Injectable Gold Research Articles

Gold complexes and their effect on antiarthritic activity and anticancer activity

Gold was considered as universal remedies for diseases like inflammation, infections, etc in 19th century. Later in 20th century Robert Koch discovered Gold complex Potassiumdicyanidoaurate(I) showing activity against Mycobacterium tuberculosis , later the treatment was proved to be ineffective subsequently. Further in 1985 Auranofin (Gold salt) was introduced for the treatment of Rheumatoid Arthritis, which had to be taken orally and believed to be the major discovery till injectable gold came into existence. The function of drugs based on gold is majorly related to Rheumatoid arthritis but engrossment has bent towards the adequacy of Gold compounds for anti cancer activities. The review article summarizes the current research on Gold complexes and their biological activities against cancer as well as in case of RA.

Effect of quality-switched laser exposure in patients with history of edible gold consumption.

Injectable gold is known to deposit in the dermis for life, and such patients are at risk of developing chrysiasis post-laser exposure. It is unknown if patients with history of edible gold consumption would develop a similar reaction after quality-switched laser exposure. Our aim is to assess if patients with history of edible gold consumption develop chrysiasis after quality-switched laser exposure. This is a proof of concept pilot study conducted between September 2017 and September 2018 at two dermatology clinics in Riyadh, Saudi Arabia. Adult patients who have history of edible gold consumption were recruited to receive a spot test with different quality-switched lasers in a hidden, non-sun-exposed skin site. The test area was photographed before, immediately after, and 10min after laser exposure. The test area was examined by two independent investigators for the development of chrysiasis. A total of 10 patients (five male and five female) were enrolled. The mean age was 31.7years. Forty percent of subjects consumed edible gold more than once, and the duration of last intake ranged from 3weeks to 3months. Chocolate was the main source of edible gold. All participants had no chrysiasis reaction post-quality-switched laser exposure. Contrary to our hypothesis, all participants with history of short-term edible gold consumption did not develop chrysiasis after quality-switched laser exposure. Further controlled studies including more patients with longer duration and higher frequency of edible gold consumption are needed.

Injectable Colloidal Gold for Use in Intrafractional 2D Image-Guided Radiation Therapy.

In the western world, approximately 50% of all cancer patients receive radiotherapy alone or in combination with surgery or chemotherapy. Image-guided radiotherapy (IGRT) has in recent years been introduced to enhance precision of the delivery of radiation dose to tumor tissue. Fiducial markers are often inserted inside the tumor to improve IGRT precision and to enable monitoring of the tumor position during radiation therapy. In the present article, a liquid fiducial tissue marker is presented, which can be injected into tumor tissue using thin and flexible needles. The liquid fiducial has high radio-opacity, which allows for marker-based image guidance in 2D and 3D X-ray imaging during radiation therapy. This is achieved by surface-engineering gold nanoparticles to be highly compatible with a carbohydrate-based gelation matrix. The new fiducial marker is investigated in mice where they are highly biocompatible and stable after implantation. To investigate the clinical potential, a study is conducted in a canine cancer patient with spontaneous developed solid tumor in which the marker is successfully injected and used to align and image-guide radiation treatment of the canine patient. It is concluded that the new fiducial marker has highly interesting properties that warrant investigations in cancer patients.

Treatment and control of bovine sarcoptic and psoroptic mange infestation with ivermectin long-acting injectable (IVOMEC(®) GOLD).

The efficacy of ivermectin long-acting injection (IVM LAI, IVOMEC® GOLD, Merial; 3.15 % ivermectin w/v) formulation was evaluated in cattle with induced Sarcoptes scabiei var. bovis or Psoroptes ovis infestations. A total of 64 cattle were included in this series of four studies, with 16 animals per study. Approximately, 8 weeks following initial induced mite infestation, cattle were allocated to treatment groups based on decreasing pre-treatment bodyweights. Treatments (saline (control) or IVM LAI (630 mcg ivermectin/kg bodyweight) at 1 mL/50 kg bodyweight) were administered by a single subcutaneous injection in front of the right shoulder on Day 0. Skin scrapings were collected prior to treatment and at approximately weekly intervals for 8 weeks thereafter to establish live mite counts. Character and extent of skin lesions were evaluated at each sampling. Animals were weighed before treatment and at the end of the studies. Mite counts of the IVM LAI-treated animals were significantly (p < 0.05) lower than those of the controls in all four studies at all occasions post-treatment. In the two Sarcoptes studies, IVM LAI-treated cattle were free of mites at 14 days after treatment and in the Psoroptes studies at 13 or 28 days post-treatment. All IVM LAI-treated cattle remained free of mites to the end of the studies while all control animals remained infested. Mange lesions of the IVM LAI-treated animals improved significantly (p < 0.05) compared to those of the controls from Day 21 (Sarcoptes studies) and from Days 28 or 34 (Psoroptes studies). In all studies, mean weight gain over the 8 week post-treatment period was significantly (p < 0.05) higher for the IVM LAI-treated animals than for the controls: Sarcoptes studies, 64.1 and 68.6 kg vs. 46.9 and 48.6 kg, respectively; Psoroptes studies, 43.0 and 43.4 kg vs. 20.8 and 34.9 kg, respectively. All animals accepted the treatment well, and no treatment-related health problems and adverse events were observed throughout the studies. These studies demonstrated the high efficacy of IVOMEC® GOLD against sarcoptic and psoroptic mange in cattle.

Activity of ivermectin long-acting injectable (IVOMEC(®) GOLD) in first-season grazing cattle exposed to natural challenge conditions in Germany.

The persistent activity of ivermectin long-acting injection (IVM LAI; IVOMEC® GOLD, Merial; 3.15% ivermectin w/v) against nematode infections of cattle was evaluated under natural challenge conditions. Seventy nematode-free Brown Swiss calves were blocked by pre-treatment bodyweight and allocated randomly to seven groups of 10 animals each: saline (control) at 1 mL/50 kg bodyweight once on day 0 or IVM LAI at 1 mL/50 kg bodyweight (630 mcg IVM/kg) on either days 0, 7, 14, 21, 28, or 35. After housing until day 35, calves were grazed as one herd on a naturally contaminated pasture for 42 days. Calves were then weighed and housed for 4 weeks before being necropsied for parasite counting. Treatment with IVM LAI prevented the establishment (>90%, p < 0.05) of Dictyocaulus viviparus (100%), Bunostomum phlebotomum (100 %), Haemonchus contortus (98.6%), Ostertagia ostertagi/lyrata (94.9%), and Oesophagostomum radiatum (93.3%) for at least 77 days; Ostertagia leptospicularis (99.1%) for 63 days; Cooperia punctata (97.7%), Trichostrongylus axei (96.5%), and Ostertagia spp. inhibited larvae 4 (93.3%) for 56 days; Cooperia oncophora/surnabada (96.9%), Trichuris discolor (93.6%), and Cooperia spp. inhibited larvae 4 (98.8%); and Nematodirus spp. inhibited larvae 4 (97.1%) for 42 days. Calves of groups treated with IVM LAI had significantly (p < 0.001) higher days 0 to 77 weight gains than the saline-treated controls (28.40-39.25 vs 2.60 kg); the weight gains of the IVM LAI-treated groups, however, were not different from one another (p > 0.3). This study demonstrated a very high efficacy of IVOMEC® GOLD in preventing the establishment of a wide range of bovine nematodes for extended periods of time which was associated with a significant benefit to productivity in terms of weight gain.

Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials

BackgroundDespite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).Methods and FindingsThe following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)).ConclusionCombination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.

Injectable Colloidal Gold in a Sucrose Acetate Isobutyrate Gelating Matrix with Potential Use in Radiation Therapy

External beam radiation therapy relies on the ability to deliver high radiation doses to tumor cells with minimal exposure to surrounding healthy tissue. Advanced irradiation techniques, including image-guided radiation therapy (IGRT), rely on the ability to locate tumors to optimize the therapeutic benefit of these techniques. Today, radiopaque fiducial tissue markers are placed in or around tumors, for example, in prostate cancer patients to enhance the precision of daily and/or real-time IGRT. A liquid injectable fiducial marker (nanogel) is developed based on PEGylated gold nanoparticles and sucrose acetate isobutyrate (SAIB) with improved properties compared to current solid fiducial markers. The developed nanogel is investigated in vitro and subsequently evaluated in vivo in immunocompetent NMRI mice. The nanogel shows high CT-contrast and excellent stability in vivo over a period of 12 weeks. The nanogel is found to be biocompatible and well tolerated. No induction of the inflammatory cytokines INF-γ, IL-6, or TNF-α is observed throughout the study period. The developed nanogel seems to be a safe injectable fiducial marker ideally suited for IGRT that may further enhance the effect of radiation.

Current Immunotherapy in Rheumatoid Arthritis

Rheumatoid arthritis is a common autoimmune disease primarily manifesting as chronic synovitis, subsequently leading to a change in joint integrity. Progressive disability and systemic complications are strongly associated with a decreased quality of life. To maintain function and health in patients with rheumatoid arthritis, early, aggressive and guided immunosuppressive therapy is required to induce clinical remission. Antirheumatic drugs are capable of controlling synovial inflammation and are therefore named 'disease-modifying antirheumatic drugs' (DMARDs). This article aims to bridge the beginning of DMARD therapy with agents such as methotrexate, leflunomide, sulfasalazine, injectable gold and (hydroxy)chloroquine with biological therapies, and with the new era of kinase inhibitors. Mechanisms of action, as well as advantages and disadvantages of DMARDs, are discussed with respect to the current literature and current recommendations.

The biological activity of auranofin: implications for novel treatment of diseases

More than 30years ago, auranofin was developed for the treatment of rheumatoid arthritis as a substitution for the injectable gold compounds aurothiomalate and aurothioglucose. Both the ease of oral administration over intramuscular injections and more potent anti-inflammatory effects in vitro made auranofin seem like an excellent substitute for the traditional injectable gold compounds. Despite efficacy in the treatment of both rheumatoid arthritis and psoriasis, currently, auranofin is seldom used as a treatment for patients with rheumatoid arthritis as more novel anti-rheumatic medications have become available. Despite the decline in its clinical applications, research on auranofin has continued as it shows promise in the treatment of several different diseases. In recent years, advances in technology have allowed researchers to use molecular techniques to identify novel mechanisms of action of auranofin. Additionally, researchers are discovering potential new applications of auranofin. Dual inhibition of inflammatory pathways and thiol redox enzymes by auranofin makes it a new candidate for cancer therapy and treating microbial infections. This review will summarize recently obtained data on the mechanisms of action of auranofin, and potential new applications of auranofin in the treatment of various diseases, including several types of leukaemia, carcinomas, and parasitic, bacterial, and viral infections.

Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus

We report a 37-year-old female of intractable rheumatoid arthritis (RA) complicated by systemic lupus erythematosus (SLE), who was successfully treated with a combination of tocilizumab (TCZ) and tacrolimus. She was diagnosed with RA when she was 21 years old, and was administered oral prednisolone, injectable gold and salazosulfapyridine, but deformity of her hands gradually developed. She developed high fever and thrombocytopenia when she was 35 years old. Renal involvement, pericarditis, positive antinuclear antibody and high level of anti-double-stranded DNA antibody were found and the patient was diagnosed with SLE. Polyarthritis and immunological abnormalities developed despite aggressive immunosuppressive therapy including high-dose corticosteroids and intravenously administered cyclophosphamide. Tacrolimus (TAC) therapy gave only partial improvement of joint symptoms. After the initiation of combination therapy with TCZ, not only was a complete remission of RA obtained, but also the serum levels of SLE markers dramatically decreased. Our report suggests the possibility that this combination therapy is effective in treating SLE as well as RA.

Triethylphosphine gold: cellular uptake and disposition after single and repeated oral doses in rats.

The tissue and subcellular pharmacokinetics of gold following single and repeated oral doses of triethylphosphine gold (auranofin) has been studied in rats. After a single dose, the tissue and subcellular gold levels were 5-10 times lower than those reached with injectable gold compounds. In the liver tissues, gold concentrations peaked within 24 h followed by a biphasic clearance, with an initial rapid phase (t1/2 32 h) and a slow terminal phase (t 1/2 11 days). Renal gold concentrations continued to increase for 3 to 5 days and then decreased exponentially with a first order t 1/2 of about 7 days. Intracellularly, between 60-80% of hepatic and 50-70% of renal gold was present in the cytosol. In rats given repeated doses of auranofin, the hepatic and renal gold concentrations were 3-5 times higher than those measured after a single dose. The proportion of cellular gold present in the cytosol was markedly lower, with 43% in the liver and 30% in kidney tissues. In both the liver and kidney, gold concentrations were dose-dependent, whereas in the gastrointestinal tissues the increases as a function of dose were minimal.

So you want to be … a rheumatologist

Even in the 19th century, when rheumatoid arthritis, the most common of the serious rheumatic diseases, was first defined, sufferers moved inexorably towards life in a wheelchair. As late as the 1950s, the only widely available treatments were aspirin for symptom relief, and cortisone which had severe side effects. However, rheumatoid arthritis was one of the first fields in medicine where treatments were subjected to controlled trials. The benefits of injectable gold, the earliest disease-modifying drug, were demonstrated by Fraser in 1944–5, following which this treatment became widely available.

Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis

ObjectivesTo assess the efficacy and safety of synthetic disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA)—a first step in a European League Against Rheumatism (EULAR) initiative to produce...

Abrupt Development of Sarcoidosis with a Prodromal Increase in Plasma Osteopontin in a Patient with Rheumatoid Arthritis During Treatment with Etanercept

To the Editor: Biologic disease-modifying antirheumatic drugs (DMARD) targeting tumor necrosis factor-α (TNF-α) are very efficacious and the number of patients with rheumatoid arthritis (RA) treated with these drugs is increasing rapidly. Because granulomatous diseases as typified by sarcoidosis are considered to develop in the Th1 cytokine milieu dominated by interferon-γ (IFN-γ) and TNF-α, anti-TNF-α agents have been used for treatment of sarcoidosis. Reports show that infliximab is effective, while etanercept is not, in the treatment of sarcoidosis1,2. In contrast, anti-TNF-α agents may have induced sarcoidosis in patients with RA and spondyloarthropathy3–6. The patient we describe had acute onset of sarcoidosis in several organs simultaneously after a long period of remission of RA while receiving etanercept. Based on serum and plasma levels of laboratory indicators related to sarcoidosis, the condition might have developed as quickly as within 1 or 2 months. A 52-year-old Japanese woman was diagnosed with RA in 1980 and had been treated with several DMARD such as injectable gold salt, sulfasalazine, actarit, methotrexate, and mizoribine with no appreciable effects. Leflunomide was started in … Address correspondence to Dr. S. Takatori, Division of Rheumatology and Clinical Immunology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-shi, Tochigi 329-0498, Japan. E-mail: stori{at}jichi.ac.jp

Clinical pharmacology of gold

Since the dawn of civilization, elemental gold and gold compounds have been revered and utilized by Shamen and medical practitioners alike for many varied pathological problems. In the 20(th) century following the observations of Jacques Forestier, injectable gold compounds were successfully used for the treatment of rheumatoid arthritis. Of the many compounds developed, gold sodium thiomalate has been the most extensively studied by basic scientists and by clinicians. In the1980s, the oral gold compound auranofin showed promise as a therapeutic contender to injectable gold, but the clinical side effect profile and fear of long term effects of immune suppression by auranofin, resulted in gold sodium thiomalate continuing as the preferred gold compound for rheumatoid treatment. However, the increased use and demonstration of effectiveness of low dose Methotrexate (MTX) in rheumatoid treatment over the last 20 years has resulted in a significant decline in the use of injectable gold sodium thiomalate, this despite the claims and evidence that it remains a useful agent in the management of rheumatoid arthritis. Several authors still contend that the injectable gold compounds can still play a valuable role, and indeed may be the correct first choice in the management of rheumatoid arthritis.

So you want to be… a rheumatologist

Even in the 19th century, when rheumatoid arthritis, the most common of the serious rheumatic diseases, was first defined, sufferers moved inexorably towards life in a wheelchair. As late as the 1950s, the only widely available treatments were aspirin, which just produced symptom relief, and cortisone which had severe side effects. However, rheumatoid arthritis was one of the first fields in medicine where treatments were subjected to controlled trials. The benefits of injectable gold, the earliest disease-modifying drug, were demonstrated by Fraser in 1944–5, following which this treatment became widely available.

Have traditional DMARDs had their day?

This review tries to answer the question of whether in the face of the recently introduced biologics conventional disease-modifying antirheumatic drugs (DMARDs) can still be recommended in the treatment of rheumatoid arthritis (RA). We start with an overview of the oldest conventional DMARD, injectable gold (Au), which was introduced in the treatment of RA in the 1920s. The effect of gold is directed at a number of different sites of the immune system. A significant improvement of clinical and biochemical disease activity parameters as well as an inhibition of X-ray progression has been shown in many studies. Head-to-head comparisons between gold and high-dose methotrexate (MTX) demonstrated no significant difference but some advantages for gold. Since trials comparing biologics with gold will never be performed, an indirect comparison was done by analyzing the results of trials with gold with those with biologics. Conclusions from such comparisons have to be drawn with caution especially since the methodology for performing trials has changed with time. We selected four trials with gold (two open, one placebo-controlled, and one comparison with MTX) and five trials with biologics (three placebo-controlled, one dose escalation study, and one comparison with MTX). In all these trials baseline data regarding swollen joint count (SJC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were roughly comparable and, with the exception of interleukin (IL)-1 RA, demonstrated a similar improvement of over 50% already after 6 months [with faster onset with tumor necrosis factor (TNF)-alpha blockade]. American College of Rheumatology (ACR) response data were not available for the older gold trials. European League Against Rheumatism (EULAR) response criteria could be calculated for the Au/MTX trial and were-for these compounds-only slightly inferior to the results with adalimumab. X-ray response is especially difficult to compare across studies. Although an inhibition with Au and MTX could be demonstrated, this occurred-similar to corticosteroid treatment-earlier and more pronounced with TNF-alpha blockers. We confirm the statement of Weinblatt that the most modern DMARDs do not appear to be much better than the oldest one indicating that conventional DMARDs are not outdated. Therefore, a sufficient trial of conventional DMARDs should precede the introduction of treatment with the very expensive biologics.

Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France)

Objective. The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. Methods. A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. Results. At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. Conclusion. Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.

Injectable Gold - Induced Hepatitis and Neutropenia in Rheumatoid Arthritis

Gold salts have been used for many years in the treatment of rheumatoid arthritis. The common side effects are mucocutaneous reactions, but hepatotoxic reaction and isolated neutropenia are rare complications. We report a 62-year-old woman with rheumatoid arthritis who had developed hepatitis and neutropenia simultaneously after receiving 137.5 mg of sodium aurothiomalate.

Life table analysis of treatment episodes with disease-modifying anti-rheumatic drugs in rheumatoid arthritis

To evaluate the utility of therapy with all the major disease-modifying anti-rheumatic drugs (DMARDs) in long-term treatment, 1666 DMARDs treatment episodes were analyzed using 5-year life tables. In total, all treatment episodes attributable to DMARDs remained in less than 20% of the patients up to 60 months. As for the prevalence of patients remaining in the follow-up study, those receiving methotrexate (MTX) were the most common, those receiving injectable gold compound (GST), bucillamine (BU), andd-penicillamine (DP) were higher than those receiving actalit (ACT) and sulfasalazine (SASP), and those receiving mizoribine (MZR), lobenzarit (CCA), and auranofin (AF) were least. The treatment terminations for inefficacy in BU, DP, and SASP increased slowly over 36 months. For all drugs but GST and MTX, the life table curve of terminations for toxicity became horizontal over time. The prevalence of terminations for toxicity in MTX increased even after 48 months. The long-term utility of DMARDs therapy for RA is unsatisfying. MTX was the most useful, and GST, BU, DP, and SASP were relatively useful. Relapse of the disease occurred with BU, DP, and SASP. We need to observe patients closely for the appearance of side effects throughout the prescription period of MTX irrespective of the duration of treatment.