Parenteral Administration Of Drug Research Articles

A REVIEW ON: ATRIGEL–THE MAGICAL TOOL

The widely effective and most common form of drug delivery is parenteral administration for active drug substances with poor bio-availability and the drugs with a narrow therapeutic index. Though parenteral administration of drug is often critical and associated with problems such as limited number of acceptable excipients, stringent requirements of aseptic production process, safety issues, patient noncompliance. Still this route maintains its value due to special advantages like quicker onset of action in case of emergency, target the drug quickly to desired site of action, prevention of first pass metabolism etc. The application of advanced drug delivery technology to parenteral administration lead to development of liposomes, nanosuspensions, solid implants etc. to overcome limitations of conventional parenteral delivery. Solid implants are reported to produce very reproducible release profiles. However, because of their size, they require surgical implantation or the use of large trochars to administer the product. Delivery systems consisting of microparticles can be injected into the body using conventional needles and syringes and have been the most widely accepted biodegradable polymer system for parenteral use. However, the manufacturing processes for microparticles are often complex and difficult to control leading to batch-to-batch product non uniformity. These methods of administration often limit the product's market potential due to patient and physician acceptance issues. Therefore, a delivery system that combines the simplicity and reliability of solid implant devices alongwith convenience and ease of administration of microparticles is desired. In situ gel forming systems represent a desired alternate. This article gives the idea about In situ gel forming system to provide drug release in sustained release manner.

A Review on: Atrigel-The Magical Tool

The widely effective and most common form of drug delivery is parenteral administration for active drug substances with poor bio-availability and the drugs with a narrow therapeutic index. Though parenteral administration of drug is often critical and associated with problems such as limited number of acceptable excipients, stringent requirements of aseptic production process, safety issues, patient noncompliance. Still this route maintains its value due to special advantages like quicker onset of action in case of emergency, target the drug quickly to desired site of action, prevention of first pass metabolism etc. The application of advanced drug delivery technology to parenteral administration lead to development of liposomes, nanosuspensions, solid implants etc. to overcome limitations of conventional parenteral delivery. Solid implants are reported to produce very reproducible release profiles. However, because of their size, they require surgical implantation or the use of large trochars to administer the product. Delivery systems consisting of microparticles can be injected into the body using conventional needles and syringes and have been the most widely accepted biodegradable polymer system for parenteral use. However, the manufacturing processes for microparticles are often complex and difficult to control leading to batch-to-batch product non uniformity. These methods of administration often limit the product's market potential due to patient and physician acceptance issues. Therefore, a delivery system that combines the simplicity and reliability of solid implant devices alongwith convenience and ease of administration of microparticles is desired. In situ gel forming systems represent a desired alternate. This article gives the idea about In situ gel forming system to provide drug release in sustained release manner.

REVIEW ON PARENTRAL DRUG DELIVERY SYSTEM: A NOVEL APPROACH

Drug delivery is a process that includes dosage form and route of administration. It refers to procedures or approaches for transporting pharmaceutical compound in the body safely to achieve its therapeutic effect. The Parenteral drug delivery system is the most common and efficient for delivery of active drug substances with poor bio-availability and the drugs with a narrow therapeutic index. Though parenteral administration of drug is often critical and associated with problems such as limited number of acceptable excipients, stringent requirements of aseptic production process, safety issues, and patient noncompliance. Still this route maintains its value due to special advantages like quicker onset of action in case of emergency; target the drug quickly to desired site of action, prevention of first pass metabolism etc. The application of advanced drug delivery technology to parenteral administration lead to development of SLNs, liposomes, niosomes, lipid nano dispersions etc. to overcome limitations of conventional parenteral delivery.Drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also to improve the quality of the therapy. Such reduction in frequency of drug dosing is achieved by the use of specific formulation technologies that guarantee the release of the active drug substance in a slow and predictable manner. The development of new injectable drug delivery system has received considerable attention over the past few years.

Cross sectional questionnaire-based internet study: Self-perception and clinical course of drug allergy in Greece

BackgroundData on self perception of drug allergy in the general population are lacking. Epidemiological studies focus either on specific populations or document adverse drug reactions in general. Our objective was to document self-reported drug allergy in Greece, through a simple, informative internet-based questionnaire. MethodsA questionnaire on drug allergy was accessible online for a 3-month period. Participants voluntarily answered 28 questions referring to: suspected drug, clinical manifestations, concomitant factors, received treatment, reaction's re-occurrence. ResultsA total of 2528 questionnaires were included in study analysis. Beta-lactams and non-steroidal anti-inflammatory drugs were the most prevalent culprit agents (53% and 27.5% respectively) while half of the participants acknowledged skin manifestations as the most common symptoms. One out of three reported subsequent exposure to the drug presumed to be responsible for the reaction and 74.5% of those stated a new reaction upon re-exposure. Only 26.7% underwent allergological evaluation. Reactions manifested with respiratory or cardiovascular symptoms, parenteral administration of the culprit drug and personal history of allergy to agents of >1 different pharmacological categories were associated with increased risk of hospitalization. ConclusionsAllergic reactions to drugs are adverse events difficult to define and diagnose. A remarkable proportion of presumed as hypersensitivity reactions are not referred to allergists; therefore these patients may be either re-exposed to potentially noxious drugs, or needlessly avoid whole classes of drugs as b-lactams for more costly or less appropriate treatments. Internet-based questionnaires may contribute to awareness programs concerning drug allergy and help improve proper referral.

STERILE PARENTERAL PRODUCTS: A NARRATIVE APPROACH

One of the first group’s toaddress these patient safety issues was the NationalCoordinating Committee on Large Volume Parenteral (NCCLVP). Parenteral medications are products which are introduced in a manner which circumvents the body’s most protective barriers, the skin and mucous membranes, and, therefore, must be “essentially” free of biological contamination. Most are injected or placed into the body tissues and do not pass thru the liver before entering the bloodstream. This can include injections, topical and inhalation routes. Generally in pharmacy, parenteral refers to injection and the topical and inhalation routes are separated into their own routes of administration. NCCLVP was established by the US Pharmacopeia Convention, Inc., and subsequently developedand recommended standards of practice for the preparation, labeling, and quality assurance of hospital pharmacyadmixture services. Parenteral administration of drug is often critical and associated with problems such as limited number of acceptable excipients, stringent requirements of aseptic production process, safety issues, and patient noncompliance. Still this route maintains its value due to special advantages like quicker onset of action in case of emergency; target the drug quickly to desired site of action, prevention of first pass metabolism etc. This review highlightsformulation of parenteral product and advanced techniques involved in parenteral products.  Keywords: NCCLVP, LVP, Aseptic area, GMP etc.

Carrier-based drug delivery system for treatment of acne.

Approximately 95% of the population suffers at some point in their lifetime from acne vulgaris. Acne is a multifactorial disease of the pilosebaceous unit. This inflammatory skin disorder is most common in adolescents but also affects neonates, prepubescent children, and adults. Topical conventional systems are associated with various side effects. Novel drug delivery systems have been used to reduce the side effect of drugs commonly used in the topical treatment of acne. Topical treatment of acne with active pharmaceutical ingredients (API) makes direct contact with the target site before entering the systemic circulation which reduces the systemic side effect of the parenteral or oral administration of drug. The objective of the present review is to discuss the conventional delivery systems available for acne, their drawbacks, and limitations. The advantages, disadvantages, and outcome of using various carrier-based delivery systems like liposomes, niosomes, solid lipid nanoparticles, and so forth, are explained. This paper emphasizes approaches to overcome the drawbacks and limitations associated with the conventional system and the advances and application that are poised to further enhance the efficacy of topical acne formulations, offering the possibility of simplified dosing regimen that may improve treatment outcomes using novel delivery system.

Optimization of the adult zebrafish ECG method for assessment of drug-induced QTc prolongation

IntroductionRecent studies have shown the utility of adult zebrafish ECG (electrocardiogram) in assessing drug-induced QTc prolongation. While the method has significant advantages over current ECG animal models including ethical issues, low compound requirement and expense, adoption of the method into drug discovery programs has been hampered by specific limitations. The limitations include the inability to determine the exact dose of test compound administered, and potential effects due to variables such as flow rate of oral perfusion and immobilization method. We describe a refined method for the reproducible recording of the adult zebrafish ECG and illustrate its application in investigating drug-induced QTc prolongation using the histamine receptor antagonist Terfenadine as a test drug. MethodWe chose to perform parenteral administration of test drug instead of perfusion on the basis of mg per kg body weight of adult zebrafish. Acclimatization and immobilization methods were optimized to avoid ECG artifacts due to sudden environmental changes. We further modified the formula for QT correction and ensured reproducible recording of stable ECGs. Various concentrations of Terfenadine were used and the resultant proarrhythmic effects were analyzed as compared to the baseline and untreated controls. ResultsNormal, stable and reproducible ECGs were recorded in all zebrafish. Terfenadine at the rate of 0.1mg/kg body weight was found to be the NOAEL. We found an excellent correlation between known QTc effects in humans and those observed in adult zebrafish at all concentrations. All Terfenadine-induced proarrhythmic effects observed in zebrafish were dose and time dependent. DiscussionWe report a refined method for reproducible recording of stable zebrafish ECGs to facilitate its routine application in preclinical investigation of QTc-prolonging drugs with reliable estimation of NOAEL. Our study is of relevance to the development and use of alternate animal models in drug discovery.

Effect of Ketoconazole on the Pharmacokinetic Profile of Buprenorphine following Administration of a Once-Weekly Buprenorphine Transdermal System

Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10 μg/hour (BTDS 10). This single-centre study enrolled 20 healthy subjects who had demonstrated ketoconazole-mediated CYP3A4 inhibition via an erythromycin breath test. Subjects were randomized into a placebo-controlled, two-treatment, two-period crossover study. Subjects participated in a 7- to 14-day screening period, two baseline evaluations (day 0 [period 1] and day 16 [period 2]), two 12-day treatment periods (periods 1 and 2) separated by a 4-day washout period, and a study completion visit. Subjects received one BTDS 10 for 7 days per treatment period, administered concomitantly with either ketoconazole 200 mg twice daily or matching placebo. The main outcome measures were the ratios of geometric means for area under the plasma drug concentration versus time curve (AUC) from time zero to time of last measurable concentration (AUC(last)), AUC from time zero to infinity (AUC(∞)), and maximum plasma drug concentration (C(max)). The ratio of geometric means (BTDS 10 with ketoconazole/BTDS 10 with placebo) was 99.4 (90% confidence interval [CI] 87.2, 113.3) for AUC(last) and 97.8 (90% CI 87.7, 109.1) for C(max). The ratio of geometric means for AUC(∞) was 86.7 (90% CI 70.7, 106.2). The plasma concentrations of the metabolites norbuprenorphine and norbuprenorphine-3β-glucuronide were slightly elevated following ketoconazole administration. BTDS 10 with ketoconazole was well tolerated and no apparent safety concerns were noted. The lack of a clinically significant CYP3A4 interaction with ketoconazole following transdermal delivery of buprenorphine is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects. Metabolism of buprenorphine during therapy with BTDS is also not expected to be affected by co-administration of other CYP3A4 inhibitors.

Encapsulation enhancement and stabilization of insulin in cationic liposomes

The purpose of this study was to enhance encapsulation efficiency and sustained-release delivery for parenteral administration of a protein drug. To reduce the administration frequency of protein drugs, it is necessary to develop sustained delivery systems. In this study, protein drug-loaded cationic liposomes were formulated with dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), dioleoyl-3-trimethylammonium-propane (DOTAP), and cholesterol (CH) at a molar ratio of DOPE/DOTAP/CH of 2/1.5/2. Five mol% of distearoylphosphatidyl ethanolamine polyethylene glycol (DSPE-PEG) was added prior to encapsulation of the drug into liposomes. Insulin was chosen as a model protein drug and encapsulation efficiency was evaluated in various liposomes with and without DSPE-PEG. Scanning electron microscopy was used to examine the insulin-loaded cationic liposomes. Structural analysis was performed using spectropolarimetry. Additionally, the stability and cytotoxicity of insulin-loaded cationic liposomes were evaluated. Liposomes coated with DSPE-PEG showed higher insulin encapsulation efficiency than did those without DSPE-PEG, but not significantly. Moreover, among the liposomes coated with DSPE-PEG, those hydrated with 10% sucrose showed higher encapsulation efficiency than did liposomes hydrated in either phosphate-buffered saline or 5% dextrose. In vitro release of insulin was prolonged by cationic liposomes. Our findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of protein and peptide drugs to prolong efficacy and improve bioavailability.

Toxidermies immunoallergiques chez l’immunocompétent

Cutaneous adverse drug reactions (CADR) are induced by the parenteral, oral, subcutaneous or intramuscular administration of a non-tolerated drug. A strict management of patients suffering from CADR is necessary and must include a description of the clinical features, photography, a chronological table drawn at the onset of the CADR in order to determine which drug is involved in the adverse effect. Urticaria can be due to an allergological or pharmacological mechanism. Vasculitis are related to circulating immune complexes and cannot be reproduced by skin tests. Maculopapular rash is the most common CADR can be difficult to distinguish from a viral rash or a transient drug intolerance during a viral infection. Drug rash with eosinophilia and systemic symptoms (DRESS) can be associated with a severe liver cytolysis. Long lasting relapses of DRESS could be due to secondary reactivation of the human herpes virus 6. Stevens Johnson syndrome and Lyell’s syndrome are due to a keratinocyte apoptosis, with not well elucidated mechanisms. Six months after a CADR, skin tests can be performed in order to determine which drugs have to be forbidden or may be allowed for the patient.

In vitro and in vivo effects of the anti-inflammatory peptides, antiflammins

The anti-inflammatory synthetic polypeptides referred to as antiflammins are thought to be inhibitors of phospholipase A 2 (PLA 2) (EC 3.1.1.4). These peptides are from the sequence of amino acids of greatest similarity between uteroglobin and lipocortin I. The effect of these peptides was studied on PLA 2 activation in rat platelets and on acute inflammatory models after local or parenteral administration of drug. We found that antiflammins decreased collagen-induced platelet activation, but had no effect when arachidonic acid was used as activator. The peptides were able to inhibit acute inflammatory processes induced by carrageenan or phorbol esters when administered locally or parenterally. However, antiflammins had no effect on inflammation induced by exogenous PLA 2 administration. These results indicate that the antiflammins may have a direct inhibitory effect on PLA 2 activation but not on the enzyme or enzyme-substrate interaction.

The effect of pentamidine salts on the respiratory burst of human neutrophilic granulocytes

Therapeutic concentrations (0.3-1.5 mg/l) of pentamidine isethionate and pentamidine mesylate, obtained after parenteral administration of either drug, did not affect oxygen consumption in the stimulated neutrophilic granulocyte. At concentrations of 0.7, 1.1 and 1.5 mg/l, superoxide production, hydrogen peroxide production, myeloperoxidase (MPO)-mediated iodination and hexose monophosphate shunt activity were suppressed relative to untreated cells (P less than 0.001 in each case). The depression in each activity was dose-related. There was no significant difference between the drugs with regard to these impairments in neutrophilic granulocyte function. This lowered respiratory burst activity, which would lead to a depression of MPO-dependent and MPO-independent processes in stimulated neutrophilic granulocytes, may be due to drug induced dysfunction of NADPH-oxidase.

Pharmacokinetics and pharmacodynamics of bromocriptine in the rat

The absorption, distribution, and excretion of bromocriptine were studied following oral and parenteral administration of non-radioactive and 14C-labelled drug in the rat. Total radioactivity was measured in blood, tissues, and excreta by liquid scintillation counting while the parent drug was determined in plasma and selected tissues by radioimmunoassay. The pharmacokinetic observations were compared with the time course of drug-induced hypothermia in cold-room acclimatized rats. The results indicated that oral doses of bromocriptine were rapidly, though incompletely (32-40 per cent), absorbed, but underwent extensive first-pass metabolism, resulting in an absolute bioavailability of only 6 per cent. The bioavailability increased to approximately 22 per cent in rats pretreated with the hepatic microsome inhibitor proadifen, thus suggesting the liver as the principal site of biotransformation. Absorbed bromocriptine showed preferential distribution into the tissues, although no apparent accumulation of drug-related material occurred in the body. The drug was eliminated almost exclusively by metabolism and biliary excretion into the faeces. Comparison of the pharmacodynamic and the pharmacokinetic profiles indicated a dose relationship between hypothermia and plasma bromocriptine concentrations but not total radioactivity levels. The hypothermic response was also intensified by proadifen pretreatment, thus confirming the parent drug as the pharmacologically active entity. It is believed that the previously reported delay in the onset of bromocriptine activity is not pharmacokinetic in nature, but is related to the properties of the receptors at the target site or to the pharmacologic events that result in the observed effects.

Efficacy of the avermectins against filarial parasites: a short review.

The avermectins are macrocyclic lactones produced by Streptomyces avermitilis. One of them has been chemically modified and given the non-proprietary name ivermectin. The compounds have shown efficacy against various stages of filarial parasites. With respect to pre-adult stages in the mammalian host, activity has been observed against Dirofilaria immitis in ferrets and dogs, and Dipetalonema viteae and Litomosoides carinii in jirds (Meriones); but activity has not been observed against the developing stages of Brugia spp. in jirds or Onchocerca spp. in cattle. The compounds have not shown activity against adult filarial worms, except in the case of Setaria equina in horses and possibly Dipetalonema viteae in jirds. With respect to the first state larva (microfilaria) in the mammalian host, efficacy has been observed against Dirofilaria immitis in dogs, Brugia malayi in multimammate rats (Mastomys), Dipetalonema viteae and Litomosoides carinii in jirds and Onchocerca spp. in horses and cattle; but activity has not been observed against microfilariae of Brugia pahangi in jirds or cats. Efficacy against filarial parasites has been observed following oral or parenteral administration of drug, sometimes at extremely low dosage. For example, a single oral dosage of 0.05 mg/kg was highly active against the third and fourth larval stages and microfilariae of D. immitis in dogs.

Fat emulsion vehicle for intravenous administration of an aqueous insoluble drug

Formulation of a sterile preparation for the parenteral administration of a water insoluble drug is described. Methyl CCNU was first dissolved in absolute alcohol and slowly added to a fat emulsion, Intralipid. The preparation was found to be stable for eight hours at room temperature and seven days under refrigeration. After administration of the preparation to approximately 100 patients, no significant side effects were attributed to the fat emulsion.

Das Verteilungsmuster des Chlorphentermins bei Ratte, Kaninchen und Schwein

Plasma concentrations and tissue distribution of chlorphentermine were determined in the rat, the rabbit and the pig after the parenteral administration of the drug. A sensitive and specific method was developed for the determination of chlorphentermine in biological fluids based on solvent extraction and gas chromatography. It can be also applied to the analysis of other anorectic drugs.

The use of sulfamerazine in infants and children

Summary A study of the absorption, methods of administration, therapeutic effectiveness, and toxicity of sulfamerazine in an unselected group of 135 infants and children with infections revealed the following pertinent data: 1. Sulfamerazine is rapidly absorbed from the gastrointestinal tract and rather slowly excreted by the kidney. Accordingly, adequate blood concentrations are easily attained by the oral administration of 0.05 Gm. per kilogram of body weight every eight hours (three-quarters of the total daily dosage usually employed with sulfathiazole and sulfadiazine). Sulfamerazine thus possesses an advantage over the other sulfonamide drugs in that they must be given in larger total dosage with more frequent doses to attain comparable blood levels. 2. High blood concentrations are easily and rapidly produced by the subcutaneous administration of sodium sulfamerazine. The absorption of sulfamerazine from the gastrointestinal tract, although more rapid and complete than is the absorption of the other sulfonamide drugs, does not lead to values sufficiently high to obviate the need for parenteral administration of the drug when very high values are desired. 3. Sulfamerazine was observed to pass into the spinal fluid to the extentof from 52 to 83 per cent of the whole blood value and 41 to 73 per cent of the plasma value, while the concentration in pleural and ascitic fluid equaled that in the plasma. 4. From a purely clinical evaluation, the therapeutic effectiveness of sulfamerazine is entirely comparable to that of sulfapyrazine, sulfadiazine and, sulfathiazole. 5. The toxic reactions encountered were relatively frequent but, for the most part, were mild, and no serious reactions occurred. On the basis of our past experience, the frequency of toxic reactions was definitely greater with the use of sulfamerazine than with sulfapyrazine and certainly as great as with sulfadiazine.