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PubMed1978

Ditheophylline succinate: transfer of theophylline across everted rat intestinal sacs.

The cumulative theophylline transfer rate across 10-cm everted rat intestinal sacs incubated at 37 degrees in pH 7.4 Krebs phosphate buffer was determined. A suspension of ditheophylline succinate ( a potential prodrug of theophylline) and a solution of theophylline at equimolar concentration were evaluated to determine the magnitude of the difference between the cumulative theophylline transfer rates from the two preparations. A linear concentration dependency for the rate across the intestinal wall was evidenced. The theophylline formation rate from ditheophylline succinate suspended in pH 7.4 Krebs buffer at 37 degrees followed apparent zero-order kinetics. The observed difference (fourfold) between the cumulative transfer rates estimated for the theophylline solution and the ditheophylline succinate suspention was attributed to the prevailing theophylline concentration in the mucosal solutions. The biopharmaceutical implication of these observations are discussed.

Animals↗

PubMed1982

Medicated tampons: intravaginal sustained administration of metronidazole and in vitro-in vivo relationships.

The technical feasibility of utilizing tampons as a drug delivery system for prolonged intravaginal drug administrations was studied. Several commercially available brands of tampons were examined. The methodology for the incorporation of various doses of metronidazole, an antitrichomonas agent, in tampons was described. The sustained-release profile of metronidazole from these medicated tampons was characterized. Intravaginal administration of metronidazole via the medicated tampons was investigated in rhesus monkeys and human volunteers, and in vitro-in vivo correlations were established. The biopharmaceutics of intravaginal absorption of metronidazole via medicated tampons was analyzed in comparison with a vaginal solution formulation.

Absorption↗

PubMed1989

Effect of temperature and fat content on the solubility of hydrochlorothiazide and chlorothiazide in milk.

The solubility of hydrochlorothiazide and chlorothiazide in milk has been studied. Experiments were carried out at 5, 15, 25, and 37 degrees C on a buffer solution of pH 6.5, a 2.6% solution of casein, bovine skim milk samples, and bovine milk samples with fat contents of 0.75, 1.70, and 3.50%. The "total" solubility of both drugs in the media studied was higher than the buffer solubility. The highest "total" solubility for both drugs was observed in skim milk. Based on binding data of thiazides to milk, the "total" solubility was split into "free" and "bound" solubility. The increases of solubility noted cannot be explained on the basis of drug-milk binding data. The enhancement of solubility was attributed to the increase of intrinsic solubility of drugs in milk. Results of the thermodynamic analysis of solubility data showed that a different solubilization process of hydrochlorothiazide may be responsible for the high solubility values found in skim milk for this drug. In contrast, the thermodynamic parameters of chlorothiazide in all types of milk are similar, indicating a common solubilization mechanism. The biopharmaceutical significance of the findings is discussed in light of the freeze-dried drug-milk formulations and coadministration of drugs with milk in general.

Animals↗

PubMed1993

Bioavailability and bioequivalence of two formulations of etodolac (tablets and suppositories).

We studied the influence of administration route on the biopharmaceutical behavior of etodolac. The levels obtained in plasma when the same dose of etodolac is administered orally (tablets, dosage form A) and rectally (suppositories, dosage form B) were compared. The study was done in a crossover design with healthy volunteers of both sexes, of average build, and younger than 35 years of age. From the concentration in plasma-time data, the maximum concentration in plasma (Cmax), time to Cmax, and area under the curve up to the last measurable concentration (AUC0t) or infinity (AUC 0 infinity) were calculated and compared by analysis of variance. With the exception of Cmax, no significant differences between treatments were found in the rest of the parameters. Finally, with formulation A (tablets) as a reference, the relative bioavailability was established, on the basis of the ratio (B:A) of AUC0t and AUC 9 infinity, within the range 100 +/- 20%. The results indicate that the two routes of administration are bioequivalent and that the rectal route is an alternative administration route for etodolac.

Adolescent↗

PubMed1995

Mathematical model and dimensional analysis of glycocholate binding to cholestyramine resin: implications for in vivo resin performance.

In large doses, cholestyramine resin lowers blood serum cholesterol by binding bile salts in the intestinal lumen and thus increases the fecal excretion of bile salts. In order to gain a better understanding of the low in vivo potency of cholestyramine, mathematical models estimating the amount of glycocholate bound per gram of cholestyramine and the free glycocholate concentration were derived and employ the capacity-corrected molar selectivity coefficient. Predictions of the quantity of glycocholate bound per gram of cholestyramine and of the free glycocholate concentration matched observed values (r2 = 0.993 and r2 = 0.998, respectively) over a wide range of conditions. Simulated binding studies indicated the relative importance of several biopharmaceutical parameters for improved resin in vivo performance. Increasing resin selectivity of glycocholate over chloride has greatest therapeutic impact if bile salt sequestering is most important in the upper portion of the intestines. Furthermore, ion exchange phenomena was subjected to dimensional analysis and revealed the controlling factors as components of two dimensionless numbers, GC* and Cl*. Placing physiologic limits on values of GC* and Cl* suggests requisite selectivity properties of more potent bile acid sequestrants and dosing strategies to optimize current resin therapy.

Binding Sites↗

PubMed2004

Synthetic peroxides as antimalarials.

The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

Antimalarials↗

PubMed2003

Comparison of the Escherichia coli proteomes for recombinant human growth hormone producing and nonproducing fermentations.

Two-dimensional electrophoretic analyses of Escherichia coli cells producing recombinant human growth hormone (Nutropin) in fermentations were conducted. The resulting two-dimensional protein profiles were compared with those of nonproducing (blank) cells. A qualitative comparison was performed to address regulatory issues in the biopharmaceutical industry, and a semiquantitative comparison was performed to reveal information about the physiological state of the cells. The protein spots unique to production fermentation profiles were all related to recombinant human growth hormone (hGH); these included intact hGH, charge variants of hGH, and a proteolytically cleaved form of hGH, as expected. There were no E. coli host cell proteins unique to either the production or blank fermentation profiles. Rather, all detectable differences in E. coli proteins were quantitative in nature. Specifically, the levels of IbpA (inclusion body binding protein A), Ivy (inhibitor of vertebrate lysozyme), and a cleaved form of GroEL (Hsp60 homolog) were higher in hGH production profiles, whereas the levels of GlmU protein and PspA (phage shock protein A) were higher in blank profiles. In general, the high degree of similarity between proteomes for hGH-producing and nonproducing cells suggests that E. coli proteins from a nonproducing (blank) fermentation are appropriate for eliciting antibodies that are then used in immunoassays to measure host cell proteins in samples from production fermentations.

Algorithms↗

PubMed2002

Approaching the problem of bioequivalence of herbal medicinal products.

Herbal medicinal products (HMP) contain exclusively herbal drugs or herbal drug preparations (HDP) and are a complex mixture of different compounds, which may act in an agonistic, synergistic, complementary, antagonistic or toxic way. A specific scientific challenge is for methods to prone the bioequivalence of herbal drug preparations (HDP). Depending on the type of herbal drug preparations, different approaches are possible. If the constituents responsible for therapeutic activity are known, the concept of essential similarity used with chemically defined substances can be fully applied. For extracts with unknown active markers, data on defined chemical constituents are useful for control purposes (charge conformity), but not sufficient to prove bioequivalence. In this case bioassays or pharmacological studies, which measure therapeutically relevant activity, should be used. A phytogeneric is only comparable to the innovator preparation under the following conditions: (i) pharmaceutical equivalence (standardization), (ii) biopharmaceutical equivalence (in vitro dissolution), (iii) bioequivalence with different endpoints (in vitro model, animal model) or (iv) clinical study. An uncritical substitution of herbal drug preparations without considering these scientific criteria should be avoided.

Chemistry, Pharmaceutical↗

PubMed2006

Operating characteristics of sample size re-estimation with futility stopping based on conditional power.

Various methods have been described for re-estimating the final sample size in a clinical trial based on an interim assessment of the treatment effect. Many re-weight the observations after re-sizing so as to control the pursuant inflation in the type I error probability alpha. Lan and Trost (Estimation of parameters and sample size re-estimation. Proceedings of the American Statistical Association Biopharmaceutical Section 1997; 48-51) proposed a simple procedure based on conditional power calculated under the current trend in the data (CPT). The study is terminated for futility if CPT < or = CL, continued unchanged if CPT > or = CU, or re-sized by a factor m to yield CPT = CU if CL < CPT < CU, where CL and CU are pre-specified probability levels. The overall level alpha can be preserved since the reduction due to stopping for futility can balance the inflation due to sample size re-estimation, thus permitting any form of final analysis with no re-weighting. Herein the statistical properties of this approach are described including an evaluation of the probabilities of stopping for futility or re-sizing, the distribution of the re-sizing factor m, and the unconditional type I and II error probabilities alpha and beta. Since futility stopping does not allow a type I error but commits a type II error, then as the probability of stopping for futility increases, alpha decreases and beta increases. An iterative procedure is described for choice of the critical test value and the futility stopping boundary so as to ensure that specified alpha and beta are obtained. However, inflation in beta is controlled by reducing the probability of futility stopping, that in turn dramatically increases the possible re-sizing factor m. The procedure is also generalized to limit the maximum sample size inflation factor, such as at m max = 4. However, doing so then allows for a non-trivial fraction of studies to be re-sized at this level that still have low conditional power. These properties also apply to other methods for sample size re-estimation with a provision for stopping for futility. Sample size re-estimation procedures should be used with caution and the impact on the overall type II error probability should be assessed.

Clinical Trials as Topic↗

PubMed1992

Sixteen S-squared over D-squared: a relation for crude sample size estimates.

I suggest for memorization an equation for calculating approximate sample size requirements intended only for a specific set of values (80 per cent power for a two-tailed alpha = 0.05 test) which seems to occur often in biopharmaceutical research. After presenting the formula in terms of variance estimate s2 and effect size d, I derive a few alternative forms and then discuss the accuracy of the approximation and other properties as well as examples of its use.

Drug Evaluation↗

PubMedDate not supplied

Computational aspects of analysing random effects/longitudinal models.

Random effects and longitudinal models are becoming increasingly popular in the analysis of many types of data, including medical and biopharmaceutical, because of their richness and flexibility. They can be, however, difficult to fit using traditional statistical tools. Fortunately, there now exists a burgeoning collection of newer computational methods that can be applied to draw inferences with such models. This review attempts to provide an introduction to some of these techniques by describing them as extensions of the EM algorithm, currently a standard tool for the analysis of longitudinal and random effects models. For clarity of exposition, the extensions are classified into three types: large-sample iterative; large-sample simulation, and small-sample simulation.

Longitudinal Studies↗

PubMed2000

Development of improved high-performance liquid chromatography conditions for nonisotopic detection of isoaspartic acid to determine the extent of protein deamidation.

A rapid and accurate ion-pairing reversed-phase high-performance liquid chromatography (IP-RP-HPLC) procedure has been developed for nonisotopic detection of isoaspartic acid residues in protein or peptides resulting from deamidation of asparagine residues. The IP-RP-HPLC procedure specifically detects and quantifies S-adenosylhomocysteine (SAH). SAH is a by-product of the reaction between protein isoaspartyl methyltransferase (PIMT), S-adenosylmethionine (SAM), and isoaspartic acid residues. The HPLC conditions described in this paper have been demonstrated to offer significantly better reproducibility compared to earlier studies. The HPLC method allows determination of the extent of protein deamidation without the use of radioisotopes and therefore offers significant advantages for biopharmaceutical development laboratories.

Animals↗

PubMed2000

Bioluminescence detection of proteolytic bond cleavage by using recombinant aequorin.

Detection of proteolytic bond cleavage was achieved by taking advantage of the bioluminescence emission generated by the photoprotein aequorin. A genetically engineered HIV-1 protease substrate was coupled with a cysteine-free mutant of aequorin by employing the polymerase chain reaction to produce a fusion protein that incorporates an optimum natural protease cleavage site. The fusion protein was immobilized on a solid phase and employed as the substrate for the HIV-1 protease. Proteolytic bond cleavage was detected by a decrease in the bioluminescence generated by the aequorin fusion protein on the solid phase. A dose-response curve for HIV-1 protease was constructed by relating the decrease in bioluminescence signal with varying amounts of the protease. The system was also used to evaluate two competitive and one noncompetitive inhibitor of the HIV-1 protease. Among the advantages of this assay is that by using recombinant methods a complete bioluminescently labeled protease recognition site can be designed and produced. The assay yields very sensitive detection limits, which are inherent to bioluminescence-based methods. An application of this system may be in the high-throughput screening of biopharmaceutical drugs that are potential inhibitors of a target protease.

Aequorin↗

PubMed1994

Protein purification: aspects of processes for pharmaceutical products.

The concept of purity is addressed for proteins as drugs. In addition to a short description of general techniques, emphasis is given to a discussion of special protein impurities and contaminants from the host cell of process additives. This includes the host homologue to the product and biologically active molecules and the quantitation of host cell proteins. Of special concern are closely related non functional proteins from the gene for the protein product itself. They pose the question of how a 'pure' protein can be defined, and to what extent potential heterogeneities caused by the purification method represent a risk. Most relevant are 'invisible' contaminants such as potential virus including the BSE agent. Critical aspects will be discussed of the current rationale for a strategy to arrive at safe biological products. The limitations of current virus enumeration methods are discussed in relation to technical limitations to prove the efficiency of virus removal steps. Another limitation is the nature of the protein product and its individual resistance to denaturing conditions in virus inactivation steps. This is amply demonstrated by the lack of methods for inactivation of the BSE agent maintaining the native state of proteins. As a general recommendation it is proposed to base risk assessment on scientific data and come to scientifically defined criteria of acceptance in both the global and national communities. This will facilitate bringing new biopharmaceuticals to the benefit of patients in the shortest period of time.

Animals↗

PubMed1997

A rapid and simple procedure to detect the presence of MVM in conditioned cell fluids or culture media.

During the manufacture of biopharmaceuticals, numerous adventitious agents have been detected in Master Cell Banks, end-of-production cells as well as bulk harvest fluid. Recently, a number of large-scale production bioreactors have become infected with Minute Virus of Mice (MVM) during cGMP (current good manufacturing practices) operations, and this has resulted in both the loss of product and the need for major cleaning validation procedures to be put in place. We have developed a simple DNA extraction/PCR assay to detect the presence of MVM in cell culture supernatant (conditioned cell fluids). This highly specific assay can detect 10 or fewer genome equivalents (copies) of MVM following PCR and gel electrophoresis visualization. For routine high-throughput detection, 300-100 copies could be consistently detected. The extraction procedure was shown to reliably detect MVM at a concentration of 1 TCID50/ml. The combination of the extraction/PCR procedure establishes a powerful, sensitive, specific assay that can detect the presence of MVM sequences with a 1-day turnaround time.

Animals↗

PubMed2001

Residual DNA quantification in clinical batches of BBG2Na, a recombinant subunit vaccine against human respiratory syncytial virus.

BBG2Na, a well-defined recombinant protein produced in Escherichia coli, is a promising human respiratory syncytial virus subunit vaccine candidate. This study describes the quantification of residual DNA in large scale batches used in phase I to III clinical trials. Two different analytical methods were developed and applied on five different final bulks of Drug Substance and their associated in process control samples, namely a chemiluminescent hybridisation assay and the total DNA Threshold System assay. These two complementary methods demonstrated the clearance of residual DNA during the downstream purification process. The amount of residual DNA found in the final bulks was below 20 pg of DNA per 300 microg BBG2Na, the highest tested clinical dose of antigen. This is very low level of residual DNA for a recombinant subunit vaccine produced in a bacteria and contribute to make for BBG2Na a well-characterised biopharmaceutical. This study also provides data concerning the validation of the hybridisation dot blot assay and the total DNA Threshold(trade mark)assay.

Clinical Trials as Topic↗

PubMed2001

Modulation of antigenicity related to changes in antibody flexibility upon lyophilization.

Lyophilization is frequently used to increase the shelf-life of biopharmaceuticals containing antibodies. A case in which an anti-idiotypic antibody, MMA 383, substantially lost its in vivo immunogenic properties although the protein was not degraded, is investigated. The scanning transmission electron microscope allowed the MMA 383 Fab and Fc moieties to be resolved. By averaging the single antibodies, the angle between the Fab moieties can be calculated. Non-lyophilized antibodies displayed a wider range of shapes than their reconstituted, lyophilized counterparts. Accordingly, the angle between the two Fab fragments varied more, indicating greater flexibility. The tryptophan steady-state fluorescence intensity, steady-state fluorescence anisotropy and fluorescence lifetime, were smaller for the lyophilized antibodies. These were also more resistant towards thermal denaturation/aggregation. Circular dichroism spectra detected temperature-dependent differences between the two antibody types in the 236 nm region. The subtle but reproducible structural changes induced by lyophilization may be related to the loss of in vivo immunogenic properties.

Antibodies, Anti-Idiotypic↗

PubMed2002

Tumor growth inhibition by interferon-alpha using PEGylated protein or adenovirus gene transfer with constitutive or regulated expression.

Inducible synthesis and secretion of therapeutic proteins following gene transfer could be a viable strategy to deliver biopharmaceuticals that currently require parenteral administration. Evaluating the protein pharmacokinetics and biological responses generated by different delivery modalities will provide a better understanding of the advantages and disadvantages of each strategy. The interferon-alpha (IFN-alpha) family of proteins, used clinically for infectious and malignant diseases, has a short half-life, and IFN-alpha therapy requires frequent administration of the drug by injection. Subcutaneous xenograft tumors were inhibited by weekly administration of polyethylene glycol modified (PEGylated) IFN-alpha protein or by a single administration of an adenovirus constitutively expressing IFN-alpha (IACB). Both treatment modalities inhibited tumor growth in a dose-dependent manner, suggesting that increasing exposure to IFN-alpha could result in effective tumor control. A single adenovirus that encodes the components necessary for tetracycline induction (IADR) expressed IFN-alpha in a ligand-dependent manner. Adding doxycycline to the drinking water of mice treated intravenously with the inducible adenovirus IADR inhibited tumor growth by 85% compared with mice that were not given doxycycline. The correlation between serum IFN-alpha concentration and the degree of tumor growth inhibition did not depend on the delivery technology used. It is likely that it will be feasible to control expression of IFN-alpha by oral administration of small molecule drugs after gene delivery to induce therapeutic concentrations of proteins.

Adenoviridae↗