RANIBIZUMAB (Lucentis)

Lucentis was discovered by Genentech and is being developed by Genentech and

Novartis for diseases or disorders of the eye. On 10 August 2012, Roche announced
that Lucentis (ranibizumab injection) was approved by the U.S. Food & Drug
Administration (FDA) for treatment of diabetic macular edema (DME), an eye
condition in people with diabetes that causes blurred vision, severe vision loss and
sometimes blindness. Lucentis is the first and only FDA-approved medicine for DME,
a condition for which the standard of care has not changed significantly in more than
25 years.

Lucentis 0.5 mg once monthly was first approved by the FDA for treatment of wet
age-related macular degeneration (AMD) in 2006 and for macular edema following
retinal vein occlusion (RVO) in 2010.

Lucentis Efficacy in DME

The approval of Lucentis in DME was based on Genentechs Phase III trials, RIDE
and RISE, two identicallydesigned, parallel, double-masked, three-year clinical trials,
which were sham-treatment controlled for 24 months. A total of 759 patients were
randomized into three groups to receive monthly treatment with 0.3 mg Lucentis
(n=250), 0.5 mg Lucentis (n=252) or sham injection (control group, n = 257). Primary
outcomes were evaluated at 24 months and have been published in Ophthalmology.

In the studies, treatment with Lucentis demonstrated improved clinical outcomes

including substantial visual gain for many DME patients. Results showed patients
who received 0.3 mg Lucentis experienced significant, early (Day 7) and sustained
(24 months) improvements in vision:

More patients who received Lucentis were able to read at least three
additional lines (15 letters) on the eye chart at 24 months: RIDE: 34 percent in
the 0.3 mg group versus 12 percent in the control group; RISE: 45 percent,
0.3 mg versus 18 percent, control (primary endpoint)
Patients who received Lucentis had average vision gains exceeding two lines
(10 letters) on the eye chart at 24 months: RIDE: 10.9 letters, 0.3 mg versus
2.3 letters, control; RISE: 12.5 letters, 0.3 mg versus 2.6 letters, control
Significant gains in average vision were observed 7 days after the first
treatment
Patients who received Lucentis were significantly more likely to maintain their
vision (lose < 15 letters on the eye chart) at 24 months: RIDE: 98 percent, 0.3
mg versus 92 percent, control; RISE: 98 percent, 0.3 mg versus 90 percent,
control

For all time points comparing 0.3 mg Lucentis to control through month 24 p < 0.01.

Vision improvements observed in patients treated with Lucentis at 24 months were

maintained with continued treatment through 36 months.
Lucentis Safety in DME
The benefit/risk profile of Lucentis was favorable in patients with DME through 36
months in the clinical trials. Pooled safety analysis of RIDE and RISE at 24 months
showed:
The ocular safety of Lucentis in patients with DME was generally consistent
with that established in patients with wet AMD and RVO (through 36 months).
The most common ocular events occurring at a higher rate in patients
receiving 0.3 mg Lucentis compared to the control groups included
conjunctival hemorrhage (bleeding under the lining of the eye): 47 percent,
0.3 mg versus 32 percent, control; eye pain: 17 percent, 0.3 mg versus 13
percent, control foreign body sensation in eyes: 10 percent, 0.3 mg versus 5
percent, control; vitreous floaters: 10 percent, 0.3 mg versus 4 percent,
control; and increased eye pressure: 18 percent, 0.3 mg versus 7 percent,
control.

Although uncommon, trends toward increased rates of arteriothromboembolic events

(ATEs) such as vascular death, deaths of unknown cause, nonfatal heart attacks and
nonfatal strokes, have been observed in prior studies of Lucentis in other diseases.

Rates of these events were similar among DME patients receiving 0.3 mg
Lucentis and the control groups at 24 months at 5.6 percent, 0.3 mg versus
5.2 percent, control. The rate of ATE events at 36 months was 10.8 percent
for patients in the 0.3 mg treatment group (control period ended at 24
months).

The rate of stroke in DME patients at 24 months was 1.2 percent, 0.3 mg
versus 1.6 percent, control. The rate of stroke at 36 months was 2.0 percent
for patients in the 0.3 mg treatment group.

Pooled analyses also showed the rate of fatal events (death from any cause) in
patients treated in the DM trials was low, and many causes of death were not
unusual for patients with advanced diabetes complications. However, a potential
relationship between the events and intravitreal use of VEGF inhibitors cannot be
excluded. The rate of fatalities at 24 months was 2.8 percent, 0.3 mg versus 1.2
percent, control. The rate of fatalities at 36 months was 4.4 percent for patients in the
0.3 mg treatment group.
DAPTOMYCIN

Discovery of Daptomycin
Daptomycin is a natural product of a soil actinomycete, as are most of the important
antibiotics developed in the past 50 years. The producing microorganism,
Streptomyces roseosporus, was isolated by scientists at Eli Lilly from a soil sample
from Mount Ararat (Turkey). This sporulating actinomycete produced a family of
lipopeptide antibiotics designated A21987C. Eli Lilly scientists also isolated a strain
of Actinoplanes utahensis that produced a secreted deacylase that could cleave the
natural long-chain lipid side chains from the A21978C factors. This enabled the
production of the core cyclic peptide for reacylation with different lipid side chains.
Daptomycin, which contains an n-decanoyl side chain, was chosen for clinical
development because of its in vivo efficacy and low toxicity in animals. Because
enzymatic deacylation, coupled with chemical reacylation with decanoate, was not
cost-effective to manufacture, scientists at Eli Lilly developed a process that fed
decanoic acid during fermentation, to directly produce daptomycin.

Scientists at Eli Lilly designed and implemented clinical studies of intravenous (IV)
daptomycin during the late 1980s and early 1990s. In the initial phase 1 trials,
daptomycin was well tolerated in healthy volunteers at up to 6 mg/kg IV in 2 divided
doses per day. For the initial phase 2 clinical trial involving complicated skin and
skin-structure infection (SSSI), the scientists at Eli Lilly used a daptomycin treatment
regimen of 2 mg/kg given once daily. In later clinical trials, daptomycin was
administered twice daily (every 12 h). In another phase 2 trial, a dosage of 6 mg/kg
given in 2 divided doses per day to patients with Staphylococcus aureus bacteremia
provided promising results. Scientists thought that a higher dosage, such as 8 mg/kg
per day in 2 divided doses, would be required to effectively treat such infections.
However, when that dosage was used for safety testing in a phase 1 study, 2 of 5
volunteers developed the unacceptable adverse effects involving the
musculoskeletal system with accompanying increases in creatine phosphokinase
(CPK) levels (a marker of potential adverse effects involving the musculoskeletal
system). Subsequently, Eli Lilly voluntarily suspended further trials. Primarily
because the therapeutic window between efficacy and safety was thought to be
small, a decision was made to discontinue daptomycin development and to put the
antibiotic on the shelf. This decision was helped by the concurring viewpoint of the
new Vice President for Infectious Diseases Discovery at Eli Lilly, Barry Eisenstein.
Meanwhile, in early 1992, Richard Baltz and colleagues at Eli Lilly began genetic
studies on S. roseosporus to develop combinatorial biosynthetic approaches of
conducting systematic modifications of the nonribosomal peptide synthetase to
reprogram the production of novel peptide cores for improvement of the therapeutic
index of daptomycin-related lipopeptides. They initiated the cloning of the
biosynthetic genes for daptomycin and its related lipopeptide (A54145) to form hybrid
molecules. This work was supported primarily as a postdoctoral project and was
terminated in 1996. Around that same time, Eli Lilly management decided to
discontinue all further work on other natural product antibiotics, including
glycopeptides, macrolides, and -lactams, and to focus on target-based drug
discovery using Streptococcus pneumoniae genomics. They also initiated a
downsizing of the Infectious Diseases Discovery Division, and many of the seasoned
researchers were reassigned to other therapeutic areas or, like Eisenstein, departed
entirely.
After witnessing the decline of the long-standing and distinguished collaboration
between Natural Products Discovery and Infectious Diseases Discovery Divisions at
Eli Lilly, Baltz attended a scientific meeting in 1996, where he was introduced to Dr.
Tally. Tally knew of Baltz's work at Eli Lilly and was aware of the recent downsizing of
the Infectious Diseases Discovery group. He inquired about Baltz's interest in a
position as Vice President of Molecular Biology at Cubist. Baltz told Tally that he
would give it some thought, and a short time later, on a lark, he agreed to interview
for the position.
The trip to Cubist (Cambridge, MA) was an interesting experience for Baltz. In the
morning, Baltz presented a seminar that briefly summarized 3 projects that he had
been working on at Eli Lilly: genetic engineering of lipopeptides related to
daptomycin, genetic engineering of novel glycopeptides, and S. pneumoniae
genomics. He led with a report on his work with daptomycin. In the introduction to the
daptomycin molecular genetics portion of the seminar, Baltz mentioned why he
thought a derivative of daptomycin might be developed into a useful antibiotic if a
sufficient increase in therapeutic index could be achieved to overcome the muscle
toxicity that Eli Lilly encountered in the phase 2 clinical trials.
At the end of the day, Tally and Baltz again discussed the vice president position at
Cubist. Baltz was within 2 years of retirement from Eli Lilly and its substantial
benefits, and he deferred the decision. Tally understood and told him, Don't be
surprised to see me at Lilly, because I am going to license daptomycin for Cubist to
develop (R. H. Baltz, personal recollection). Tally had come to that decision within a
few hours after hearing the seminar.
It took Tally and Cubist nearly a year to negotiate a license agreement with Eli Lilly.
After the agreement was signed, Tally called Baltz to ask whether he would help
Cubist with the daptomycin project as a consultant. Baltz was still 1 year away from
early retirement but told Tally that he would inquire with the Eli Lilly upper
management. Eli Lilly stood to benefit from a healthy royalty if Cubist was
successful; management agreed to let Baltz consult, but on his own time. This
started a fruitful scientific relationship and friendship with Tally that eventually
brought Baltz to Cubist full-time in 2001, after retirement from Eli Lilly and 3 years of
consulting with Cubist. With Tally's support and with the acquisition of TerraGen in
2000, Cubist continued with molecular engineering where Eli Lilly had stopped and
developed combinatorial biosynthesis as a robust means to generate derivatives of
daptomycin that were not attainable through medicinal chemistry.

The Cubist daptomycin in-licensing agreement was finalized on 7 November 1997,

the same day that Frederick Oleson, trained in nonclinical development and
toxicology, joined Cubist as a full-time employee to work with Dr. Tally on the
development of daptomycin. For several months, Oleson had been consulting with
Tally and the Cubist team in the due diligence evaluation process. During the initial
23 months after in-licensing, Tally and Olesonin addition to others at Cubist,
including Jan-Ji Laifocused their efforts on developing daptomycin formulations
and treatment approaches for oral and topical clinical indications (ie, elimination of
colonization of the gastrointestinal tract with vancomycin-resistant enterococci and
treatment of dermal gram-positive bacterial and/or S. aureus infections,
respectively). One of the main reasons for these treatment approaches was to limit
the systemic exposure to daptomycin, which was only minimally absorbed after oral
or dermal administration. Thus, these treatment approaches would minimize any
risks for the adverse effects involving the musculoskeletal system that resulted in the
termination of the IV daptomycin clinical programs at Eli Lilly.
During this initial development phase, Tally and Oleson had numerous discussions
about the possibility of reinitiating the IV clinical programs. They, along with leaders
in the infectious diseases community, were concerned about the lack of antibiotics in
development across the pharmaceutical industry. The Cubist scientists were
convinced that daptomycin had good attributes (eg, high potency, bactericidal
activity, and high efficacy in animal models against a broad array of gram-positive
pathogens, including drug-resistant and drug-susceptible S. aureus and vancomycin-
resistant enterococci) and that it was worth their further effort to overcome the
toxicity problems that had confounded Eli Lilly scientists. A number of factors were
considered, including the level of muscle toxicity related to daptomycin (based on the
Eli Lilly preclinical and clinical data), the clinical trial efficacy data from the Eli Lilly
phase 2 trials involving skin and bloodstream infections, and the increasing rates of
vancomycin-resistant or intermediately susceptible gram-positive organisms in the
hospitals. The adverse effects involving the musculoskeletal system could be
monitored by measuring the level of the serum enzyme CPK. The phase 2 trial
results suggested that daptomycin could be an effective therapy for complicated
SSSI and for bacteremia (although higher doses would be desirable). From a
medical need viewpoint, the increasing rates of vancomycin-resistant enterococci
and methicillin-resistant S. aureus made it abundantly clear that a drug such as
daptomycin would be an ideal candidate for the treatment of serious and life-
threatening gram-positive, hospital-acquired infections. Consequently, in February
1998, only 3 months after in-licensing, Cubist senior management decided to pursue
the development of daptomycin as an IV antibiotic for the treatment of serious gram-
positive infections, including complicated SSSI and bacteremia with suspected
infective endocarditis, and subsequently discontinued the oral and dermal programs.
In March 1998, a preinvestigational new drug document was submitted to the US
Food and Drug Administration (FDA) to inform the agency of the Cubist plans to
develop daptomycin for the IV treatment of serious gram-positive infections and to
solicit its advice on this program. At the same time, Cubist signed a manufacturing
agreement with ASC Dobfar in Italy to manufacture daptomycin for its clinical
development program.

In 2003, daptomycin for injection (Cubicin), a first-in-class acidic lipopeptide IV

antibiotic, was approved by the FDA at a dosage of 4 mg/kg given once daily for the
treatment of complicated SSSI caused by specific gram-positive bacteria. Since its
launch in November 2003, the drug has had the most financial success (in nominal
dollars of sales) of any IV antibiotic in US history. In 2006, it was approved in the
United States for the treatment of S. aureus bacteremia, including right-sided
infective endocarditis, at a dosage of 6 mg/kg given once daily.
PHYSOSTIGMINE

Physostigmine, as the salicylate salt, is being developed as a drug for the treatment
of Alzheimers disease. The memory and learning enhancement capabilities as well
as other pharmacological effects of physostigmine will be thoroughly reviewed in this
paper. Physostigmine (Antilirium, Isopto, eserine), an alkaloid from the West
African perennial shrub Physostigma venenosum, is the oldest known
acetylcholinesterase (AChE) inhibitor. Naturally occurring physostigmine was initially
used clinically for ophthalmic purposes in 1877. Physostigmine was first synthesized
in 1935. The general and dominant pharmacology of physostigmine is due to a short-
acting inhibition of the enzymes AChE and butyrylcholinesterase (BuChE).
Physostigmine exerts a stereoselective inhibition by acting as a pseudosubstrate and
transferring a carbamate residue to the enzymes active site. Spontaneous
hydrolysis regenerates the native enzyme and function. This activity underlies
physostigmine use in the treatment of glaucoma and atropine and organophosphate
intoxication and its potential role in the amelioration of the symptoms of Alzheimers
disease.
The history of physostigmine has been reviewed by Holmstedt and more recently by
Somani and Dube. Physostigmine is extracted from the seeds of
Physostigma venenosum. As ordeal beans these seeds were used in trials for
witchcraft and an early therapeutic use in ophthalmology was described in 1863.
The structure of physostigmine (1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-
pyrrolo[2,3-b] indo-5-ol-methylcarbamate) was determined by Stedman and Barger
in 1925 and its effect in prolonging acetylcholine action, subsequently revealed as
mediated through the inhibition of AChE, was discovered by Loewi and Navratil a
year later. Physostigmine is a lipid soluble tertiary amine with a pKa value of 7.9 and
is approximately 75% ionized at the pH of blood and brain.
AChE is a hydrolytic enzyme of the serine class that is of major significance to the
hydrolysis of acetylcholine in the cholinergic synapses of the somatic system, the
autonomic nervous system and the central nervous system. The pharmacology of
physostigmine is dominated by its interactions with this enzyme. Naturally occurring
physostigmine is levorotatory () and the inhibition of AChE is enantioselective, with
the () enantiomer being some 1000 times more potent than the (+) enantiomer in
studies using acetylcholinesterase from human tissues. The major metabolic
products of physostigmine, including eseroline, rubreserine and the condensation
products eserine blue and eserine brown are significantly less active inhibitors of
AChE than physostigmine itself.
Physostigmine was used therapeutically in the treatment of glaucoma in 1877 and
its first use as an antidote in the treatment of atropine toxicity was some 125
years ago. The current clinical roles of physostigmine include treatment of glaucoma,
myasthenia gravis, the relief of central cholinergic intoxication from atropine,
scopolamine, and belladonna alkaloid and from the intoxication induced by
overdoses of tricyclic antidepressants, antihistamines, antipsychotics, and
benzodiazepines. These actions all derive from the ability of physostigmine to
increase acetylcholine levels by inhibition of AChE and BuChE. These increased
levels facilitate neuromuscular transmission in skeletal muscle, decrease pupillary
size, and increase aqueous humor outflow in the eye and block the anticholinergic
effects of atropine and the anticholinergic effects of high concentrations of
antihistamines, antidepressants, and antipsychotics.
Physostigmine has also gained prominence as a potential prophylactic agent against
organophosphate intoxication by competition for the active sites of AChE. An early
observation by Koster showed that a non-lethal dose of physostigmine protected
cats against the effects of several lethal doses of the organophosphate
diisopropyl fluorophosphate. Many subsequent studies have confirmed
this observation and have demonstrated the efficacy of physostigmine prophylaxis
against a variety of organophosphates, including Soman. This use would be in
conjunction with post-exposure anticholinergic and oxime therapy.
Pyridostigmine bromide, a quaternary charged carbamate cholinesterase inhibitor,
has been advanced by the military as an orally active protective drug against
organophosphate exposure under battlefield conditions. Pyridostigmine does not
cross the blood-brain barrier, however, and hence does not protect against
performance deficits produced by central cholinesterase intoxication. Physostigmine,
because of its ability to cross the blood-brain barrier, has been demonstrated
experimentally to be more effective than pyridostigmine against Soman poisoning.

Physostigmine has also generated considerable attention in both experimental and

clinical protocols as a memory- and cognition-enhancing agent. The role of the
central cholinergic nervous system in memory processes was summarized by
Deutsch in 1971 and in 1983. The role of physostigmine in the memory process
has assumed increasing importance with many observations indicating that
degeneration of central cholinergic neurons in the basal forebrain is associated with
geriatric memory dysfunction and with Alzheimers disease. The cholinesterases are
the principal pharmacological targets of physostigmine and the pharmacological
effects of administered physostigmine are almost entirely due to its actions on these
enzymes.
VARIVAX

Varicella is an acute infectious disease caused by varicella zoster virus (VZV). The
recurrent infection (herpes zoster, also known as shingles) has been recognized
since ancient times. Primary varicella infection (chickenpox) was not reliably
distinguished from smallpox until the end of the 19th century. In 1875, Steiner
demonstrated that chickenpox was caused by an infectious agent by inoculating
volunteers with the vesicular fluid from a patient with acute varicella. Clinical
observations of the relationship between varicella and herpes zoster were made in
1888 by von Bokay, when children without evidence of varicella immunity acquired
varicella after contact with herpes zoster. VZV was isolated from vesicular fluid of
both chickenpox and zoster lesions in cell culture by Thomas Weller in 1954.
Subsequent laboratory studies of the virus led to the development of a live
attenuated varicella vaccine in Japan in the 1970s. The vaccine was licensed for use
in the United States in March 1995. The first vaccine to reduce the risk of herpes
zoster was licensed in May 2006.
Varicella vaccine (Varivax, Merck) is a live-attenuated viral vaccine, derived from the
Oka strain of VZV. The vaccine virus was isolated by Takahashi in the early 1970s
from vesicular fluid from an otherwise healthy child with varicella disease. Varicella
vaccine was licensed for general use in Japan and Korea in 1988. It was licensed in
the United States in 1995 for persons 12 months of age and older. The virus was
attenuated by sequential passage in human embryonic lung cell culture, embryonic
guinea pig fibroblasts, and in WI-38 human diploid cells. The Oka/ Merck vaccine
has undergone further passage through MRC-5 human diploid cell cultures for a total
of 31 passages. The reconstituted vaccine contains small amounts of sucrose,
processed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium
diphosphate, potassium phosphate, and potassium chloride, and trace quantities of
residual components of MRC-5 cells (DNA and protein), EDTA, neomycin, and fetal
bovine serum. The vaccine is reconstituted with sterile water and contains no
preservative. The Food and Drug Administration (FDA) approved this vaccine in
1995 for use in people 1 year of age and older.

Before the FDA licensed the vaccine, studies were done to determine the safety of 2
doses of the vaccine. In children 12 months through 12 years old:
1 of 5 children had side effects, such as soreness, swelling, and redness,
within 3 days of getting the first dose compared with 1 of 4 children after the
second dose
7 of 100 children had fever after the first dose compared with 4 of 100 children
after the second dose
3 of 100 children had chickenpox-like rash after the first dose compared with 1
of 100 children after the second dose

In 2008, a CDC-FDA report analyzed VAERS data on patients who reported

side effects after getting chickenpox vaccine during May 1995 through
December 2005. The vaccine manufacturer Merck distributed 50 million doses
of chickenpox vaccine during this time. The report found that the vast majority
of people had no or very mild side effects, such as rash and soreness, with
the vaccine. Serious side effects linked to the vaccine were extremely rare.
 Rarely, serious adverse events after chickenpox vaccination have been
reported. These include thrombocytopenia (low platelet count), acute
cerebellar ataxia (brain injury that leads to balance problems), and acute
hemiparesis (paralysis on part the body). It is not known if these side effects
were caused by the vaccine. Lab testing was either not done or did not
confirm if the problems were caused by vaccine.
Although pregnant women should not get the chickenpox vaccine, there are
women who may get the vaccine by mistake. In 1995, Merck, Inc., in
collaboration with CDC, established a Pregnancy Registry to monitor the fetal
and pregnancy outcomes of women who inadvertently received chickenpox
vaccine 3 months before or at any time during pregnancy. After 17 years of
monitoring, no cases of congenital chickenpox syndrome or increased risk for
other birth defects have been identified.
Oxycodone is a derivative of the natural product morphine. Morphine was first
discovered in the 1800s and was used for relief of pain after the invention of
hypodermic needles in the 1850s. Oxycodone was discovered about half a century
later in Germany and used more commonly thereafter because its effects did not last
as long or did its onset occur as quickly. With the synthesis of this chemical,
alternative for morphine is available without the side effects of morphine.

Oxycodone does not occur naturally and is y synthesize from thebaine, morphine or
codeine, all naturally occurring in the opium poppy, Papaver somniferum. Papaver
somniferum is native to South-East Europe and Western Asia but has been
cultivated and spread throughout the world because it can be easily grown, given the
right amount of fertilizer and sufficient room. Freund and Speyer of the University of
Frankfurt in Germany first synthesized oxycodone from thebaine in 1916, a few
years after the German pharmaceutical company Bayer had stopped the mass
production of heroin due to hazardous use, harmful use, and dependence. It was
hoped that a thebaine-derived drug would retain the analgesic effects of morphine
and heroin with less dependence. Unfortunately, this was ultimately not found to be
the case.
The first clinical use of the drug was documented in 1917, the year after it was first
developed. It was first introduced to the US market in May 1939. In early 1928,
Merck introduced a combination product containing scopolamine, oxycodone, and
ephedrine under the German initials for the ingredients SEE, which was later
renamed Scophedal (SCOpolamine ePHEDrine and eukodAL). This combination is
essentially an oxycodone analogue of the morphine-based Twilight Sleep, with
ephedrine added to reduce circulatory and respiratory effects. The personal notes of
Adolf Hitler's physician, Dr. Theodor Morell, indicate Hitler received repeated
injections of "eukodal" (oxycodone).
In the early 1960s, the United States government classified oxycodone as a
schedule II drug in the new Controlled Substances Act. According to the Drug
Enforcement Administration (DEA): Schedule II drugs, substances, or chemicals are
defined as drugs with a high potential for abuse, less abuse potential than Schedule I
drugs, with use potentially leading to severe psychological or physical dependence.
These drugs are also considered dangerous. In1974, oxycodone is approved by the
Food and Drug Administration (FDA). In 1996, Purdue Pharma introduced
OxyContin, a controlled release formulation of oxycodone. The product has been a
commercial success and since its introduction, Purdue has earned more than $31
billion from OxyContin.
Iron salts have been used by physicians since the time of Hip-ocrates. It has been
stated that iron therapy takes its origin in sympathetic magic, the weakly sufferer
having hoped to assume something of the strength of steel by drinking the water in
which a sword had rusted.
The Greek physicians employed iron for the cure of weakness, a prominent symptom
of anaemia, with a view to impart to the patient the strength of iron. Sydenham was
probably the first physician to employ iron in a manner that would be approved even
today. Three centuries ago he introduced ircn into clinical medicine for the treatment
of "Chlorosis" for which he found iron or steel of great value.

In 1684, Sydenham introduced iron as a therapeutic agent in clinical medicine. Since

then, the number of iron preparations available for the treatment of iron deficiency
anaemia has steadily increased. A rational basis for the use of iron was provided
almost one hundred years letfer when iron was demonstrated in the ash of the blood,
and it was show that the iron of the blood could be increased by feeding iron-
cantaining foods.

In 1832, Blaud emphasized the specific action of iron in the treatment of chlorosis
and described the use of pills deservedly famous pills known as Blauds pills. Blauds
original pills consisted of a mixture of equal parts of Ferrous sulphate and potassium
carbonate, and he gave sufficient and gradually increasing dose to supply 0.4 to 1.6
grams of ferrous carbonate daily.51 This would be considered adequate therapy
today. Many excellent observers, including Niemeyer and Osier, confirmed his
findings.

The use of larger doses of Ferrous Sulphate e.g. up to 2 gm. of Ferrous Sulphate or
720 mg of elemental daily, as recommended by some workers dates from the time
when iron by mouth was the only practical means, apart from transfusion, of treating
iron deficiency anaemia. However, since the introduction (Nissim 1947, Slack and
Wilk/lnson 1950) of a stable and relatively non-toxic Intravenous preparation, and
with the subsequent development of a reliable intramuscular preparation of iron, the
treatment of cases resistant to oral iron has few difficulties either in hospital or in
general practice.

In 1930, Cappel for the first time showed that iron could be given intravenously as a
saecharated iron oxide without the usual dangers of parenteral therapy.

In 1933, Davidson urged the use of Ferrous Sulphate tablets, adequate treatment
with which still costs only one penny a week. It was suggested that ascorbic acid
given by mouth may itself aid in the Haemoglobin synthesis. Thus, in 1936,
Hellmeyer and Plotner found that intravenous infection of ferrous ascorbite produces
Haemoglobin regeneration in excess of that calculated from the amount
of iron injected.
In 1952, Girdvood drew attention to a strong psychological intolerance shown by his
patients towards the tablets of ferrous sulphate, but only when they were quoted
green.

In 1956, Edgar and Bice found that the usual high rate of Intolerance to Ferrous
Sulphate reported in pregnant women was reduced to less than 5 per cent when the
product was given in the form of a white tablet instead of the well-known green form,
thus suggesting the psychological element.

According to Bourcart, ferrous sulphate may be used in many different ways. In

cultivation it is spread as crystals, or in solutions by watering carts; it may also be
mixed with soil and broadcast by hand or machine. To cure trees of chlorosis, the
iron sulphate may be sprayed on the plants or injected into the trunks of trees. When
used by injection the action is felt much quicker than when it is absorbed by the
roots.