension, osteoporosis, bone diseases, rickets, psoriasis and infectious diseases. This invention also discloses compositions of the analogs of the non-toxic and inert Vitamin D3 and the non-toxic and mostly inert Vitamin D3 pre-hormone.
Embodiments of the present invention are directed to the administration of bryostatins and bryostatins and retinoids for the treatment of disease responsive to increases in alpha secretase activity. Inventions of the present application are directed to the treatment of neuro-degenerative diseases such as Hutchinson Disease, Parkinson's disease, Down's syndrome and Alzheimer's disease and virus latency diseases such as HIV and Herpes, cancers such as prostate, melanomas, lymphomas and renal cancers, esophageal and opthalmic diseases such as glaucoma.
A61K 31/352 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
A61K 31/22 - Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
A61K 31/23 - Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
Embodiments of the present invention are directed to methods and dosage forms for treating inflammation and rejection in transplantation injuries with Bryostatin-1, Bryostatin-1 analogs and pharmaceutically acceptable salts thereof.
C07D 493/22 - Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
31.
BRYOID COMPOSITIONS, METHODS OF MAKING AND USE THEREOF
Embodiments of the present invention feature novel Bryoid compositions, methods of making and methods of treating disease. Embodiments of the present invention are directed to compositions having utility as therapeutics in neurodegenerative diseases such as Hutchinson Disease, Parkinson's disease, Down's syndrome and Alzheimer's disease, virus latency diseases such as HIV and Herpes, cancers such as prostate and other amyloid mediated diseases such as glaucoma.
Embodiments of the present invention are directed to the administration of bryostatins and bryostatins and retinoids for the treatment of disease responsive to increases in alpha secretase activity. Inventions of the present application are directed to the treatment of neuro-degenerative diseases such as Hutchinson Disease, Parkinson's disease, Down's syndrome and Alzheimer's disease and virus latency diseases such as HIV and Herpes, cancers such as prostate, melanomas, lymphomas and renal cancers, esophageal and opthalmic diseases such as glaucoma.
A61K 31/357 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
33.
Drug delivery system and method for the treatment of neuro-degenerative disease
For the Board of Supervisors of Louisiana State University and Agricultural and Mechanical College acting on behalf of Louisiana State University Health Sciences Center at Shreveport (USA)
Inventor
Castor, Trevor Percival
Alexander, Jonathan Steven
Purdum, Geoffrey
Rios, J. David
Schrott, Lisa M.
Tyler, Theodore A.
Vizcaino, Maria I.
Abstract
Embodiments of the present invention are directed to the oral administration of Bryostatins for the treatment of neuro-degenerative disease.
Embodiments of the present invention are directed to articles of manufacture and methods of making such articles having utility for the delivery of cannabinoids as a therapeutic. One embodiment of the present invention directed to the article of manufacture comprises a lyophilized particle or sphere having a diameter of about 100 to 500 nanometers having a shell and comprising a biodegradable polymer containing a cannabinoid. A featured cannabinoid is delta-9-tetrahydrocannabinol (delta-9-THC).
A61K 31/35 - Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
38.
Apparatus and methods for making nanosomes loaded with nucleic acid
Embodiments of the present invention are directed to an apparatus and methods for making nucleic acid loaded nanosomes. One embodiment of the present invention directed to an apparatus comprises a first containment means for containing a mixture of an aqueous solution of nucleic acid and a phospholipid solution with a supercritical, critical or near critical fluid. The apparatus further comprises injection means in fluid communication with said first containment means for receiving the mixture and releasing the mixture as a stream into a decompression liquid. The apparatus further comprises a decompression vessel in fluid communication with the injection means for holding a decompression liquid and receiving the mixture as a stream. The stream forms one or more nanosomes loaded with a nucleic acid in the decompression liquid.
B01J 13/04 - Making microcapsules or microballoons by physical processes, e.g. drying, spraying
A61K 9/127 - Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
A61K 31/713 - Double-stranded nucleic acids or oligonucleotides
B82Y 5/00 - Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
C12N 15/88 - Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using liposome vesicle
39.
Nanotechnology formulation of poorly soluble compounds
Embodiments of the present invention are directed to articles of manufacture, spheres having a diameter of 50 to 500 nanometers which contain poorly soluble drugs and methods of making such spheres. Embodiments of the present invention have particular application for the following drug candidates and closely related poorly soluble derivatives of such candidates: (i) indole hydrazinecarbothioamide [NSC 73306]; (ii) fenretinide (4HPR) [NSC 374551]; (iii) safingol [NSC 714503]; (iv) 17-allylamino demethoxygeldanamycin (17-AAG) [NSC 330507]; and (v) an aminoflavone drug [NSC 686288].
Embodiments of the present invention are directed to apparatus and methods for the substantially continuous processing of cellulosic biomasses with a supercritical, critical or near critical fluid to produce ethanol, bio-fuels and high value end products.
This invention is for an improved process to co-encapsulate hydrophobic drugs and hydrophilic drugs in phospholipid liposomes. Non-toxic supercritical or near-critical fluids with/without polar cosolvents are utilized to solubilize phospholipid materials and hydrophobic drugs, and form uniform liposomes to encapsulate hydrophobic drugs and hydrophilic drugs.
