Pharmacokinetic Studies with a Long-Acting sulfnamide in Subjects of Different Ages: A Modern Approach to Drug Dosage Problems in Developmental Pharmacology

Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6 µg kg–1 follitropin β, 6, 12 or 42 µg kg–1 corifollitropin α or 3, 6 or 12 µg kg–1 long acting protein/peptide discovery-follicle-stimulating hormone (LAPS-FSH). As a result, the animals treated with 12 µg kg–1 LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs.

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Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05429-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5560-5567 ◽

Cited By ~ 66

Author(s):

S. Thee ◽

J. A. Seddon ◽

P. R. Donald ◽

H. I. Seifart ◽

C. J. Werely ◽

...

Keyword(s):

World Health Organization ◽

Drug Dosage ◽

World Health ◽

Pharmacokinetic Studies ◽

First Line ◽

Time Curve ◽

Hiv Coinfection ◽

Acetylator Status ◽

The Mean ◽

Health Organization

ABSTRACTThe World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (Cmax), the time toCmax(tmax), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The meanCmax(μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The meanCmaxand AUC differed significantly between doses. There was no difference in thetmaxvalues achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.

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Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment

Blood ◽

10.1182/blood-2009-11-254755 ◽

2010 ◽

Vol 116 (2) ◽

pp. 270-279 ◽

Cited By ~ 164

Author(s):

Baisong Mei ◽

Clark Pan ◽

Haiyan Jiang ◽

Hendri Tjandra ◽

Jonathan Strauss ◽

...

Keyword(s):

Factor Viii ◽

Rational Design ◽

Hemophilia A ◽

Treatment Options ◽

Pharmacokinetic Studies ◽

Functional Assay ◽

Coagulation Activity ◽

Long Acting

Abstract A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A.

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Development of Long-Acting Injectable Ketamine Loaded PLGA Microparticles as a Non-opioid Analgesic

Proceedings of IMPRS ◽

10.18060/25777 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Juma N. Daniels ◽

Andrew Otte

Keyword(s):

Drug Release ◽

Release Kinetics ◽

Drug Loading ◽

Opioid Analgesic ◽

Aqueous Extraction ◽

Pharmacokinetic Studies ◽

Burst Release ◽

Processing Conditions ◽

Significant Difference ◽

Long Acting

Background/Objective: Ketamine, a psychedelic, is a noncompetitive N-methyl-D-aspartate receptor antagonist that may also bind to mu opioid receptors. Historically, it has been used as an anesthetic (KetalarÒ), although now has found uses as a novel, quick acting, antidepressant for treatment-resistant depression (SpravatorÒ) and could be used as an adjuvant to opioid analgesia providing opioid-sparing effects. One major advantage over opioids is Ketamine does not suffer from respiratory depression and maintains patent airways during anesthesia. Ketamine is only available as a short-acting injectable solution or a nasal spray. Our goal is to develop a long-acting injectable form in a biodegradable matrix poly(lactic-co-glycolic) acid (PLGA) that does not have a burst release and provides 5-7 days of steady-state plasma levels. Methods: A mechanistic approach towards development of a long-acting injectable began with a solubility screen of Ketamine. Based on these results, experiments began with an oil in water emulsification with two theoretical drug loadings (25% and 40%) and two processing conditions – (1) aqueous extraction and (2) aqueous extraction, intermediate drying, and a 25% Ethanol wash. The formulations were characterized for drug loading, drug release, and crystallinity and imaged using scanning electron microscopy (SEM). Results: Minimal differences were noted in the release profiles between formulations. Although, a significant difference was noted between the two processing conditions, where the extra intermediate drying step and 25% ethanol wash resulted in a significant slowing of the drug release rate. Conclusion and Implications: The difference in release kinetics is hypothesized to be due to densification of the PLGA matrix, based on the increase in surface roughness/wrinkling in the SEM images, crystallinity increase, and on their respective powder x-ray diffraction patterns. Our preliminary results demonstrate the feasibility of a longer acting Ketamine using PLGA. Further refinement of these formulations and rodent pharmacokinetic studies will be done in future.

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Radioimmunoassay of [d-Trp6]-luteinizing hormone-releasing hormone: its application to animal pharmacokinetic studies after single injection and long-acting formulation administration

Regulatory Peptides ◽

10.1016/0167-0115(86)90216-8 ◽

1986 ◽

Vol 14 (2) ◽

pp. 155-167 ◽

Cited By ~ 16

Author(s):

Eric Ezan ◽

Katy Drieu ◽

Maryvonne Chapelat ◽

Catherine Rougeot ◽

Fernand Dray

Keyword(s):

Luteinizing Hormone ◽

Single Injection ◽

Pharmacokinetic Studies ◽

Luteinizing Hormone Releasing Hormone ◽

Releasing Hormone ◽

Long Acting

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The Protective Effect of a Long-Acting and Multi-Target HM-3-Fc Fusion Protein in Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms19092683 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2683 ◽

Cited By ~ 3

Author(s):

Ruijing Huang ◽

Jian Li ◽

Yibo Wang ◽

Lihua Zhang ◽

Xiaohui Ma ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Fusion Protein ◽

Protective Effect ◽

Half Life ◽

Integrin Αvβ3 ◽

Current Treatment ◽

Pharmacokinetic Studies ◽

Long Acting

Current treatment of rheumatoid arthritis (RA) is limited by relative shortage of treatment targets. HM-3 is a novel anti-RA polypeptide consisting of 18 amino acids with integrin αVβ3 and α5β1 as targets. Previous studies confirmed that HM-3 effectively inhibited the synovial angiogenesis and the inflammatory response. However, due to its short half-life, the anti-RA activity was achieved by frequent administration. To extend the half-life of HM-3, we designed a fusion protein with name HM-3-Fc, by combination of modified Fc segment of immunoglobulin 4 (IgG4) with HM-3 polypeptide. In vitro cell experiments demonstrated that HM-3-Fc inhibited the proliferation of splenic lymphocytes and reduced the release of TNF-α from macrophages. The pharmacodynamics studies on mice paw in Collagen-Induced Arthritis (CIA) model demonstrated that HM-3-Fc administered once in 5 days in the 50 and 25 mg/kg groups, or once in 7 days in the 25 mg/kg group showed a better protective effect within two weeks than the positive control adalimumab and HM-3 group. Preliminary pharmacokinetic studies in cynomolgus confirmed that the in vivo half-life of HM-3-Fc was 15.24 h in comparison with 1.32 min that of HM-3, which demonstrated that an Fc fusion can effectively increase the half-life of HM-3 and make it possible for further reduction of subcutaneous injection frequency. Fc-HM-3 is a long-acting active molecule for RA treatment.

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