Section 2 ‘Brufen’ in the short-term treatment of rheumatoid arthritis

Summary

In a short-term double-blind crossover trial in 100 patients with rheumatoid arthritis, 1200?mg. ibuprofen daily was compared with 600?mg. phenylbutazone daily. Subjective and objective assessments showed little difference in analgesic effectiveness of the two drugs, but ibuprofen produced a significant improvement in grip strength and in the class of functional disability. Side-effects were substantially fewer during ibuprofen treatment.     

Section 2 Fenoprofen in the treatment of osteoarthrosis

Summary

Three controlled trials were carried out in a total of 58 patients with osteoarthrosis to assess the effectiveness of and patient preference for fenoprofen compared with paracetamol, ibuprofen and phenylbutazone. Subjective assessments of pain relief showed fenoprofen to be superior to paracetamol and placebo, and that it provided slightly better and more effective treatment than ibuprofen. These differences, however, were not statistically significant, neither was that between the subjective and objective assessments of fenoprofen and phenyibutazone.     

Section 3 Ibuprofen (‘Brufen’) in the treatment of ankylosing spondylitis

Summary

Sixty-five patients with ankylosing spondylitis, all of whom were intolerant of or had failed to respond to previous therapy with phenylbutazone or indomethacin, were treated with 1200?mg. ibuprofen daily for at least 2 months. Clinical or subjective improvement was noted in 32 (49%), and the drug was well tolerated by all the patients, including 14 with gastro-intestinal disorders.     

Section 2 Nephropathies in rheumatic diseases: therapeutic problems

Summary

Many of the connective tissue disorders are associated with renal pathology. Lupoid nephropathy is well documented, but 15 % of cases of rheumatoid disease also develop renal lesions, and of these patients 25 % die of renal failure. All this justifies an approach to the problem under the heading of ‘rheumatoid nephropathy’.

In such cases it is difficult to ascertain whether the renal lesions are due to the disease process or to previous medication. In the antirheumatic group of drugs gastro-intestinal upsets, skin rashes and cardiovascular problems are well recognised, but not the nephrotoxic potential of the drugs.

Groups of patients were chosen suffering from rheumatoid arthritis, rheumatic fever or systemic lupus erythematosus. The patients studied were being treated with either corticosteroids, gold salts, phenylbutazone or antimalarials. In a similar fashion, a group of 50 patients were treated for 6 weeks with ibuprofen, and two separate groups of 15 patients were treated with either antimalarials plus prednisolone, or antimalarials plus ibuprofen. Blood urea and creatinine clearance were measured and the urine examined for leucocytes, microscopic haematuria and proteinuria. The investigations were carried out before and after treatment and any correlation between therapy and renal abnormalities were noted.

It was found that most of the routinely used antirheumatic drugs tended to enhance renal problems but that following treatment with ibuprofen no adverse effects on renal function were noted that could be attributed to the drug. Proteinuria decreased in patients on corticosteroids and antimalarials, but the reduction was more marked with ibuprofen in cases with pre-existing nephrotic syndrome, pyelonephritis, and renal amyloidosis. Ibuprofen significantly decreased urinary leucocyte excretion whereas corticosteroids and phenylbutazone caused no obvious change. Microscopic haematuria persisted in those patients receiving corticosteroids, actually increased with phenylbutazone, but decreased with antimalarials and particularly so with ibuprofen.     

Species Differences of Serum Albumins: I. Drug Binding Sites

Purpose. The purpose of this study was the classification and identification of drug binding sites on albumins from several species in order to understand species differences of both drug binding properties and drug interaction on protein binding. Methods. Binding properties and types of drug-drug interaction on the different albumins were examined using typical site I binding drugs, warfarin (WF) and phenylbutazone (PBZ), and site II binding drugs, ibuprofen (IP) and diazepam (DZ) on human albumin. Equilibrium dialysis was carried out for two drugs and the free concentrations of drugs were then treated using the methods of Kragh-Hansen (Mol. Pharmacol. 34. 160–171, (1988)). Results. Binding affinities of site I drugs to bovine, rabbit and rat albumins were reasonably similar to human albumin. However, interestingly, those to dog albumin were considerably smaller than human albumin. On the other hand, binding parameters of DZ to bovine, rabbit and rat albumins were apparently different from those of human albumin. These differences are best explained by microenvironmental changes in the binding sites resulting from change of size and/or hydrophobicity of the binding pocket, rather than a variation in amino acid residues. Conclusions. We will propose herein that mammalian serum albumins used in this study contain specific drug binding sites: Rabbit and rat albumins contain a drug binding site, corresponding to site I on human albumin, and dog albumin contains a specific drug binding site corresponding to site II on the human albumin molecule.     

Section 3 The absence of effect of the antirheumatic drug ibuprofen on Oral anticoagulation with phenprocoumon

Summary

Nineteen patients receiving oral anticoagulant therapy with phenprocoumon were treated concomitantly with 600?mg. ibuprofen daily for 2 weeks. Plasma concentrations of phenprocoumon, bleeding time, prothrombin time and the concentration of a number of coagulation factors were measured before, during and after ibuprofen treatment. No significant changes were noted in any of the parameters measured and no bleeding was reported in any patient. It is concluded that ibuprofen can be given safely to patients on long-term anticoagulant therapy.     

Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag,Tlow, Tmed,and a novel parameter,TCmaxRef

Objective: This study evaluated the early absorption characteristics of ibuprofen salt formulations and standard ibuprofen acid (the reference).

Methods: In this open-label, crossover, single-center study (NCT02452450) in 32 healthy, fasted adults receiving single oral doses (400?mg ibuprofen) of ibuprofen lysine, ibuprofen liquid capsule, ibuprofen sodium, ibuprofen acid, and paracetamol, intensive blood sampling was conducted for up to 6?h. Time between dosing and the start of absorption (T_lag); a novel parameter, time at which the test formulations (ibuprofen salts) reached the observed maximum plasma concentration (C_max) of the reference (standard ibuprofen acid) (T_CmaxRef); and time to achieve therapeutic plasma concentration were measured.

Results: Ibuprofen was absorbed more rapidly from the salt formulations than the reference; T_lag was 3.3–6.4?min for salt formulations compared with 10.9?min for the reference, and 100% of subjects had a T_lag ≤ 5?min for ibuprofen lysine, compared with 61% for ibuprofen liquid capsule, 21% for ibuprofen sodium, and 7% for the reference. T_CmaxRef was 3.22–5.74-times shorter for salt formulations than for the reference (all p?p?Conclusions: This study shows that ibuprofen salts are absorbed faster than ibuprofen acid. T_lag and T_CmaxRef demonstrated early start and increased speed of absorption of salts compared with the reference, and may predict more rapid onset of analgesia.     

The action of azapropazone, oxyphenbutazone and phenylbutazone on lysosomes

Azapropazone, oxyphenbutazone and phenylbutazone have a stabilizing action on isolated lysosomes over a wide concentration range but a lytic action at high concentrations. The lytic action of phenylbutazone was greater than the other drugs. Phenylbutazone at a high concentration was found to accelerate the breakdown of lysosomes in isolated stomach preparations in vitro. Phenylbutazone was found to have a greater ulcerogenic action than azapropazone in rats and rabbits. Tissues removed from rats and rabbits dosed with phenylbutazone showed evidence of lysosomal damage when examined histochemically for acid phosphatase. In contrast, tissues from control and azapropazone-treated rats showed no evidence of lysosomal damage. Sections of rat gut incubated with azapropazone and phenylbutazone in vitro showed similar results. The possibility is discussed that drugs in high concentration may damage lysosomes in the gastrointestinal tract. It is suggested that lysosomal damage may contribute to the ulcerogenic action of the drugs in vivo.     

Section 4 Adverse reactions to non-steroidal antirheumatic drugs

Summary

The method of collection, processing and evaluation of adverse reaction reports received by the U.K. Committee on Safety of Medicines is outlined.

By utilising adverse reaction profiles, the major reactions associated with established and more recently introduced antirheumatic drugs are enumerated, compared and specific problems discussed. The profiles show that both phenylbutazone and oxyphenbutazone are predominantly associated with blood dyscrasias while indomethacin is predominantly associated with gastro-intestinal haemorrhage and minor reactions affecting the central nervous system. Aspirin shows a similar profile to indomethacin but in addition, a renal component due to papillary necrosis associated with the use of combined preparations containing phenacetin. The use of gold salts and D-penicillamine is also predominantly associated with blood dyscrasias. Some specific problems related to the use of ibufenac and alclofenac are discussed, and also the current profiles of ibuprofen, naproxen and ketoprofen.

Some of these profiles of human drug toxicity are considered in relation to the information which can be derived from animal toxicity studies.     

Acute Gastrointestinal Toxic Effects of Suspensions of Unencapsulated and Encapsulated Ibuprofen in Rats

Purpose. The study examined the gastrointestinal (GIT) toxicity effects of suspensions of encapsulated and unencapsulated ibuprofen in male Wistar rats. Methods. Rats were randomly divided into four experimental groups and four control groups, and dosed with suspensions of encapsulated and unencapsulated ibuprofen (17 mg/kg and 44 mg/kg). Bethanechol chloride, a cholinomimetic agent (5 mg/kg), was administered 30 minutes after the dosing, to induce gastric irritation. Blood plasma concentrations were monitored in another set of rats for 12 hours using the encapsulated and unencapsulated systems, to establish drug release and exposure to the mucosa. Results. Evaluation of the upper GI segments after 7 hours revealed that the 44 mg/kg dose of the encapsulated drug significantly reduced the number of lesions present compared to the unencapsulated drug (p < 0.05). At 17 mg/kg, the encapsulated drug reduced toxicity, but not significantly compared to the unencapsulated ibuprofen. Necrosis of the mucosa was observed histopathologically in the unencapsulated drug at both doses, whereas the encapsulated drug treatment revealed preserved mucosa. The encapsulated system had a maximum plasma concentration, Cmax, and time taken to reach Cmax, (Tmax) of 26.7 µg/ml ± 1.5 and 3.6 ± 0.2 hr, respectively. The area under the plasma concentration-time curve, (AUC_0–12), was 158.8 ± 23.5 µg·h/ml, confirming drug release and absorption. Conclusions. Encapsulation of ibuprofen significantly reduced gastrointestinal toxicity especially at the higher dose level and drug was released enough to subject the GI mucosa to irritation, but without the usual toxic effects.     

Synthesis,in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery

New glycosyl derivatives of ibuprofen (I, II, III, and IV) were synthesized in order to overcome the ineffective delivery of ibuprofen across the blood–brain barrier owing to its low permeability, using d-glucose as a drug targeting agent. Ibuprofen was linked directly to the C-2, C-3, C-4, and C-6 positions of glucose via ester bonds. Furthermore, in vitro stabilities of the four ester derivatives were evaluated to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase in biological samples to regenerate the original drug. From the obtained results, compounds I–IV appeared to be moderately stable in pH 7.43 buffer solution, rat plasma, and brain tissue extracts. In vivo experiments showed that the AUC_0–t of ibuprofen in plasma after the injection of prodrugs is several times higher than that of AUC_0–t after the injection of ibuprofen. In addition, the maximal concentration of ibuprofen in brain after the administration of ester IV was three fold higher than that of the control group. Also, the concentration of ibuprofen was kept stable in brain for about 4?h for four esters, which was beneficial for the treatment of Alzheimer’s disease and highlighted the possibility of brain drug delivery of ibuprofen using prodrug strategies.     

Species Differences of Serum Albumins: III. Analysis of Structural Characteristics and Ligand Binding Properties During N-B Transitions

Purpose. The aim of this study was to investigate the characteristics of the structural transitions and changes in ligand binding properties of different albumins during the pH-dependent structural transition, often referred to as the N-B transition. Methods. Structural transitions were evaluated by means of spectrometry, differential scanning calorimetry and chemical modification. In addition, ligand binding properties were investigated using typical site-specific bound drugs (warfarin, phenylbutazone, ibuprofen and diazepam). Results. Conformational changes, including N-B transition, clearly occurred in albumins from all species used in this study. The conformational stabilities of all the albumins were clearly lost in the weakly alkaline pH range. This was probably the result of the destruction of salt bridges between domain I and domain III in the albumin molecule. In addition, the profiles of the ANS-induced fluorescence were different and could be classified into two patterns, suggesting that hydrophobic pockets in the albumin molecules were different for the different species. The data suggest that the amino acid residues responsible for the transitions were some of the His residues located in domain I. Further, the ligand binding properties of the albumins were slightly different but statistically significant. Conclusions. The overall mechanisms of the N-B transition may be similar for all the albumins, but its impact is considerably different among the species in terms of both structural characteristics and ligand binding properties. Furthermore, the transitions appear to be multi-step transitions.     

布洛芬原料药及部分杂质的细胞毒性研究

摘 要 目的：评价布洛芬原料药及6种杂质的细胞毒性。方法: 不同浓度的布洛芬原料药及6种杂质作用于小鼠成纤维细胞（L929）72 h后,显微镜观察细胞毒性。结果: 在布洛芬原料药中,杂质B的细胞毒性最弱,为轻微毒性;杂质N、D、J、V细胞毒性均呈中度毒性,杂质E的细胞毒性呈现重度细胞毒性。结论:在该原料药中,同等浓度条件下,杂质E的毒性最强,应对其在布洛芬制剂中的含量进行严格地控制。     

Controlled Release Gel of Ibuprofen and Lidocaine in Epidural Use—Analgesia and Systemic Absorption in Pigs

Purpose. Reduction of the frequency of injections and localization of the absorption of drug molecules to the injection site would be of great advantage in epidural pain treatment. The epidural use of a controlled release gel of lidocaine and ibuprofen was studied. Methods. The effect of a poloxamer gel (25%) containing 2% lidocaine HC1 and 2% ibuprofen Na on the duration of analgesia after epidural administration to pigs was compared with drug in solution. Analgesia was assessed by observing the motor function and the nociceptive reflex-withdrawal response to painful pressure stimulation on the feet. Pharmacokinetic and histological examinations were performed. Results. Analgesia lasted significantly longer after epidural lidocaine gel injection in comparison with the solution. The gel prolonged the systemic absorption, thereby increasing the epidural availability of lidocaine for spinal analgesia. Although the absorption of ibuprofen was prolonged after epidural gel injection, the duration of analgesia as compared with the solution was not prolonged. After epidural injection, only slight inflammatory changes were observed in the tissue structures of the epidural space, but none in the spinal cord. Conclusions. These results demonstrate poloxamer gel to be a promising controlled-release, injectable epidural formulation for the management of pain.     

Lethal Dose Curve: Should its Determination be Made in healthy or in Animal Models of Disease?

ABSTRACT

The lethal dose curve of phenylbutazone was assayed in control animals (A) and in animals in which an experimental arthritis had been produced by injection of Feund's complete adjuvant (B).

Thirty male Wistar rats 3 months old were divided into two groups of 15 rats each: group A consisted of the control group and group B the adjuvant treated group. Arthritis was produced by a single injection of 0.15 Freund's complete adjuvant on the right footpad. The control group was injected with the adjuvant vehicle at the same site. Injections of 200 mg/kg of phenylbutazone once daily for ten days started fifteen days after administration of Freund's adjuvant.

After the first injection of phenylbutazone the LD_6.6 in group A corresponded to LD₅₃ in group B while after the second injection the LD_46.6 for the control group corresponded to LD₁₀₀ in group B. We assume that the therapeutic index would be more representative if lethal dose curves were evaluated in animals suffering from a disease that the drug in question has been designated for.     

Section 1 Ibuprofen (‘Brufen’) tested with bilateral oral surgery as a model for evaluation of anti-inflammatory effects

Summary

Twenty-four healthy patients, who had two separate operations for the removal of an impacted 3rd molar from one side or the other of the lower jaw, took part in a double-blind crossover study of ibuprofen (1200?mg. daily) and placebo given for 5 days, commencing the day before surgery. A number of objective and subjective assessments were recorded for paired comparison of the post-operative course, including swelling (measured by a special device), trismus, and pain. Ibuprofen significantly reduced pain on the day of the operation, which might have accounted in part for less trismus and patient preference for ibuprofen treatment. Patients with less swelling after ibuprofen were not always those with high serum concentrations of the drug. Side-effects were infrequent and ibuprofen did not have any significant effect on wound healing, bleeding, or various haematological parameters investigated.     

Inhibition of tolbutamide 4-methylhydroxylation by a series of non-steroidal anti-inflammatory drugs in V79-NH cells expressing human cytochrome P4502C10

1. To study the role of cytochrome P4502C10 in the metabolism of the non-steroidal antiinflammatory drugs (NSAIDs) diclofenac, phenylbutazone, fenoprofen, ibuprofen, flurbiprofen, ketoprofen and naproxen, a cell line was developed stably expressing CYP2C10 cDNA. A retroviral vector construct, containing a human CYP2C10 cDNA, was transfected in V79-NH Chinese hamster lung cells by calcium phosphate co-precipitation. Sublines stably expressing human cytochrome P450 cDNA were established by selection with the neomycin analogue G418.

2. Enzymatic activity of CYP2C10 was detected by 4-methylhydroxylation of tolbutamide. This activity was inhibited to background levels by preincubation with the CYP2C9/10 inhibitor sulphaphenazole.

3. Preincubations with the NSAIDs ketoprofen, phenylbutazone, flu-biprofen and diclofenac (all 250 μM) caused a decrease in 4-methylhydroxylation of tolbutamide (500 μM), significantly different from control values (p < 0.05). Inhibition of this activity was not seen in preincubations with the NSAIDs fenoprofen, ibuprofen and naproxen (250 μM).

4. The V79-NH CYP2C10 cell line we have developed has been shown to be a useful tool to predict drug-drug interactions.     

Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu

SUMMARY

Objective: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations.

Study design: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers.

Methods: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400mg, pseudoephedrine 60 mg.

Results: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events.

Conclusion: Blood levels would predict that the present slow-release fo rmulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.     

Influence of antirheumatic phenylacetic acid derivatives on glycosaminoglycan metabolism of fibroblast culture (author's transl)]

Murine embryonic fibroblast monolayer cultures were used to study the influence of the antirheumatic phenylacetic acid derivatives ibufanac, ibuprofen, alclofenac and bufexamac and of phenylbutazone as a reference compound on glycosaminoglycan (GAG) metabolism viability and multiplication of cells cultured in vitro. The phenylacetic acid derivatives as well as phenylbutazone showed in concentrations between 10(-3) and 10(-5) M a significant inhibitory effect on GAG production and in concentrations between 10(-3) and 3.3 X 10(-4) M a cytostatic effect; bufexamac was cytostatically active up to the concentration of 10(-5) M. Ibufenac, ibuprofen and alclofenac exhibited a similar behaviour as other non-steroidal antirheumatic drugs regarding their influence of GAG metabolism and on cell multiplication.     

The effect of phenylbutazone on the growth of murine fibroblasts in dependence of the degree of serum-protein binding

Summary The influence of phenylbutazone (Butazolidin^®) on the growth of mouse fibroblasts (L 929) in-vitro was studied. The substance was added in concentrations of 190, 364 and 667 g/ml to cultures in media containing different amounts of serum ranging from 10 to 50%. The inhibition of cell growth was found to be proportional to the concentration of phenylbutazone. Furthermore, the inhibition of growth was found to be inversely proportional to the serum content of the media.The free and protein bound ¹⁴C-phenylbutazone present in Eagle's basal medium, supplemented with different volumes of foetal bovine serum, was determined by both equilibrium dialysis and ultracentrifugation method. The results indicated that the unbound phenylbutazone was responsible for the inhibition of growth. In the culture medium containing added serum protein the percentage of bound phenylbutazone was found to be relatively small, in contrast to in-vivo where, at therapeutic levels of the drug in plasma, up to about 98% is bound.