Some of the biomedical words first cited from 1978 in the Oxford English Dictionary (OED) (Table 1) are connected with calcium—nimodipine, calmodulin, and alfacalcidol.

Table 1. Biomedical words (n=28) in the OED for which the earliest citations are from 1978 (out of a total of 210); I have found six antedatings, from 1 to 39 years

*Antedatings: macrofilaricide (1968), psychonaut (1968), helicase (1939), oligo (1964), nucleoskeleton (1977), nutritionism (1957)

Nimodipine is a one of several me-too dihydropyridine calcium channel blockers (Figure 1). The first in class drug, nifedipine, was named from a contraction of its chemical name, dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate: “ni” from nitro, “fe” from phenyl, and “dipine” from dihydropyridine.

Figure 1. Dihydropyridine calcium channel blockers and their approximate dates of introduction into clinical use; the structure of nimodipine is shown

Calmodulin is an endogenous calcium-binding peptide (148 amino acids long), activated by complexing with up to four calcium ions. It regulates such cellular mechanisms as kinases and phosphorylases, ion channels, and muscle contraction. The name was suggested by Cheung, Lynch, and Wallace in 1978: “… the activator may serve as a Ca²⁺ mediator, or as a Ca²⁺-dependent modulator [and] may be designated calmodulin.” The name is a contraction of “calcium-modulated protein”.

Alfacalcidol, or 1α-hydroxycholecalciferol is a synthetic form of vitamin D, a group of sterols, whose metabolism is illustrated in Figure 2. They include: ergocalciferol (calciferol or vitamin D₂); colecalciferol (vitamin D₃); dihydrotachysterol; 25-hydroxycholecalciferol (calcifediol); 1α-hydroxycholecalciferol (alfacalcidol); 1α,25-dihydroxycholecalciferol (calcitriol); 24,25-dihydroxycholecalciferol; and 1α,24,25-trihydroxycholecalciferol.

Figure 2. Members of the vitamin D family; the structure of alfacalcidol is shown

The Greek word ῥαχις meant the spine. Add –itis and you get rachitis, inflammation of the spine. But in 1650 the physician and anatomist Francis Glisson (1597–1677), in a treatise curiously titled, in a mixture of Latin and English, De rachitide, sive, morbo puerili qui vulgo the rickets dicitur, tractatus [On the treatment of rachitis, a children’s disease, commonly called rickets], appropriated the word to provide a term, hitherto uncoined, more scientific than “rickets”. He thought that the fault lay in the spinal marrow, The similarity between “rachitis” and “rickets” is probably coincidental; the origin of the latter is not known.

In 1931 T C Angus and colleagues reported that they had prepared a crystalline substance by vacuum distillation of irradiated ergosterol, previously prepared in smaller quantities by Askew and colleagues, and had shown it to have antirachitic properties: “We think the provisional adoption of a name is justified … and suggest “Calciferol” in view of the high antirachitic activity of the substance”. Their extract was later shown to contain calciferol and two inactive sterols. The name, which implies transport of calcium, gives rise to the names of other members of the family. Colecalciferol is so called because cholesterol is a precursor.

Vitamin D₂ (ergocalciferol, found in plants) and vitamin D₃ (colecalciferol, found in animal tissues and synthesized in the skin by exposure to ultraviolet light) are pharmacologically inactive and are activated in the liver and kidneys (Figure 2). Colecalciferol is hydroxylated in the liver to 25-hydroxycholecalciferol, which is weakly active. In the kidney further hydroxylation produces 24,25-dihydroxycholecalciferol, also weakly active, and 1α,25-dihydroxycholecalciferol, the most active form. Orally administered 1α-hydroxycholecalciferol is rapidly converted in the liver to 1,25-dihydroxycholecalciferol.

Vitamin D promotes absorption of calcium and phosphate from the gut and reabsorption by the proximal renal tubules. These effects increase plasma concentrations of calcium and phosphate and make them available for mineralization of bone. Since cells of the immune system contain its intracellular receptor, vitamin D also modulates immune function.

Trials have been registered describing the use of vitamin D in prevention and treatment of covid-19. Most involve high doses of colecalciferol. A pilot study in 76 patients, described as “open label, double-masked”, has suggested that calcifediol (25-hydroxycholecalciferol) may reduce mortality, but the results of a large randomized double-masked trial are awaited.

Meanwhile, some are advocating vitamin D supplements, in the hope of preventing covid-19, especially since synthesis of vitamin D in the skin is reduced in the absence of sunlight in the winter. Over-the-counter oral supplements typically provide colecalciferol (vitamin D₃) in varying doses; 400 iu (10 micrograms) a day should be sufficient to prevent deficiency in those who absorb it. For treatment of deficiency 800 iu/day is sufficient. Higher doses can cause adverse effects.

Jeffrey Aronson is a clinical pharmacologist, working in the Centre for Evidence Based Medicine in Oxford’s Nuffield Department of Primary Care Health Sciences. He is also president emeritus of the British Pharmacological Society.

Competing interests: None declared.

This week’s interesting integer: 303 Primes and semiprimes There are 303 primes less than 2000, the 303rd being 1999 303 is a semiprime = 3 × 101 ad the third member of a semiprime triplet, 301, 302, and 303 Palindromes 303 is a palindrome in base 10 and no other base The divisors of 303 (3 and 101) are both palindromes 111 in base 10 is 303 in base 6, both palindromes Named numbers (291 + 2 + 9 + 1) = (300 + 3 + 0 + 0) = 303; numbers that can be formed in this way from at least two other numbers, adding them to their digits, are called junction numbers; there are only 81 such numbers less than 1000 The mean of the divisors of 303 (1, 3, 101, and 303) is an integer, 102; this makes it an arithmetic number 303 is a binary Smith number (see Interesting integer 265), since the sum of its digits in binary form equals the sum of the digits of its two prime factors in binary form:                303 in binary = 100101111; the digits add up to 6                3 in binary = 11 and 101 in binary = 1100101; the combined digits add up to 6 303 is a lucky number, so called because it survives the following sieving process: (a) List the integers, starting with 1:   1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 … (b) Remove every second number:   1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 … (c) The first lucky number to survive is 3, so now remove every third number:   1 3 7 9 13 15 19 21 25 27 31 … (d) The next lucky number to survive is 7, so now remove every seventh number:   1 3 7 9 13 15 21 25 27 31 … (e) Now remove every ninth number and so on; the list that emerges is as follows:    1, 3, 7, 9, 13, 15, 21, 25, 31, 33, 37, 43, 49, 51, 63, 67, 69, 73, 75, 79, 87, 93, 99, 105,   111, 115, 127, 129, 133, 135, 141, 151, 159, 163, 169, 171, 189, 193, 195, 201, 205,    211, 219, 223, 231, 235, 237, 241, 259, 261, 267, 273, 283, 285, 289, 297, 303 Sums of 303 303 is the sum of four squares but no fewer. Lagrange’s four square theorem, which he proved in 1770, states that all integers can be expressed as the sum of four squares. However, although 303 can be so expressed (303 = 12 + 22 + 32 + 172), it cannot be expressed as the sum of two or three squares. Not all numbers have this property. 303 is the sum of 102 and its reversal 201 It is the sum of all the digits of the first 36 prime numbers It is the sum of three consecutive odd integers = 99 + 101 + 103 It is the sum of two consecutive integers = 151 + 152 It is the sum of three consecutive integers = 100 +101 + 102 It is the sum of six consecutive integers = 48 + 49 + 50 + 51 + 52 + 53 Miscellaneous 303 is the 54th entry in Aronson’s sequence. 303, base 10, is 100101111 in base 2 and 213 in base 12; in all three cases the digit sum is 6