Drug Formulation Design

Transport Mechanisms within Living Brain Tissue

Drug Transport Mechanism Cells

The physical and chemical phenomena which can affect the transport of a drug (once it is released from its dosage form) within the living brain tissue are very complex and yet not fully understood. Excellent overviews on the importance of diffusion and related processes have been given by Tao and Nicholson (33,34). Nicholson and his co-workers as well as the group of Saltzman made major contributions towards a better understanding of these phenomena (35-41). A large variety of processes can be...

Factors Affecting Nasal Absorption

A combination of the structure and function of the nasal mucosa as a barrier to absorption, the properties of the active drug and the formulation within which it is contained will affect the extent to which a compound is absorbed nasally. The following factors are commonly reported as significantly influencing the extent of nasal absorption. Generally, drugs which are in solution will be rapidly absorbed nasally (31), although it appears that hydrophilic compounds are not readily absorbed above...

Dry Powder Inhalation

Drug Powder Formulation

The Montreal protocol of 1989 banning the use of chlorofluorocarbons (CFCs) was a laudable achievement for the protection of the environment. However, while this ban was aimed at industries that used large volumes of these harmful materials, it also affected highly beneficial medicinal products, such as pMDIs, which had traditionally contained low levels of these CFCs. The consequence of this has been that existing pMDI products have had to be reformulated to contain hydrofluroalkane systems...

Non Invasive CNS Drug Delivery

Cns Drug Formulations

Compound lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism, and excretion (ADME) of therapeutic agents. A parabolic relationship often exists between measured lipophilicity and in vivo brain penetration of drugs, where those moderate in lipophilicity often exhibit highest uptake (45). One Table 2 General Approaches to Enhance CNS Drug Delivery Table 2 General Approaches to Enhance CNS Drug Delivery Transdermal drug...

Nasal Anatomy And Physiology Anatomy

Nasal Vestibule Images Anatomy

The human nose consists of two nasal cavities separated by the septal wall, the narrowest section being the nasal valve near the front of the nose. Each nasal cavity opens onto the face through the nostril and extends posteriorly to the nasopharanyx with a length of approximately 10 cm. The combined surface area of both cavities is approximately 150 cm2 and the volume approximately 15 mL. The vestibular area serves as a baffle system whose surface is covered by a common pseudostratified...

Beclomethasone and Betamethasone

What Drugs Interact With Azathioprine

Beclomethasone and betamethasone are two very closely related glucocorticoid immunosuppressants with identical structures, except in betamethasone, the heteroatom substituent on the steroidal backbone is fluorine 12 , while in beclomethasone, the heteroatom substituent is chlorine 13 . The chemical structures of beclomethasone and betamethasone dipropionate are depicted in Figure 1. Frequently, these two drugs are administered as salt forms dipropionate, sodium phosphate due to their low...

Formulation of pMDI Systems

Modified Release Medication

Advances in Suspension-Based pMDI Systems Due to the poor solvent properties of HFAs, suspension based systems are a popular formulation route for current pMDIs. In general, research in this area has focused on two main themes over the past 5 years particle engineering and the application physical stabilizers. As with DPI systems, the drug particles used in suspension based systems should ideally have a diameter of less than 6 m to achieve a therapeutic affect upon administration. As previously...

Efflux Transport Barriers in the CNS

Rosuvastatin Efflux Bcrp

Besides the physiologic barriers discussed above, there are several passive and active efflux mechanisms that will influence drug concentrations in the brain (Fig. 2). Active efflux of drugs from the CNS by these transporters may result in reduced drug concentration, even though drugs possess preferable physicochemical properties for BBB penetration (e.g., lipid solubility). Efflux mechanisms in the CNS include multi-drug resistance protein (MRP), P-gp and breast cancer resistant protein...

Attention DeficitHyperactivity Disorder

Formulation Design

Attention-deficit hyperactivity disorder (ADHD) is a common neurobeha-vioral disorder that is often recognized in early childhood, and can persist into adulthood. The principal characteristics of ADHD are inattention, hyper-activity, and impulsivity. In the United States, between 3 and 6 of school-aged children meet accepted diagnostic criteria for ADHD (183). Over 60 of children with a diagnosis of ADHD continue to exhibit ADHD symptoms through their adult life (184). Methylphenidate (MPH), a...

To Optimize Therapeutic Outcomes

Advanced Drug Formulation Design to Optimize Therapeutic Outcomes DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs James Swarbrick PharmaceuTech, Inc. Pinehurst, North Carolina University of Maryland Baltimore, Maryland Johann Wolfgang Goethe University Frankfurt, Germany University of Florida College of Pharmacy Gainesville, Florida The Association of the British Pharmaceutical Industry London, United Kingdom University of Southern California Los Angeles, California...

Recent Advances in Nebulizer Technology

Conventional Jet Nebulizer

Nebulizers have been used for asthma therapy for many years and are used for the delivery of fine droplets of drugs to the lungs. For this reason they have been optimized for aerosol delivery in the upper range of inhalation Figure 21 Median adhesion between an albuterol particle and the internal walls of five pMDI canisters in model propellant using colloid probe microscopy. Canister coatings were as follows Aluminum ALU , anodized aluminum AN-ALU , polytetrafluoroethylene PTFE , fluorinated...

Congestive Heart Failure

Heart failure usually results from damage to the myocardium typically from ischemic heart disease, cardiomyopathy or myocarditis. Hypertension also contributes to cardiac failure especially if it is poorly controlled or results from damage to the heart valves and fluid overload. Apart from drugs, metabolic diseases such as, for example, thyrotoxicosis also makes a contribution. The overall result is that cardiac failure results in poor perfusion of vital organs and tissues and causes congestion...

Chemotherapy

Classification Chemotherapeutic Drugs

Since cancer cells divide more rapidly than normal cells, traditional chemotherapy involves treating patients with cytotoxic compounds designed to kill growing cells. The general approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cell. These medications target various phases of the cell cycle (Fig. 1), resulting in one of the following effects damaging cellular DNA, inhibiting DNA synthesis, or stopping mitosis (splitting of the original cell into two new...

Doxorubicin

Novel Liposomal Herbal Drug Formulation

Doxorubicin is an anthracycline antibiotic used to treat various cancers including breast, ovarian and lung cancer. While anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous Table 5 Advanced Formulation Strategies Examples of Drug Products Used to Treat Cancer Pegylated liposomal doxorubicin Nanoparticle doxorucin Surfactant-free formulation that prolongs circulation time, lowers drug distribution to healthy tissues, promoting tumor uptake...

Reversal of Multidrug Resistance

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for Pgp and other ABC transporters have been studied as an approach to improve therapeutic outcomes in cancer patients. There have been a number of clinical studies conducted to determine whether modulation of Pgp activity improves the efficacy of cancer chemotherapy (135). Studies have shown that Pgp modulators such as verapamil and cyclosporin indeed reverse resistance in a small...

Barriers And Obstacles To Cns Drug Delivery Physiological Barriers

Transcellular Pathway Bbb

There are several physiological or pathological factors preventing systemic drug delivery to CNS, including the BBB and the blood-cerebrospinal fluid barrier (BCB). Of these, the BBB is the most important barrier in the drug transport process. The BBB can be defined as a physiological mechanism that alters the permeability of brain capillaries so that the majority of substances are prevented from entering brain tissue, although some molecules are allowed to enter freely. In the late 19th...

Class IB Antiarrhythmic Agents

Pics Self Employed

Lidocaine hydrochloride. 2-(Diethylamino)-2',6'-acetoxylidide monohydro-chloride. This drug was conceived as a derivative of gramine (3-dimethyla-minomethylindole) and introduced as a local anesthetic, is now being used intravenously as a standard parenteral agent for suppression of arrhythmias associated with acute myocardial infarction and cardiac surgery. Lidocaine is the drug of choice for the parenteral treatment of premature ventricular contractions. Lidocaine hydrochloride administration...

Fexinidazole Preformulation Study Results.

See ATP-binding cassette ABC Abraxane , 205 Absorption enhancers, 286 ABT-963, 462 Accelerated idioventricular rhythm, 368 ACG. See Acycloguanosine ACG Active pharmaceutical ingredient API powder, DPI technology, 5 API modification to improve respiratory deposition, 17-21 Active vibrating mesh ultrasonic nebulizers, 39 ACV. See Acyclovir ACV Acycloguanosine ACG , 148 Acyclovir ACV , 147-149 Adaptive aerosol delivery technology, 38 Adenocarcinoma, 82 Adenosine, 375 Adenovirus infections,...

Liposomes and Lipoplexes

Liposomes are the most widely studied carrier system for anticancer drug delivery. A liposome is a spherical vesicle ranging from 50 nm to several microns in size, with a membrane composed of a phospholipid and cholesterol bilayer, usually containing a hydrophilic core. The main advantages of liposomal formulations include the following (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability...

Advanced Formulations Targeting the Oral Cavity

Advantages of targeting the oral cavity include the relatively large surface area for drug absorption the total surface area is approximately 170 cm2 with the buccal membranes being approximately 50 cm2 of this total area (2) and the ready accessibility of this site. The rich blood supply of the oral cavity is also advantageous for systemic absorption of drugs as well as the low metabolic activity within the mouth compared to the remainder of the GI tract. In the treatment of local infections...

Insoluble Drug Subcutaneous Formulation Design

Pirozynski M. 100 years of lung cancer. Respir Med 2006 100 12 2073-84. 2. Yang QE, Fong SE, Li K, Gonda MA, Tobin GJ. Ex vivo expanded murine bone marrow cells with a multiple cytokine cocktail retain long-term hematopoietic reconstitution potentials. Med Sci Monit 2005 11 6 BR154-61. 3. Bonfill X, Serra C, Sacristan M, Nogue M, Losa F, Montesinos J. Second-line chemotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2002 2 CD002804. 4. Agra Y, Pelayo M, Sacristan M,...

References

Optimizing drug delivery to brain tumors. Cancer Treat Rev 1987 14 1-28. 2. Abott NJ, Romero IA. Transporting therapeutics across the blood-brain barrier. Mol Med Today 1996 2 106-13. 3. Wang PP, Frazier J, Brem H. Local drug delivery to the brain. Adv Drug Deliver Rev 2002 54 987-1013. 4. Kornblith PL, Walker M. Chemotherapy for malignant gliomas. J Neurosurg 1988 68 1-17. 5. Pardridge WM. Vector-mediated drug delivery to the brain. Adv Drug Deliver Rev 1999 36 299-321. 6....

Modification of the API to Improve Respiratory Deposition

As previously discussed, in order to achieve efficient respiratory delivery, the drug powder requires an aerodynamic diameter of 60 RH). Other methods capable of producing discrete particle precipitation, rapid nucleation, and high rates of micro-mixing include sonication (73), high gravity precipitation (74-76), and impinging jet methodology (77). Recent work by Kaerger and Price (73) has suggested that aerosol droplets produced via electro-hydrodynamic or an air pressure atomizer could be...

Exubera System

Exubera is the first Food and Drug Administration approved inhaled insulin product. It is approved for the treatment of adult patients with T1DM and T2DM 22 . Exubera is currently available in a short acting formulation to control post prandial glucose excursions. In patients with T1DM, Exubera should be used in combination with long acting insulin, which provides basal insulin replacement. In patients with T2DM, Exubera can be used either as monotherapy or in combination with long acting...

Introduction

Pharmacologically active substances have been administered to humans for thousands of years. However, it is only in relatively recent times that the true nature of drug delivery to the human body has become an exact science. Today, drugs are delivered via many portals into the body using a variety of dosage forms which allow medicament administration, for example, orally or parenterally. One relatively recent pharmaceutical development is delivery via the lung. Although the breathing of vapors...

Biological Therapy

Over the past few years, a number of novel new cancer medicines have been marketed that have collectively been termed biological therapy. Biological therapy encompasses those strategies that employ substances that occur naturally in the body to destroy cancer cells. Compared to chemotherapy, which exert cytotoxic effects on both cancer and normal cells, biological therapy is regarded as targeted therapy because its effects are directed toward the cancer cell itself. Medicines in this category...

Advanced Formulations Targeting the Small Intestine

Transit time through the upper small intestine is relatively short and a prolonged residence in the stomach can be used to target drugs to this area. Time-controlled oral delivery systems which delay the release of the drug until they reach the target tissue can also be used. Delayed delivery systems can be categorized into reservoir, capsular, and osmotic devices. Reservoirs comprise single or multiple units and, according to their functional coating characteristics, can be rupturable or...

Fungal Keratitis

This form of keratitis is frequently caused by filamentous fungi such as species of Fusarium, Aspergillus and Curvularia, and by yeast-like fungi such as Candida (107). The symptoms include blurred vision, red and painful eye, increased sensitivity to light, and excessive tearing or discharge. Clinically, it is often difficult to differentiate between fungal and bacterial infections. Diagnosis can be done by corneal culture, tissue biopsy or confocal microscopy (108). The commonly used...

Advanced Formulations Targeting the Esophagus

Infections of the esophagus are primarily associated with immunocompro-mised hosts, including patients undergoing cancer chemotherapy or those with HIV. Available antifungals for the treatment of esophageal candidiasis include polyenes, azoles, nystatin, and AmB. Therapy with these agents is not always successful due to the poor permeation of the esophagus and their low systemic availability. The treatment of choice is fluconazole 100-200 mg daily which will achieve endoscopic clearance in more...

Physicochemical Properties of Medications

In terms of physicochemical requirements for good CNS delivery, low molecular weight, lack of ionization at physiological pH, and lipophilicity are the most important (13). As a general rule, maximum CNS delivery potential occurs for compounds with a log octanol-water partition coefficient (log Po w) near 2 (19). The log Po w parameter represents an informative physicochemical parameter used in medicinal chemistry, and it been shown to be a fairly useful descriptor of CNS penetration (20)....

Conclusion For Dosage Formulation

The cardiovascular system is a complex network of blood vessels with the heart at its center. The function of the system is to circulate oxygenated blood and nutrients to the various tissues in the body and return deoxygenated blood to the lungs for reoxygenation. The pharmacology of the sympathetic nervous system is important in cardiovascular medicine in view of the stimulating action of the sympathetic receptors. The beta-blockers are among some of the most commonly used drugs. They cause...

Overview of Solid Dispersion Technologies

The term dispersion is typically used to describe a heterogeneous, multiphase system in which discrete domains of a discontinuous phase are distributed within a second, continuous phase 3 . Although the term, dispersion, implies immiscibility of phases, the term, solid dispersion, as applied to drug delivery is often used generically to describe all systems in which an active agent is dispersed in an inert excipient carrier, including systems in which the drug may exist as a molecular...

Recent Advances in pMDI Technology

Although the respiratory tract has been a therapeutic target for many centuries, the pMDI is generally considered the first generation of marketed inhalation products that adhere to the vigorous regulatory requirements. Marketed since their introduction by Riker Laboratories, Santa Barbara (now 3M Healthcare) (86) in 1956 and many authors have described their basic form and functionality (87,88). Fundamentally, pMDIs rely on aerosol propellant technology, in which a high vapor pressure gas...

Polymer Conjugates

Macromolecular drug carriers are an attractive cancer drug delivery method because they appear to target tumors and have limited toxicity in normal tissues. The polymer-based medicines are the most important macro-molecular drug carriers for the diagnosis and treatment of cancer, and they have been extensively investigated for this purpose. Polymer drug conjugate (PDC) delivery relies on the EPR effect for targeting tumors. EPR allows for passive targeting of large molecular weight compounds,...

Vaccination as Therapy for Stomach Infections

Although effective antimicrobial delivery strategies are a major component in the treatment of H. pylori infections, there is also a need for a preventative strategy as many long-term infections are asymptomatic. The underlying chronic gastritis is a risk factor for gastric cancer and unless the host develops gastrointestinal disease (e.g. peptic ulcer), it is likely to remain untreated. A critical question is whether it is necessary or possible to induce local mucosal immune responses in the...

Parkinsons Disease

Parkinson's disease (PD) is a chronic, progressive disorder of the CNS that belongs to a group of conditions called motor system disorders. Approximately 4 million patients worldwide suffer from this condition, which results from a lack of dopamine, a chemical messenger responsible for transmitting signals within the brain. Loss of dopamine causes neurons to fire out of control, leaving patients unable to direct or control their movement in a normal manner (197). As described previously, a...

Class lA Antiarrhythmic Agents

Procainamide hydrochloride monohydrochloride. It was developed in the course of research for compounds structurally similar to procaine, which had limited effect as an antiarrhythmic agent because of its central nervous system side effects and short-lived action resulting from the rapid hydrolysis of its ester linkage by plasma esterases. Procainamide hydrochloride is also more stable in water than procaine because of its amide structure. Metabolism of procainamide hydrochloride occurs through...

Treatment Of Cardiovascular Disorders

Fenofibrate Tmax

Solid dispersion technologies have been applied to several drug molecules that are indicated for the treatment of cardiovascular disorders. Several drugs belonging to classes of lipid lowering agents, anti-hypertensives, anti-angina, etc. demonstrate poor aqueous solubility resulting in dissolution rate limited absorption when administered orally. Hence, solid dispersion technologies have been utilized to enhance the dissolution properties of these drugs with the aim of improving in vivo drug...

Cancer Therapy

Solid dispersion technologies have also been explored for improving drug therapies for the treatment of various conditions associated with cancer. Many anticancer drugs have poor aqueous solubility characteristics that preclude the efficacy of traditional oral dosage forms. Therefore, these drugs are commonly administered to the patient as parenteral injections. Since intrusive methods of drug administration are inconvenient and undesirable for the patient, there would be substantial benefit to...

AERx System

The liquid insulin based AERx system utilizes a microprocessor controlled inhaler device that monitors the breathing pattern of the patient and actuates when a combination of breathing parameters falls in a predetermined range (28,29). A fine mist is created by driving the insulin solution through a disposable nozzle, which prevents clogging. The inhaler is about the size of a paperback book and utilizes a slot for the insertion of the insulin strip. The insulin strip uses a one-time use nozzle...

Conventional Drug Delivery

The primary aim of the management of many gastrointestinal infections is appropriate therapy for self-limiting disorders. However, in immunocom-promised patients often the infections are not self-limiting and the pathogen needs to be identified to enable administration of an effective, safe antimicrobial chemotherapeutic agent. In other gastro-intestinal infections specific therapy is required. In this chapter conventional drug delivery refers to current usual dosage forms for oral drug...

Methods For Enhancing Nasal Absorption Absorption Enhancers

The use of absorption enhancers in the formulation is a commonly employed method for increasing absorption of substances across the nasal mucosa. Many reports on the use of absorption enhancers have shown positive results, although it is often unclear whether or not long term use will result in harmful side effects to the nasal mucosa. Bile salts have often been investigated as absorption enhancers and are possibly the most widely used means of aiding absorption via use of a surfactant 49 ....

Hypertension

Hypertension (high blood pressure) is considered to be one of the major medical problems of the world. In the United States nearly 25 million cases are diagnosed each year. Research shows that effective control of high blood pressure can reduce associated morbidity (notably stroke, kidney, and congestive heart failure) and prolong life. It may be argued whether hypertension is a disease or merely a risk factor towards disease. Nevertheless, hypertension increases the chance of developing organ...

Types of Arrhythmias

Sinus tachycardia is an arrhythmia originating in the SA node (10,11) characterized by rate of over 100 beats per minute. Sinus tachycardia may caused by numerous conditions such as fever, hypotension, heart failure, thyrotoxicosis, stimulation of the sympathetic nervous system, and life style drugs such as alcohol, caffeine, and nicotine. Treatment of sinus tachycardia (6,10) should be directed towards identifying the underlying cause of the arrhythmia. The P, QRS, and T deflection are all...

Tools To Study Cns Drug Delivery

Penetration of the BBB is essential for effective pharmacotherapy of CNS disorders. Various techniques have been used to study the pharmacokinetics and pharmacodynamics of CNS active agents by determining unbound drug concentrations in the extracellular fluid of the brain. In vivo techniques include the brain uptake index (27), the brain efflux index (BEI) (28), brain perfusion (29), the unit impulse response method (30) and micro-dialysis (31). BEI, an intracerebral microinjection technique,...

Invasive Drug Delivery

In recent years, various strategies have been designed to circumvent the BBB. Transient BBB disruption and osmotic BBB disruption are such strategies, and have been studied extensively in preclinical and clinical studies. After the BBB is being weakened, drugs can undergo enhanced extravasation rates in the cerebral endothelium, resulting in increased parenchymal drug concentrations. A variety of techniques that transiently disrupt the BBB have been investigated, such as administration of...

Targeting Transport Mechanisms

Receptor mediated transport is a potential pathway for delivery of large molecule peptides or proteins. This is particularly important for the drug delivery in the brain, in which the molecule is shuttled across the BBB into brain interstitial fluid by specific receptors (discussed in Chapter 10). The endothelial transferrin receptor (TfR) is a bidirectional transporter, and is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the...

Controlled Release Microparticles

Formulation Design

Different types of anticancer drugs have been incorporated into biodegradable microparticles (62-69). Compared to implants these systems offer the advantage that they can be injected directly into the wall of the resection cavity (the neighboring tissue of the debulked tumor) at multiple positions. As drug transport within the brain tissue is generally restricted to a few millimeters, this type of devices allows to more easily cover larger brain regions. For instance, Emerich et al.(67)...

The Mucus Layer

Water, containing proteins (including albumin, immunoglobulins, lysozyme and lactoferin) and electrolytes amongst other compounds, makes up the largest part of the mucous layer (90-95 ) (25,26). Mucins or glycoproteins of varying molecular weights (100-10,000,000 Da) constitute 3 of the mucus layer, with carbohydrates making up 80 of the weight of these mucins (26). The mucus layer is actually thought to be a double layer about 5-10 m thick (12,27), with an upper slow moving viscous layer (gel...

Azathioprine

Azathioprine AZA is a cytostatic drug, which, as stated previously, is a prodrug analog of the purine molecule, a component of nucleic acids. Until the discovery of cyclosporin in 1978, the combination of azathioprine and corticosteroid medications was the standard for treatment of transplant rejection. In the body, the AZA molecule is cleaved and converted to 6-mercaptopurine, the active form of the drug. This metabolite then goes on to antagonize purine synthesis which halts the synthesis of...

Case Study Aerosol Delivery Of Camptothecin Analogues

Patient Aerool Coverings

During the replication of the genome, the double-helix must be unwound prior to the arrival of the DNA polymerase. As DNA helicase proceeds down the strand, unwinding the DNA ahead of the replication machinery, the double-stranded DNA in front of the replication fork becomes increasingly super-coiled. This increased coiling creates a stress that must be relieved or else the entire replication process would abruptly and prematurely terminate. The enzymes responsible for alleviating this...

Pharmacokinetics Of Inhalation Aerosols Implications For Cancer Treatment

The absorption and distribution of drug following deposition of the aerosol particles in the airways is a complex process. However, it is of paramount importance to understand the dynamics of drug fate in order to achieve optimal efficacy of chemotherapeutic agents. Much information on the fate of inhaled drugs has been obtained from asthma medications that have been investigated extensively (114), though recently a great amount of research on this topic has arisen due to the interest in using...

Drug Formulation Cns Research

Brain and central nervous system (CNS) disorders are major causes of disability. Despite extensive research, clinical treatment options are still limited for the majority of CNS diseases, and therapeutic outcomes are sometimes disappointing. The blood-brain barrier (BBB) presents a formidable obstacle to effective drug delivery to the CNS. Although biologically intended to protect the brain and spinal cord and provide a very stable fluid environment, the presence of a BBB makes treatment of...

Itraconazole Prophylaxis

Itraconazole Fungal Infections

Although prophylactic use of fluconazole is safe and effective in preventing invasive candidiasis, this strategy is ineffective against invasive aspergillosis. Many transplant centers have instituted prophylactic strategies utilizing agents with activity against Aspergillus species such as itraconazole secondary to the high morbidity and mortality rates associated with invasive aspergillosis in high-risk immunocompromised patients. In a Figure 2 Percent of patients who developed invasive fungal...

Survey Of Glucody Products In Indian Market

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002 106(25) 3143-421. 2. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998 339 (4) 229-34. 3. Centers for Disease Control...

Lung Cancer

Despite the decades of awareness, and the introduction of newer therapies and treatment regimens, overall lung cancer survival rates remain low, and the urgency of replacing conventional approaches with novel or combination therapies exhibiting enhanced anti-cancer efficacy is now being recognized. The most telling statistic regarding lung cancer is that the annual number of deaths attributed to this disease continues to rise with each passing year (Fig. 1). This dual lack of success in both...

The Oral Cavity Infections of the Oral Cavity

Infections of the oral cavity are often caused by overactivity of endogenous flora (e.g. dental caries) and also by primary pathogens (e.g. candidiasis). Typical disorders include viral infections such as Herpes simplex (cold sores) fungal infections such as oral thrush caused by the Candida albicans and other Candida species bacterial-induced infection such as gingivitis leading to periodontitis in some cases. Standard treatments for oral infections are systemic administration of antifungal or...

Lung Function Parameters

Forced expiratory volume in 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO) are parameters utilized to evaluate lung function in studies testing inhaled insulin products. FEV1 measures the volume of air exhaled during the first second of a forced expiratory maneuver. Values are reported as a percentage of predicted normal values and are used to measure airway obstructions or changes in airway diameter. DLCO reveals oxygen-diffusing capacity influenced by lung surface area,...

Emerging Cancer Therapies Gene Therapy

Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, suggest that cancer growth can be arrested or reversed by delivering a single growth inhibitory or pro-apoptotic gene, or a gene that can elicit immune responses against the tumor. Gene therapy is a technique that is currently being developed to treat a number of different cancers. A main requirement for gene therapy is the development of efficient,...

Immunosuppression

Tacrolimus is an immunosuppressive drug primarily indicated for the reduction of immune response following organ transplantation to reduce the risk of rejection. The solubility of tacrolimus in water is 1-2 mg mL 61 , and thus has shown low oral bioavailability 62 . Solid dispersion systems for improved oral bioavailability of tacrolimus have recently been explored by Yamashita et al. 63 . These researchers evaluated solid dispersion systems of tacrolimus with PEG 6000, PVP, and HPMC in order...

Candida Infections

Candida can cause both exogenous and endogenous endophthalmitis. Candidal exogenous endophthalmitis is comparatively rare and usually occurs following eye surgery (keratoplasty, cataract extraction), traumatic ulcers, and contaminated ophthalmic irrigation solutions (117). Candida spp. commonly causes endogenous endophthalmitis particularly in the retina producing both retinal and vitreal lesions (118). It also causes cotton wool spots and white centered hemorrhages. Sometimes it can affect the...

Overcoming Severe Systemic Side Effects Pharmacokinetic Advantage

The severe systemic side-effects experienced by patients during lung cancer chemotherapy have the dual disadvantage of limiting the effectiveness of therapeutic regimens while significantly decreasing the patient's quality of life (16,17). During therapy, the delicate balance between patient tolerability and effectiveness of intravenously infused chemotherapy must be rigorously maintained, and any deviations can result in sub-optimal treatment. As a means of overcoming this obstacle, it would...

Aerosol Delivery To Treat Lung Cancer

To date, reports of aerosolized chemotherapy for the treatment of lung cancer and pulmonary metastases have been quite limited. Table 1 summarizes all known studies that have investigated local lung delivery of anticancer agents including cytotoxics, gene therapy, chemopreventative agents, Benzotaph, endoxan, thiophosphamid, cyclophosphan Mitomycin-C FU Liquid aerosol Intratracheal instillation Human 8 58 showed tumor disappearance, 6 58 significant reduction 1 of the 4 patients showed...

Future And Clinical Translation

Presently, lung cancer accounts for approximately one-third of cancer deaths, of which the vast majority of patients present or develop advanced lung cancer, and ultimately experience a rapid demise. Early trials with chemotherapy in NSCLC were quite disappointing, exhibiting a response rate of around 10-15 , and an approximate 5 week prolonged survival relative to supportive care. Moreover, in many cases chemotherapy regimens were found to be associated with worse results than supportive care...

Microparticles Nanoparticles Nanofibers and Nanotubes

The use of microparticles (> 1 m) and nanoparticles (< 1 m) as delivery vehicles for anticancer therapeutics has great potential to revolutionize the future of cancer therapy. Microparticles have been used a carrier system for anticancer drugs using different types of polymers, such as poly(d,l-lactic-co-glycolic acid) (PLGA). For example, sustained-release anastrozole-loaded PLGA microparticles have been developed for the long-term treatment of breast cancer (73). Nanoparticles have been...

Polymer Implants

Cancer chemotherapy is not always effective. Difficulties in drug delivery to the tumor, drug toxicity to normal tissues, and drug stability in the body contribute to this problem. Polymeric materials provide an alternate means for delivering chemotherapeutic agents. When anticancer drugs are encapsulated in polymers, they can be protected from degradation. Implanted polymeric pellets or injected microspheres localize therapy to specific anatomic sites, providing a continuous sustained release...

Ideal Pulmonary Delivery of Insulin

The concept of inhaled insulin was first introduced in 1925 where it was studied in five diabetic patients (18). Variability in bioavailability and system portability made pulmonary insulin delivery at the time unfeasible. Interest in pulmonary delivery resurfaced in the 1970s and 1980s in the clinical setting (19). With the advancements in drug delivery technology, the pulmonary delivery of insulin became more viable. Pulmonary delivery of insulin is ideal due to the large surface area of the...

Herpes Simplex Virus Infections

Two types of herpes simplex viruses (HSVs) can cause infections, HSV-1 and HSV-2. HSV-1 primarily affects the cornea causing herpes simplex keratitis. A variety of clinical manifestations such as infectious epithelial keratitis, follicular conjunctivitis, neurotrophic keratopathy, necrotizing stromal keratitis, immune stromal keratitis, and endothelitis are associated with HSV keratitis (11). Neurotrophic keratopathy results mainly from decreased corneal innervations and tear secretion as a...

Inhalation Aerosols

Modern inhalation aerosol therapies have been in existence since the 1950s, but only in recent times have considerable efforts been devoted to producing inhaled technologies with increased capabilities over their predecessors. For example, we have recently witnessed the FDA approval of the first non-injectable insulin product inhaled insulin, Exubera (11). Due to these efforts, understanding the dynamics of aerosols and their interactions with the lungs has recently borne witness to major...

Class II Beta Adrenegic Blockers

These agents exert antiarrhythymic effects by blocking sympathetic nervous system stimulation of beta receptors in the heart and decrease risks of ventricular fibrillation (5,6,9,15). These drugs diminish phase 4 depolarization, thus depressing automaticity, prolonging AV conduction, and decreasing heart rate and contractility (4,7). Blockage of receptors in the SA node and ectopic pacemaker decrease automaticity, and blockage of receptors in the AV node increase the refractory period. These...

Aerosolized Amphotericin B

Amphotericin B has been the most widely studied aerosolized antifungal agent thus far. One survey reported use of aerosolized amphotericin B as prophylaxis in 61 of transplant centers (65). However, variability exists between centers as to the formulation and dose administered and the aerosolization procedures (i.e. nebulizer) used. Several centers have reported the aerosolization of amphotericin B deoxycholate. Nebulized amphotericin B lipid complex has also been used and shown to be safe in...

Clinical Studies And Efficacy Exbera System

The efficacy and safety of Ex bera has been evaluated in over 4000 individuals with T1DM (4 studies) and T2DM (7 studies). Type 1 Diabetes Mellitus Skyler reported on two trials in T1DM. In a proof-of-concept trial conducted in 72 T1DM patients (41), a similar reduction in A1C was achieved when randomized to twice daily isophane insulin plus Exubera before meals versus once daily ultralente insulin plus SC regular insulin before meals (Table 4). Second, 328 patients with T1DM (baseline A1C...